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Local Activation or Implantation of Cardiac Progenitor Cells Rescues Scarred Infarcted Myocardium Improving Cardiac Function
... These two factors have important characteristics, it is known that the hepatocyte factor is chemoattractant for cardiac progenitor cells. At the same time, insulin-like factor causes a strong cellular proliferation and increases the viability of these cells [10]. ...
... In the analysis of chromosomes of myocardiocytes was shown that in the process of recovery of myocardium there is no "merger" of cells. As an alternative to introduction of stem cells the authors propose using a combination of growth factors [10]. ...
... According to other researchers, the effect of AMSCBMO is mainly due to the expression of various factors of angiogenesis and other cytokines [8,9,12]. M. Rota et al. [10] believe that there is a combination of direct involvement of stem cells with paracrine mechanisms. So, there is no common opinion and until there is remained not clear what happens to AMSCBMO after implantation into the tissues and organs of the body. ...
The results of injecting of autologic mesenchymal stem cells of bone marrow origin (AMSCBMO), transfected by the GFP gene, into the scar of rat uterine horns were studied by methods of light microscopy. After the introduction of AMSCBMO into the formed scar on the right (2 months after the ligation) large groups of blood vessels with cellular elements inside were present; groups like that were not found in the opposite side. Studying unstained sections under reflected ultraviolet light the sufficient bright luminescence in the endothelium and the external membrane of scar vessels was found in uterine horn only on the side of introduction of AMSCBMO. It was concluded that after the introduction of AMSCBMO into the scar tissue they form blood vessels by differentiation into endotheliocytes and pericytes. GFP gene expression not only in endothelium of vessels, but also in their external membrane indicates that differentiation of AMSCMBO is possible in endothelial and in pericytal directions.
... Importantly, the limited ability of the heart to regenerate lost cardiomyocytes and vascular cells contributes to the severity of LV remodeling. Therefore, administration of various types of presumed cardiac regenerative cells including skeletal muscle myoblasts, marrow derived mesenchymal stem cells (MSCs), endogenous cardiac stem cells (CSCs), endothelial progenitor cells, induced pluripotent stem cells (iPSCs) and embryonic stem cells to hearts following acute infarction (acute MI) has been attempted in the hope of stimulating cardiac regeneration456789. It is well known that many animal and clinical trials have indicated that cell transplantation modestly improves cardiac function in post-MI hearts. ...
... Moreover, intramyocardial HGF gene therapy post-MI is associated with increased angiogenesis and preservation of cardiac contractile function2122. Consistent with these observations, studies from the laboratories of Anversa and his colleagues have shown, in both large and small animal studies, that the intra-myocardial combined injection of HGF and IGF facilitated survival of endogenous c-kit + CSCs (the majority of which were Sca-1 + ) and enhanced their migration to injured areas, their proliferation, and differentiation into cardiomyocytes and vascular cells [6,232425. Significant cardiomyocyte regeneration from CSCs associated with partial repopulation of the infarct scar zone was also present and it is likely that survival of native cardiomyocytes was also increased in these post-MI hearts. ...
... It is possible that IGF+ HGF administration might be a useful adjuvant to therapeutic cell transplantation at the time of acute revascularization therapy for acute MI. Moreover, it may be that the co-administration of IGF+ HGF with Sca-1 + /CD31 2 cells during a later phase of MI recovery might be associated with more significant cardiomyocyte regeneration [6,36].Figure S1 IGF+HGF added to cell transplantation results in increased vascular density as compared to cell transplantation alone. (A). ...
Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are two potent cell survival and regenerative factors in response to myocardial injury (MI). We hypothesized that simultaneous delivery of IGF+HGF combined with Sca-1+/CD31- cells would improve the outcome of transplantation therapy in response to the altered hostile microenvironment post MI. One million adenovirus nuclear LacZ-labeled Sca-1+/CD31- cells were injected into the peri-infarction area after left anterior descending coronary artery (LAD) ligation in mice. Recombinant mouse IGF-1+HGF was added to the cell suspension prior to the injection. The left ventricular (LV) function was assessed by echocardiography 4 weeks after the transplantation. The cell engraftment, differentiation and cardiomyocyte regeneration were evaluated by histological analysis. Sca-1+/CD31- cells formed viable grafts and improved LV ejection fraction (EF) (Control, 54.5+/-2.4; MI, 17.6+/-3.1; Cell, 28.2+/-4.2, n = 9, P<0.01). IGF+HGF significantly enhanced the benefits of cell transplantation as evidenced by increased EF (38.8+/-2.2; n = 9, P<0.01) and attenuated adverse structural remodeling. Furthermore, IGF+HGF supplementation increased the cell engraftment rate, promoted the transplanted cell survival, enhanced angiogenesis, and minimally stimulated endogenous cardiomyocyte regeneration in vivo. The in vitro experiments showed that IGF+HGF treatment stimulated Sca-1+/CD31- cell proliferation and inhibited serum free medium induced apoptosis. Supperarray profiling of Sca-1+/CD31- cells revealed that Sca-1+/CD31- cells highly expressed various trophic factor mRNAs and IGF+HGF treatment altered the mRNAs expression patterns of these cells. These data indicate that IGF-1+HGF could serve as an adjuvant to cell transplantation for myocardial repair by stimulating donor cell and endogenous cardiac stem cell survival, regeneration and promoting angiogenesis.
... CPCs have been reported to express c-Met and insulin-like growth factor-1 (IGF-1) receptors and synthesize and secrete the corresponding ligands, hepatocyte growth factor (HGF) (which mobilizes CPCs) and IGF-1 (which promotes their survival and proliferation) [26]. In infarcted hearts of dogs [27], mice [26], and rats [28], the intramyocardial injection of HGF and IGF-1 enhanced the translocation of CPCs from the surrounding myocardium to the dead tissue and their viability and growth within the damaged area, fostering cardiac regeneration and improving mechanical function. In the present study, we tested the hypothesis that activating the lineage commitment and progeny formation of resident CPCs, via the HGF/IGF-1-receptor systems, can also ameliorate the electrical competence of the infarcted heart, in a rat model of chronic myocardial infarction (MI). ...
... In contrast, lower mRNA levels of asubunit Kv1.4 and b-subunit KChIP2 were found in the remote and remote/peri-infarcted myocardium respectively. In support of previous data262728, we also found that resident CPCs, stimulated locally by GF treatment, invaded the scarred myocardium and generated new electromechanically-connected myocytes and vessels. Additionally, experimental evidence was provided for a partial recovery of mechanical competence in the regenerated heart, associated with attenuation of unfavorable remodeling. ...
... Recent studies in animal models of chronic myocardial infarction [28] have documented a negative impact of the scarred myocardium on the migration and engraftment of CPCs when compared with acute infarcts. Yet, in spite of the less favorable environment related to chronic collagen deposition after infarction , GF-activated CPCs retain the ability to infiltrate the scar, digest part of the connective tissue, and form cardiomyocytes and coronary vessels via enhanced activity of metalloproteases. ...
Heart repair by stem cell treatment may involve life-threatening arrhythmias. Cardiac progenitor cells (CPCs) appear best suited for reconstituting lost myocardium without posing arrhythmic risks, being commissioned towards cardiac phenotype. In this study we tested the hypothesis that mobilization of CPCs through locally delivered Hepatocyte Growth Factor and Insulin-Like Growth Factor-1 to heal chronic myocardial infarction (MI), lowers the proneness to arrhythmias. We used 133 adult male Wistar rats either with one-month old MI and treated with growth factors (GFs, n = 60) or vehicle (V, n = 55), or sham operated (n = 18). In selected groups of animals, prior to and two weeks after GF/V delivery, we evaluated stress-induced ventricular arrhythmias by telemetry-ECG, cardiac mechanics by echocardiography, and ventricular excitability, conduction velocity and refractoriness by epicardial multiple-lead recording. Invasive hemodynamic measurements were performed before sacrifice and eventually the hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. When compared with untreated MI, GFs decreased stress-induced arrhythmias and concurrently prolonged the effective refractory period (ERP) without affecting neither the duration of ventricular repolarization, as suggested by measurements of QTc interval and mRNA levels for K-channel α-subunits Kv4.2 and Kv4.3, nor the dispersion of refractoriness. Further, markers of cardiomyocyte reactive hypertrophy, including mRNA levels for K-channel α-subunit Kv1.4 and β-subunit KChIP2, interstitial fibrosis and negative structural remodeling were significantly reduced in peri-infarcted/remote ventricular myocardium. Finally, analyses of BrdU incorporation and distribution of connexin43 and N-cadherin indicated that cytokines generated new vessels and electromechanically-connected myocytes and abolished the correlation of infarct size with deterioration of mechanical function. In conclusion, local injection of GFs ameliorates electromechanical competence in chronic MI. Reduced arrhythmogenesis is attributable to prolongation of ERP resulting from improved intercellular coupling via increased expression of connexin43, and attenuation of unfavorable remodeling.
... In contrast, M2 macrophages, the major macrophages in phase 2 of MI, promote collagen deposition and angiogenesis to the infarct area [40]. The inflammatory microenvironments not only activate cardiofibroblasts for myocardium remodelling , but also activate endogenous stem cells for heart regeneration, either by cell fusion or transdifferentia- tion [42][43][44] . Despite that the endogenous cardiac progenitor cells (CPCs) are activated in response to heart damage [42, 43], nevertheless an as yet unclear interaction between CPCs and macrophages in the infarct area remains to be elucidated. ...
... The inflammatory microenvironments not only activate cardiofibroblasts for myocardium remodelling , but also activate endogenous stem cells for heart regeneration, either by cell fusion or transdifferentia- tion [42][43][44] . Despite that the endogenous cardiac progenitor cells (CPCs) are activated in response to heart damage [42, 43], nevertheless an as yet unclear interaction between CPCs and macrophages in the infarct area remains to be elucidated. One key factor that bridges CPCs and macrophages in the injured heart is prostaglandin E 2 (PGE 2 ), whose release from the injured heart regulates macrophage populations and exerts a salutary effect on the myocardium [45][46][47]. ...
Cardiac inflammation is considered by many as the main driving force in prolonging the pathological condition in the heart after myocardial infarction. Immediately after cardiac ischemic injury, neutrophils are the first innate immune cells recruited to the ischemic myocardium within the first 24 h. Once they have infiltrated the injured myocardium, neutrophils would then secret proteases that promote cardiac remodeling and chemokines that enhance the recruitment of monocytes from the spleen, in which the recruitment peaks at 72 h after myocardial infarction. Monocytes would transdifferentiate into macrophages after transmigrating into the infarct area. Both neutrophils and monocytes-derived macrophages are known to release proteases and cytokines that are detrimental to the surviving cardiomyocytes. Paradoxically, these inflammatory cells also play critical roles in repairing the injured myocardium. Depletion of either neutrophils or monocytes do not improve overall cardiac function after myocardial infarction. Instead, the left ventricular function is further impaired and cardiac fibrosis persists. Moreover, the inflammatory microenvironment created by the infiltrated neutrophils and monocytes-derived macrophages is essential for the recruitment of cardiac progenitor cells. Recent studies also suggest that treatment with anti-inflammatory drugs may cause cardiac dysfunction after injury. Indeed, clinical studies have shown that traditional ant-inflammatory strategies are ineffective to improve cardiac function after infarction. Thus, the focus should be on how to harness these inflammatory events to either improve the efficacy of the delivered drugs or to favor the recruitment of cardiac progenitor cells.
... Eliminating the arrhythmogenic foci as in FCs, the autologous skeletal myoblasts showed survival with differentiated muscle fibres after transplantation [16]. Also, the resident cardiac stem cells, though sparse in the scene; when locally stimulated by hepatocyte growth factor and insulin-like growth factor-1, it reduced the scar area by half, owing to the degradation of collagen proteins by the matrix metalloproteinase synthesised by them [17]. But these cells have the major disadvantage that, they have to be procured from the same host, which is invasive and risky. ...
... The need of the hour is to define an efficient, economic and reliable method of using the ideal cell type for improved cell delivery and cell retention at the infarct zone amidst the adverse micro-niche and enhance their survival post-transplantation. This can be overcome by the following approaches like injecting the cells with bioactive in situ polymerizable hydrogels, preconditioning with pro-survival agents, genetic manipulation to limit cell death or via the transplantation of the tissue-engineered patch (cross reference [17]); of which the last technique support survival of delivered cells for long-term and proved to reconstruct the cardiac tissue both structurally and functionally [12]. Rat neonatal cardiomyocytes seeded on the mix of fibrinogen monomers with thrombin enabled the generation of triple-layered well-organised construct with connexin 43 expressions [47]. ...
With limited regenerative capacity and most complex structural and electrophysiological properties; recapitulating the cardiac tissue is a challenging task for the researchers. The cell injection was found unreliable due to the cell loss and low retention of the transplanted cells. This could be overcome by the technique of cell sheet engineering. Scaffold free, thick, cell dense, three dimensional constructs could be generated for suture free transplantation. For the generation of the cardiac constructs the neonatal cardiomyocytes and myoblasts were mostly used. They were tedious to isolate and culture and the risk of arrhythmogenic foci prevailed. Hence the concept of differentiating a suitable allogeneic cell source to myocardial lineage seemed relevant. Human umbilical cord mesenchymal stem cells (hUCMSCs) are emerging with the assistance of differentiating agents and cell sheet engineering for addressing the cardiac regeneration. The preliminary report on this regard has been published. The cells attained cardiomyocyte-like morphology with the expression of alpha-actinin and myosin heavy chain on culturing with cardiac conditioned medium and the inducer sphingosine-1-phosphate. It presented cardiomyocyte-like action potential and voltage gated currents. Hence the cell sheet engineering approach with cells differentiated to cardiac lineage using specific agents is a recent area to be explored.
... R esident cardiac progenitor cells (CPC) are multipotent cells that are found in the adult heart1234, possess the capacity to differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells (SMC), and play an important role in cardiac cellular homeostasis and myocardial regeneration in acutely injured [1,2,4,5] and scarred myocardium [6,7]. Cardiosphere derived cells (CDC), a major source of cardiac multipotent stem cells, express GATA4 and Nestin and can differentiate into cardiomyocytes and typical neural crest–derived cells, including neurons, glia, and SMC [8]. ...
... Pathophysiologically , a similar mechanism could be operative during vessel regeneration in ischemic heart disease. Recent studies have shown that activated CPC can regenerate conductive, small, and intermediate-sized arteries and capillary structures and improve cardiac function in chronically injured rat hearts long after infarction and scar formation [6,7]. Data are conflicting regarding SMC differentiation of Notch1 activated cells. ...
Cardiosphere derived cells (CDC) are present in the human heart and include heterogeneous cell populations of cardiac progenitor cells, multipotent progenitors that play critical roles in the physiological and pathological turnover of heart tissue. Little is known about the molecular pathways that control the differentiation of CDC. In this study, we examined the role of Notch 1/J kappa-recombining binding protein (RBPJ) signaling, a critical cell-fate decision pathway, in CDC differentiation. We isolated CDC from mouse cardiospheres and analyzed the differentiation of transduced cells expressing the Notch1 intracellular domain (N1-ICD), the active form of Notch1, using a terminal differentiation marker polymerase chain reaction (PCR) array. We found that Notch1 primarily supported the differentiation of CDC into smooth muscle cells (SMC), as demonstrated by the upreguation of key SMC proteins, including smooth muscle myosin heavy chain (Myh11) and SM22α (Tagln), in N1-ICD expressing CDC. Conversely, genetic ablation of RBPJ in CDC diminished the expression of SMC differentiation markers, confirming that SMC differentiation CDC is dependent on RBPJ. Finally, in vivo experiments demonstrate enhanced numbers of smooth muscle actin-expressing implanted cells after an injection of N1-ICD-expressing CDC into ischemic myocardium (44±8/high power field (hpf) vs. 11±4/high power field (hpf), n=7 sections, P<0.05). Taken together, these results provide strong evidence that Notch1 promotes SMC differentiation of CDC through an RBPJ-dependent signaling pathway in vitro, which may have important implications for progenitor cell-mediated angiogenesis.
... Taken together, these data support the hypothesis that the primary cause of the cardiomyopathy in W41/W42 mice are the decreased numbers and functional capacities of CPCs and that functionally defective mutant BM progenitor cells, though possibly contributory to the development of cardiomyopathy, were not causal factor. There is a large literature describing the roles played by c-Kit receptor bearing progenitor cells in tissue maintenance and regeneration18192021. Although much of the reported work has been concerned with the hematopoietic system, the roles of resident and/or BM originating c-Kit + progenitor cells in normal cardiomyocyte turnover and regeneration has recently become a major area of investigation and many reports have suggested that resident c-Kit + cardiac progenitor cells are crucial to these processes; it has also been suggested that BM derived c-Kit + progenitor cells themselves may support myocardial regeneration18192021. Thus functionally significant mutations of c-Kit alleles could impact physiological cardiomyocyte turnover rates and, therefore, the maintenance of LV structure and function over the lifespan of the organism. ...
... There is a large literature describing the roles played by c-Kit receptor bearing progenitor cells in tissue maintenance and regeneration18192021. Although much of the reported work has been concerned with the hematopoietic system, the roles of resident and/or BM originating c-Kit + progenitor cells in normal cardiomyocyte turnover and regeneration has recently become a major area of investigation and many reports have suggested that resident c-Kit + cardiac progenitor cells are crucial to these processes; it has also been suggested that BM derived c-Kit + progenitor cells themselves may support myocardial regeneration18192021. Thus functionally significant mutations of c-Kit alleles could impact physiological cardiomyocyte turnover rates and, therefore, the maintenance of LV structure and function over the lifespan of the organism. ...
Both bone marrow (BM) and myocardium contain progenitor cells expressing the c-Kit tyrosine kinase. The aims of this study were to determine the effects of c-Kit mutations on: i. myocardial c-Kit(+) cells counts and ii. the stability of left ventricular (LV) contractile function and structure during aging. LV structure and contractile function were evaluated (echocardiography) in two groups of Kit mutant (W/Wv and W41/W42) and in wild type (WT) mice at 4 and 12 months of age and the effects of the mutations on LV mass, vascular density and the numbers of proliferating cells were also determined. In 4 month old Kit mutant and WT mice, LV ejection fractions (EF) and LV fractional shortening rates (FS) were comparable. At 12 months of age EF and FS were significantly decreased and LV mass was significantly increased only in W41/W42 mice. Myocardial vascular densities and c-Kit(+) cell numbers were significantly reduced in both mutant groups when compared to WT hearts. Replacement of mutant BM with WT BM at 4 months of age did not prevent these abnormalities in either mutant group although they were somewhat attenuated in the W/Wv group. Notably BM transplantation did not prevent the development of cardiomyopathy in 12 month W41/W42 mice. The data suggest that decreased numbers and functional capacities of c-Kit(+) cardiac resident progenitor cells may be the basis of the cardiomyopathy in W41/W42 mice and although defects in mutant BM progenitor cells may prove to be contributory, they are not causal.
... Recent basic research studies have shown that myocyte loss plays a major role in the induction and progression of most if not all forms of heart failure [5,6,7,8,9,10]. In parallel, studies have revealed that many adult tissues, notably bone marrow, but also skeletal muscle, synovium and adipose tissue, contain self-renewing, pluripotent cells capable of repairing injured myocardium and/or improving blood flow to the heart ([11,12, 13,14], reviewed in [15]). These insights have led to a rapid and intensive pursuit of regenerative strategies to increase the number of functional cardiac myocytes and blood vessels in the damaged and failing myocardium (reviewed in[16,17,18,19,20,21]). ...
... Several different types of cardiac precursor cells (CPCs) have been described, distinguished by method of isolation and/or expression of surface markers, including c-kit, stem cell antigen (sca-1), transporter protein ABC1, and transcription factor islet-1 (Isl1). Each of these has been reported to be self-renewing, to differentiate along three major myocardial lineages (cardiac myocytes, smooth muscle and endothelial cells) [11,39,40,41,42,43,44,45,46], and to be capable of reconstituting injured myocardium [11,13,39,42,47,48,49]. Despite the greater accessibility of other progenitor cell types, cardiac-derived stem cells have excited considerable therapeutic interest, because of their greater potential for cardiomyogenic differentiation, engraftment and survival within the myocardi- um[34], and the potential of endogenous CPCs to respond to exogenous or paracrine mobilization signals. ...
The adult myocardium has been reported to harbor several classes of multipotent progenitor cells (CPCs) with tri-lineage differentiation potential. It is not clear whether c-kit+CPCs represent a uniform precursor population or a more complex mixture of cell types.
To characterize and understand vasculogenic heterogeneity within c-kit+presumptive cardiac progenitor cell populations.
c-kit+, sca-1+ CPCs obtained from adult mouse left ventricle expressed stem cell-associated genes, including Oct-4 and Myc, and were self-renewing, pluripotent and clonogenic. Detailed single cell clonal analysis of 17 clones revealed that most (14/17) exhibited trilineage differentiation potential. However, striking morphological differences were observed among clones that were heritable and stable in long-term culture. 3 major groups were identified: round (7/17), flat or spindle-shaped (5/17) and stellate (5/17). Stellate morphology was predictive of vasculogenic differentiation in Matrigel. Genome-wide expression studies and bioinformatic analysis revealed clonally stable, heritable differences in stromal cell-derived factor-1 (SDF-1) expression that correlated strongly with stellate morphology and vasculogenic capacity. Endogenous SDF-1 production contributed directly to vasculogenic differentiation: both shRNA-mediated knockdown of SDF-1 and AMD3100, an antagonist of the SDF-1 receptor CXC chemokine Receptor-4 (CXCR4), reduced tube-forming capacity, while exogenous SDF-1 induced tube formation by 2 non-vasculogenic clones. CPCs producing SDF-1 were able to vascularize Matrigel dermal implants in vivo, while CPCs with low SDF-1 production were not.
Clonogenic c-kit+, sca-1+ CPCs are heterogeneous in morphology, gene expression patterns and differentiation potential. Clone-specific levels of SDF-1 expression both predict and promote development of a vasculogenic phenotype via a previously unreported autocrine mechanism.
... In the last years efforts have been performed to promote cardiac tissue regeneration with bone marrow [2] and, recently, with cardiac stem cell (CSC) transplantation [3]. Further, in animal models, it has been shown that it is possible to promote resident CSC proliferation and differentiation in vivo, by injecting cytokines or growth factors directly into the heart either in the acute [4,5] and chronic [6] phase following infarction. High Mobility Group Box-1 protein (HMGB1) is a highly conserved nuclear protein that acts as a chromatin-binding factor capable of promoting access of transcriptional complexes to the DNA. ...
... Indeed, NF-kB is the intracellular target of HMGB1 and its activation results in cell migration [37] and in the modulation of the inflammatory response [38]. It is noteworthy that enhanced MMPs activity may favour the migration of activated resident progenitor cells into the scar and cardiac regeneration as it has been shown to occur in response to the intramyocardial injection of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1)[6]. Activated MMPs can be directly inhibited by interaction with TIMPs resulting in the prevention of matrix degradation [39]. ...
HMGB1 injection into the mouse heart, acutely after myocardial infarction (MI), improves left ventricular (LV) function and prevents remodeling. Here, we examined the effect of HMGB1 in chronically failing hearts.
Adult C57 BL16 female mice underwent coronary artery ligation; three weeks later 200 ng HMGB1 or denatured HMGB1 (control) were injected in the peri-infarcted region of mouse failing hearts. Four weeks after treatment, both echocardiography and hemodynamics demonstrated a significant improvement in LV function in HMGB1-treated mice. Further, HMGB1-treated mice exhibited a ∼23% reduction in LV volume, a ∼48% increase in infarcted wall thickness and a ∼14% reduction in collagen deposition. HMGB1 induced cardiac regeneration and, within the infarcted region, it was found a ∼2-fold increase in c-kit⁺ cell number, a ∼13-fold increase in newly formed myocytes and a ∼2-fold increase in arteriole length density. HMGB1 also enhanced MMP2 and MMP9 activity and decreased TIMP-3 levels. Importantly, miR-206 expression 3 days after HMGB1 treatment was 4-5-fold higher than in control hearts and 20-25 fold higher that in sham operated hearts. HMGB1 ability to increase miR-206 was confirmed in vitro, in cardiac fibroblasts. TIMP3 was identified as a potential miR-206 target by TargetScan prediction analysis; further, in cultured cardiac fibroblasts, miR-206 gain- and loss-of-function studies and luciferase reporter assays showed that TIMP3 is a direct target of miR-206.
HMGB1 injected into chronically failing hearts enhanced LV function and attenuated LV remodelling; these effects were associated with cardiac regeneration, increased collagenolytic activity, miR-206 overexpression and miR-206 -mediated inhibition of TIMP-3.
... CSCs can differentiate into cardiomyocyte, endothelial, and smooth muscle cell lineages [49,51,52], although their degree of contribution to the generation of new cardiomyocytes is controversial [52][53][54][55]. Despite ongoing controversy [53][54][55], multiple preclinical studies, including a recent meta-analysis [56], have demonstrated that injection of CSCs into animal models of ischemic heart disease slowed the progression of pathological cardiac structural changes and improved cardiac function [24,25,49,[56][57][58][59]. ...
... Biomed Res Ther 2016, 3(11): 951-972 ! 956 scar tissue is believed to be related to matrix metalloproteinase (MMP)-9 and -14 mediated regulation (Bax et al., 2012; Huang et al., 2011; Rota et al., 2008). ...
It is known that myocardial infarction (MI) causes damages to the heart tissue and that present medical therapies, such as medication, stenting and coronary artery bypass surgery, cannot recover the injured heart. Fortunately, advances in stem cell research have brought hope of full heart recovery for myocardial ischemia patients. There have been many studies using cell therapies for myocardial ischemia, from preclinical trials to clinical trials. However, the biggest concern is the effect of transplanted cells in myocardial recovery. This review will focus on analyzing both the positive and negative effects of transplanted cells in myocardial recovery to better understand the underlying biological mechanisms and ways to evaluate safety and efficacy of cell transplantation in myocardial ischemia treatment.
... Recent developments in stem cell biology, including those related to induced pluripotent stem cells (iPSCs) and tissue-derived stem/ progenitor cells, are a giant leap toward the goal. Recently, myocardium-derived stem/progenitor cells were isolated by several institutes123. These cell populations have the potential to repair the diseased heart, and clinical trials are currently ongoing. ...
... One such population consists of cells that form cardiospheres in suspension and differentiate to CMs, endothelial cells (ECs), and smooth muscle cells (SMCs) (Messina et al., 2004; Smith et al., 2007). Cardiac stem cells (CSCs) also include c-Kit expressing cells, which generate CMs, ECs, and SMCs after injury (Beltrami et al., 2003; Rota et al., 2008; Ellison et al., 2013). A different CSC type consists of Side Population (SP) cells (Hierlihy et al., 2002; Martin et al., 2004; Mouquet et al., 2005). ...
During development, cardiovascular progenitor cells expressing the endothelial-specific gene VEGFR-2 differentiate into all major cell types of the heart. We hypothesized that an endothelial-like progenitor population exists in the adult heart, contributing to cardiac homeostasis and tissue repair after injury. To test this model, we traced endothelial cell fates using three independent transgenic mouse lines with constitutive Cre recombinase expression in endothelial cells (Tie1.Cre, VE-Cadherin.Cre), or inducible endothelial-specific Cre expression to label adult endothelial cells (End-SCL.CreERT) crossed to ROSA.LacZ or ROSA.EGFP mice. In all lineage-tracing models, we observed labeling of both endothelial cells (ECs) and ventricular cardiomyocytes (CMs) within the healthy adult heart. Whereas EC labeling was homogeneously distributed throughout the entire myocardium, CMs of EC origin were localized within specific patches in the subepicardial area near coronary arteries. Use of the ROSA.Brainbow-2.1 reporter line demonstrated that each CM patch was of a distinct clonal origin.
Employing the inducible End-SCL.CreERT line, we pulse-labeled ECs and followed their fate both short and long-term during homeostasis. We found that EC-derived CMs had a transient lifespan, reaching peak numbers three weeks after EC labeling, but declining thereafter. From these pulse-labeling studies, we estimated a global annual turnover rate of 0.4% for EC-derived CMs in the adult mouse heart. Interestingly, the regenerative rates of EC-like progenitors declined significantly after LAD ligation in a myocardial infarction (MI) model. Instead, these cells contributed almost exclusively to scar tissue formation through generation of infarct myofibroblasts.
In summary, our findings suggest that an EC-like progenitor population exists in the adult heart with cardiomyogenic regenerative capacity that replenishes high turnover CMs within localized ventricular sites. In contrast, these progenitor cells acquire a pro-fibrotic phenotype after MI. Understanding the biology of this novel adult progenitor population may lead to new methods of enhancing the regenerative capacity of the heart after acute ischemic injury or during heart failure.
... Indeed, both resident and transplanted CPCs secrete HGF [80][81][82], enhancing the survival of cardiomyocytes to hypoxia, as well as inducing formation of new endothelium [83]. Thus, treatment of injured heart with a cocktail of growth factors, including HGF, may represent a valid strategy not only for cardioprotection but also for cardiac regeneration [82,84,85]. Recently, a population of cardiac progenitors of epicardial origin has been found, which promotes vessel formation and collateral growth [86] and contributes to cardiac repair after injury [87]. ...
Hepatocyte growth factor (HGF) and its tyrosine kinase receptor (Met) play
important roles in myocardial function both in physiological and pathological situations.
In the developing heart, HGF influences cardiomyocyte proliferation and differentiation.
In the adult, HGF/Met signaling controls heart homeostasis and prevents oxidative stress in
normal cardiomyocytes. Thus, the possible cardiotoxicity of current Met-targeted anti-cancer
therapies has to be taken in consideration. In the injured heart, HGF plays important roles
in cardioprotection by promoting: (1) prosurvival (anti-apoptotic and anti-autophagic)
effects in cardiomyocytes, (2) angiogenesis, (3) inhibition of fibrosis, (4) anti-inflammatory
and immunomodulatory signals, and (5) regeneration through activation of cardiac stem
cells. Furthermore, we discuss the putative role of elevated HGF as prognostic marker of
severity in patients with cardiac diseases. Finally, we examine the potential of HGF-based
molecules as new therapeutic tools for the treatment of cardiac diseases.
... The presence of stem cells in the heart after infarction is now well-documented and has received much attention [31]. In particular, c-kit pos cells have been identified in the adult mammalian heart after infarction [30,32] and have also been shown to have therapeutic effects when injected into mouse, rat and porcine infarct models [31,37,38]. Although the mechanisms underlying the therapeutic effects of cardiac stem cells are still under investigation, as well as contention, it has been shown that following injection of cardiac stem cells, large numbers of newly formed, albeit immature, cardiomyocytes are seen [39] . ...
A naturally-occurring fragment of tyrosyl-tRNA synthetase (TyrRS) has been shown in higher eukaryotes to 'moonlight' as a pro-angiogenic cytokine in addition to its primary role in protein translation. Pro-angiogenic cytokines have previously been proposed to be promising therapeutic mechanisms for the treatment of myocardial infarction. Here, we show that systemic delivery of the natural fragment of TyRS, mini-TyrRS, improves heart function in mice after myocardial infarction. This improvement is associated with reduced formation of scar tissue, increased angiogenesis of cardiac capillaries, recruitment of c-kitpos cells and proliferation of myocardial fibroblasts. This work demonstrates that mini-TyrRS has beneficial effects on cardiac repair and regeneration and offers support for the notion that elucidation of the ever expanding repertoire of noncanonical functions of aminoacyl tRNA synthetases offers unique opportunities for development of novel therapeutics.
... One such population consists of cells that form cardiospheres in suspension and differentiate to CMs, endothelial cells (ECs), and smooth muscle cells (SMCs) (Messina et al., 2004; Smith et al., 2007). Cardiac stem cells (CSCs) also include c-Kit expressing cells, which generate CMs, ECs, and SMCs after injury (Beltrami et al., 2003; Rota et al., 2008; Ellison et al., 2013). A different CSC type consists of Side Population (SP) cells (Hierlihy et al., 2002; Martin et al., 2004; Mouquet et al., 2005). ...
Cardiac tissue undergoes renewal with low rates. Although resident stem cell populations have been identified to support cardiomyocyte turnover, the source of the cardiac stem cells and their niche remain elusive. Using Cre/Lox-based cell lineage tracing strategies, we discovered that labeling of endothelial cells in the adult heart yields progeny that have cardiac stem cell characteristics and express Gata4 and Sca1. Endothelial-derived cardiac progenitor cells were localized in the arterial coronary walls with quiescent and proliferative cells in the media and adventitia layers, respectively. Within the myocardium, we identified labeled cardiomyocytes organized in clusters of single-cell origin. Pulse-chase experiments showed that generation of individual clusters was rapid but confined to specific regions of the heart, primarily in the right anterior and left posterior ventricular walls and the junctions between the two ventricles. Our data demonstrate that endothelial cells are an intrinsic component of the cardiac renewal process.
... These observations suggest that ischemic preconditioning may activate innate signaling mechanisms, which in turn support myocardial protection. These innate mechanisms may include, but are not limited to; ischemia-induced upregulation of growth factors to support cardiomyocytes urvival and angiogenesis16171819, activation of cardiac resident stem cells20212223242526 and mobilization of bone marrow cells to the heart to stimulate cardiomyocyte regeneration272829303132. Investigations on these natural protective mechanisms provide insights into the development of cardioprotective strategies for treatment of myocardial infarction. ...
Myocardial ischemia activates innate cardioprotective mechanisms, including expression of growth factors,
activation of cardiac resident stem cells and mobilization of bone marrow cells to the ischemic myocardium, which alleviate ischemic injury and promote cardiomyocyte regeneration. This review addresses a newly recognized cardioprotective mechanism involving the liver. Myocardial ischemia induces liver responses, including mobilization of hepatic cells to the circulatory system and upregulation of hepatic secretory proteins, such as fibroblast growth factor 21 (FGF21) and trefoil factor 3 (TFF3). The mobilized hepatic cells either engraft to the ischemic myocardium or disintegrate in the circulatory system, facilitating delivery of the hepatic secretory proteins. These proteins contribute to myocardial protection, alleviating myocardial infarction. These investigations provide new information for understanding the innate cardioprotective mechanisms and developing therapeutic strategies for myocardial infarction.
... The ultimate goal of any regenerative therapy for ischemic myocardium is to regenerate lost cardiomyocytes and facilitate cardiovascular neovascularization, in order to lead to clinical improvement in cardiac functions. An array of adult stem cell types including skeletal myoblasts, bone marrow derived stem cells, endothelial progenitor as well as cardiac stem cells have been shown to lead to functional benefit in animal models of infarction2345, but clinical trials have generated mixed results678. Hence, a search for a novel stem cell type that is capable of restoring cardiac function is of paramount importance. ...
Mesenchymal stem cells (MSC) have emerged as a potential stem cell type for cardiac regeneration after myocardial infarction (MI). Recently, we isolated and characterized mesenchymal stem cells derived from rat fetal heart (fC-MSC), which exhibited potential to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in
vitro. In the present study, we investigated the therapeutic efficacy of intravenously injected fC-MSC in a rat model of MI using multi-pinhole gated SPECT-CT system. fC-MSC were isolated from the hearts of Sprague Dawley (SD) rat fetuses at gestation day 16 and expanded ex
vivo. One week after induction of MI, 2×106 fC-MSC labeled with PKH26 dye (n = 6) or saline alone (n = 6) were injected through the tail vein of the rats. Initial in
vivo tracking of 99mTc-labeled fC-MSC revealed a focal uptake of cells in the anterior mid-ventricular region of the heart. At 4 weeks of fC-MSC administration, the cells labeled with PKH26 were located in abundance in infarct/peri-infarct region and the fC-MSC treated hearts showed a significant increase in left ventricular ejection fraction and a significant decrease in the end diastolic volume, end systolic volume and left ventricular myo-mass in comparison to the saline treated group. In addition, fC-MSC treated hearts had a significantly better myocardial perfusion and attenuation in the infarct size, in comparison to the saline treated hearts. The engrafted PKH26-fC-MSC expressed cardiac troponin T, endothelial CD31 and smooth muscle sm-MHC, suggesting their differentiation into all major cells of cardiovascular lineage. The fC-MSC treated hearts demonstrated an up-regulation of cardio-protective growth factors, anti-fibrotic and anti-apoptotic molecules, highlighting that the observed left ventricular functional recovery may be due to secretion of paracrine factors by fC-MSC. Taken together, our results suggest that fC-MSC therapy may be a new therapeutic strategy for MI and multi-pinhole gated SPECT-CT system may be a useful tool to evaluate cardiac perfusion, function and cell tracking after stem cell therapy in acute myocardial injury setting.
... Recent developments in stem cell biology, including those related to induced pluripotent stem cells (iPSCs) and tissue-derived stem/ progenitor cells, are a giant leap toward the goal. Recently, myocardium-derived stem/progenitor cells were isolated by several institutes123. These cell populations have the potential to repair the diseased heart, and clinical trials are currently ongoing. ...
Cell-based regeneration therapies have great potential for application in new areas in clinical medicine, although some obstacles still remain to be overcome for a wide range of clinical applications. One major impediment is the difficulty in large-scale production of cells of interest with reproducibility. Current protocols of cell therapy require a time-consuming and laborious manual process. To solve this problem, we focused on the robotics of an automated and high-throughput cell culture system. Automated robotic cultivation of stem or progenitor cells in clinical trials has not been reported till date. The system AutoCulture(R) used in this study can automatically replace the culture medium, centrifuge cells, split cells, and take photographs for morphological assessment. We examined the feasibility of this system in a clinical setting.
We observed similar characteristics by both the culture methods in terms of the growth rate, gene expression profile, cell surface profile by fluorescence-activated cell sorting, surface glycan profile, and genomic DNA stability. These results indicate that AutoCulture(R) is a feasible method for the cultivation of human cells for regenerative medicine.
An automated cell-processing machine will play important roles in cell therapy and have widespread use from application in multicenter trials to provision of off-the-shelf cell products.
... C-kit+ cells isolated from neonatal hearts can differentiate into cardiomyocytes, but the cardiomyogenic potential of adult c-kit+ cells is not apparent in cells from normal adult heart [41]. Cardiac progenitor cells can contribute to the growth potential of the heart through their differentiation into cardiomyocytes in many different conditions, including the addition of growth factors [18,42,43], as well as after an infarction [44]. There has also been some evidence that progenitor cells will proliferate under hypertrophic conditions [17]. ...
The extent of heart disease varies from person to person, suggesting that genetic background is important in pathology. Genetic background is also important when selecting appropriate mouse models to study heart disease. This study examines heart growth as a function of strain, specifically C57BL/6 and DBA/2 mouse strains.
In this study, we test the hypothesis that two strains of mice, C57BL/6 and DBA/2, will produce varying degrees of heart growth in both physiological and pathological settings.
Differences in heart dimensions are detectable by echocardiography at 8 weeks of age. Percentages of cardiac progenitor cells (c-kit+ cells) and mononucleated cells were found to be in a higher percentage in DBA/2 mice, and more tri- and quad-nucleated cells were in C57BL/6 mice. Cardiomyocyte turnover shows no significant changes in mitotic activity, however, there is more apoptotic activity in DBA/2 mice. Cardiomyocyte cell size increased with age, but increased more in DBA/2 mice, although percentages of nucleated cells remained the same in both strains. Two-week isoproterenol stimulation showed an increase in heart growth in DBA/2 mice, both at cardiomyocyte and whole heart level. In isoproterenol-treated DBA/2 mice, there was also a greater expression level of the hypertrophy marker, ANF, compared to C57BL/6 mice.
We conclude that the DBA/2 mouse strain has a more immature cardiac phenotype, which correlates to a cardiac protective response to hypertrophy in both physiological and pathological stimulations.
... In regenerating the functional cardiac tissue, stem cell therapy is an effective method for the recovery of the injured myocardium. We selected CPCs because of their incomparable cardiac regenerative capacity3334 . Presently, CPCs are based exclusively on the expression of a stem cell-related surface antigen, namely, c-kit and Sca-1. ...
Cardiac progenitor cells (CPCs) have been proven suitable for stem cell therapy after myocardial infarction, especially c-kit(+)CPCs. CPCs marker c-kit and its ligand, the stem cell factor (SCF), are linked as c-kit/SCF axis, which is associated with the functions of proliferation and differentiation. In our previous study, we found that stromal cell-derived factor-1α (SDF-1α) could enhance the expression of c-kit. However, the mechanism is unknown.
CPCs were isolated from adult mouse hearts, c-kit(+) and c-kit(-) CPCs were separated by magnetic beads. The cells were cultured with SDF-1α and CXCR4-selective antagonist AMD3100, and c-kit expression was measured by qPCR and Western blotting. Results showed that SDF-1α could enhance c-kit expression of c-kit(+)CPCs, made c-kit(-)CPCs expressing c-kit, and AMD3100 could inhibit the function of SDF-1α. After the intervention of SDF-1α and AMD3100, proliferation and migration of CPCs were measured by CCK-8 and transwell assay. Results showed that SDF-1α could enhance the proliferation and migration of both c-kit(+) and c-kit(-) CPCs, and AMD3100 could inhibit these functions. DNA methyltransferase (DNMT) mRNA were measured by qPCR, DNMT activity was measured using the DNMT activity assay kit, and DNA methylation was analyzed using Sequenom's MassARRAY platform, after the CPCs were cultured with SDF-1α. The results showed that SDF-1α stimulation inhibited the expression of DNMT1 and DNMT3β, which are critical for the maintenance of regional DNA methylation. Global DNMT activity was also inhibited by SDF-1α. Lastly, SDF-1α treatment led to significant demethylation in both c-kit(+) and c-kit(-) CPCs.
SDF-1α combined with CXCR4 could up-regulate c-kit expression of c-kit(+)CPCs and make c-kit(-)CPCs expressing c-kit, which result in the CPCs proliferation and migration ability improvement, through the inhibition of DNMT1 and DNMT3β expression and global DNMT activity, as well as the subsequent demethylation of the c-kit gene.
... FABP4, fatty acid binding protein 4. needed to ensure the expected outcomes by cellular cardiomyoplasty . In addition, several literature data report the existence of heart-resident stem (progenitor) cells, which can be isolated from post-infarct hearts and may also be stimulated to modulate the processes downstream the initial tissue damage [76] . These cellular populations may be differentiated towards heart-resident cell types both in vitro and in vivo [77]. ...
Mesenchymal stem cells (MSC) are virtually present in all postnatal organs as well as in perinatal tissues. MSC can be differentiated towards severalmature cytotypes and interestingly hold potentially relevant immunomodulatory features. Myocardial infarction results in severe tissue damage, cardiomyocytes loss, and eventually heart failure. Cellular cardiomyoplasty represents a promising approach for myocardial repair. Clinical trials using MSC are underway for a number of heart diseases, even if their outcomes are hampered by low long-term improvements and the possible presence of complications related to cellular therapy administration. Therefore elucidating the presence and role of MSC which reside in the post-infarct human heart should provide essential alternatives for therapy. In the present paper we show a novel method to reproducibly isolate and culture MSC from the sub-endocardial zone of human left ventricle from patients undergoing heart transplant for post-infarct chronic heart failure. By using both immunocytochemistry and RT-PCR, we demonstrated that these cells do express key MSC markers, do express heart-specific transcription factors in their undifferentiated state, while lacking strictly cardiomyocyte-specific proteins. Moreover, these cells do express immunomodulatory molecules which should disclose their further potential in immune modulation processes in the post-infarct microenvironment. Standard MSC trilineage differentiation experiments were also performed. The present paper adds new data on the basic biological features of heart-resident MSC which populate the organ following myocardial infarction. The use of heart-derived MSC to promote in-organ repair or as a cellular source for cardiomyoplasty is a fascinating and challenging task, which deserves further research efforts.
... The development of stem cell therapies for treating cardiovascular diseases has been a major goal of research scientists and clinicians [77,78]. While successful stem cell interventions have been obtained using animal models [17,798081, as well as promising results in clinical trials on cardiac patients828384, the outcomes from these studies has not always been repeatable and has often been rather modest in effect [85,86]. It is not yet clear what the best sources are of stem cells for cardiac repair, and whether these various stem cell populations have been optimized in their cardiac capacity . ...
Bone marrow has long been considered a potential stem cells source for cardiac repair due to its abundance and accessibility. Although previous investigations have generated cardiomyocytes from bone marrow, yields have been low, and far less than produced from ES or induced pluripotent stem cells (iPSCs). Since differentiation of pluripotent cells is difficult to control, we investigated whether bone marrow cardiac competency could be enhanced without making cells pluripotent. From screens of various molecules that have been shown to assist iPSC production or maintain ES cell phenotype, we identified the G9a histone methyltransferase inhibitor BIX01294 as a potential reprogramming agent for converting bone marrow cells to a cardiac competent phenotype. Bone marrow cells exposed to BIX01294 displayed significantly elevated expression of brachyury, Mesp1, and islet1, which are genes associated with embryonic cardiac progenitors. In contrast, BIX01294 treatment minimally affected ectodermal, endodermal, and pluripotency gene expression by bone marrow cells. Expression of cardiac-associated genes Nkx2.5, GATA4, Hand1, Hand2, Tbx5, myocardin, and titin was enhanced 114, 76, 276, 46, 635, 123 and 5-fold in response to the cardiogenic stimulator Wnt11 when bone marrow cells were pretreated with BIX01294. Immunofluorescent analysis demonstrated that BIX01294 exposure allowed for the subsequent display of various muscle proteins within the cells. The effect of BIX01294 on bone marrow cell phenotype and differentiation potential corresponded to an overall decrease in methylation of histone H3 at lysine9, which is the primary target of G9a histone methyltransferase. In summary, these data suggest that BIX01294 inhibition of chromatin methylation reprograms bone marrow cells to a cardiac-competent progenitor phenotype.
... Each adult heart was divided into ,800 sections as previously described in detail [9,18,19], whereas kidney regions containing the fetal hearts were divided into ,500 sections using a cryostat. Detailed histology methods employed in this study have been described previously [18,20,21] . Briefly, tissues were either cryostained or paraffin-stained to characterize the fetal heart transplant and to evaluate the cardiac repopulation. ...
Debate surrounds the question of whether the heart is a post-mitotic organ in part due to the lack of an in vivo model in which myocytes are able to actively regenerate. The current study describes the first such mouse model--a fetal myocardial environment grafted into the adult kidney capsule. Here it is used to test whether cells descended from bone marrow can regenerate cardiac myocytes. One week after receiving the fetal heart grafts, recipients were lethally irradiated and transplanted with marrow from green fluorescent protein (GFP)-expressing C57Bl/6J (B6) donors using normal B6 recipients and fetal donors. Levels of myocyte regeneration from GFP marrow within both fetal myocardium and adult hearts of recipients were evaluated histologically. Fetal myocardium transplants had rich neovascularization and beat regularly after 2 weeks, continuing at checkpoints of 1, 2, 4, 6, 8 and12 months after transplantation. At each time point, GFP-expressing rod-shaped myocytes were found in the fetal myocardium, but only a few were found in the adult hearts. The average count of repopulated myocardium with green rod-shaped myocytes was 996.8 cells per gram of fetal myocardial tissue, and 28.7 cells per adult heart tissue, representing a thirty-five fold increase in fetal myocardium compared to the adult heart at 12 months (when numbers of green rod-shaped myocytes were normalized to per gram of myocardial tissue). Thus, bone marrow cells can differentiate to myocytes in the fetal myocardial environment. The novel in vivo model of fetal myocardium in the kidney capsule appears to be valuable for testing repopulating abilities of potential cardiac progenitors.
... 53] showed that intravascular administration of CPCs migrate to the myocardium, promote myocyte regeneration, form new coronary vasculature, and reduce infarct size. A recent study also revealed that the engrafted CPCs not only enhanced function and reduced ventricular dilation, but also replaced almost 42% of the scar with newly formed myocardium. [54] Despite these advantages, the therapeutic use of CPCs becomes complicated, owing to the difficulties in acquiring myocardial samples from patients and their expansion in quantities of therapeutic significance. [55] Therefore, local injection of factors to incite the resident CPCs has been offered as an effective approach to mediate myoc ...
The fields of regenerative medicine and cellular therapy have been the subject of tremendous hype and hope. In particular, the perceived usage of somatic cells like mesenchymal stromal cells (MSCs) has captured the imagination of many. MSCs are a rare population of cells found in multiple regions within the body that can be readily expanded ex vivo and utilized clinically. Originally, it was hypothesized that transplantation of MSCs to sites of injury would lead to de novo tissue-specific differentiation and thereby replace damaged tissue. Now, it is generally agreed that MSC home to sites of injury and direct positive remodeling via the secretion of paracrine factors. Consequently, their clinical utilization has largely revolved around their abilities to promote neovascularization for ischemic disorders and modulate overly exuberant inflammatory responses for autoimmune and alloimmune conditions. One of the major issues surrounding the development of somatic cell therapies like MSCs is that despite evoking a positive response, long-term engraftment and persistence of these cells is rare. Consequently, very large cell doses need be administered for raising production, delivery, and efficacy issues. In this review, we will outline the field of MSC in the context of ischemia and discuss causes for their lack of persistence. In addition, some of the methodologies be used to enhance their therapeutic potential will be highlighted.
... Although these cells can regenerate lost cardiac muscle in lower vertebrates [6], they are unable to reconstruct heart tissue after extensive injury in mammals, including humans789. Nevertheless, the discovery of stem cells within the mammalian heart has renewed the interest for cardiac regeneration, based on the idea that recruiting resident cells inherently programmed to reconstitute the damaged myocardium may achieve better results than forcing extra-cardiac stem cells to differentiate into contractile myocytes [10,11]. Indeed, experimental models and clinical trials performed using different exogenous stem cell lineages transplanted into the post-ischemic heart have only demonstrated a modest cell engraftment and myocardial regenerative capacities, being the observed beneficial effects mainly attributable to the paracrine improvement of tissue remodeling and preservation of the residual myocardium by the engrafted cells1213141516. ...
The possibility to induce myocardial regeneration by the activation of resident cardiac stem cells (CSCs) has raised great interest. However, to propose endogenous CSCs as therapeutic options, a better understanding of the complex mechanisms controlling heart morphogenesis is needed, including the cellular and molecular interactions that cardiomyocyte precursors establish with cells of the stromal compartment. In the present study, we co-cultured immature cardiomyocytes from neonatal mouse hearts with mouse bone marrow-derived mesenchymal stromal cells (MSCs) to investigate whether these cells could influence cardiomyocyte growth in vitro. We found that cardiomyocyte proliferation was enhanced by direct co-culture with MSCs compared with the single cultures. We also showed that the proliferative response of the neonatal cardiomyocytes involved the activation of Notch-1 receptor by its ligand Jagged-1 expressed by the adjacent MSCs. In fact, the cardiomyocytes in contact with MSCs revealed a stronger immunoreactivity for the activated Notch-intracellular domain (Notch-ICD) as compared with those cultured alone and this response was significantly attenuated when MSCs were silenced for Jagged-1. The presence of various cardiotropic cytokines and growth factors in the conditioned medium of MSCs underscored the contribution of paracrine mechanisms to Notch-1 up-regulation by the cardiomyocytes. In conclusions these findings unveil a previously unrecognized function of MSCs in regulating cardiomyocyte proliferation through Notch-1/Jagged-1 pathway and suggest that stromal-myocardial cell juxtacrine and paracrine interactions may contribute to the development of new and more efficient cell-based myocardial repair strategies.
... Several studies have been carried out to test the effects of growth factors such as HGF, IGF-1, FGF2 and EGF on the migration of CPCs, with encouraging results revealing their potential to stimulate progenitor cell proliferation and their migration to the ischemic myocardium to replenish damaged tissue69707172. These findings suggest that in situ activation of CPCs by specific factors can be as effective as cardiac stem cell transplantation, exploiting the potential of endogenous autologous cells, without the added complications of culture and expansion ex vivo and engraftment. ...
Stem cell therapy has recently emerged as an innovative strategy over conventional cardiovascular treatments to restore cardiac function in patients affected by ischemic heart disease. Various stem cell populations have been tested and their potential for cardiac repair has been analyzed. Embryonic stem cells retain the greatest differentiation potential, but concerns persist with regard to their immunogenic and teratogenic effects. Although adult somatic stem cells are not tumourigenic and easier to use in an autologous setting, they exist in small numbers and possess reduced differentiation potential. Traditionally the heart was considered to be a post-mitotic organ; however, this dogma has recently been challenged with the identification of a reservoir of resident stem cells, defined as cardiac progenitor cells (CPCs). These endogenous progenitors may represent the best candidates for cardiovascular cell therapy, as they are tissue-specific, often pre-committed to a cardiac fate, and display a greater propensity to differentiate towards cardiovascular lineages. This review will focus on current research into the biology of CPCs and their regenerative potential. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".
... Finally, in order to maximize the therapeutic effect of the delivered CPCs through increased cell survival it may be necessary to modify the delivery method in order to ensure decreased apoptosis and localized inflammatory response as well as prime the cells to cope with the increased stress associated with the entire process [36]. The recent identification and characterization of adult [48] and ESC-derived CPCs with multipotential but cardiac tissue-restricted differentiation capacity has reinvigorated the field of cell-based cardiac therapies. Taken together, our results clearly demonstrate the therapeutic value of the ESC-derived CPCs in the infarcted mouse heart. ...
Stem cell transplantation holds great promise for the treatment of myocardial infarction injury. We recently described the embryonic stem cell-derived cardiac progenitor cells (CPCs) capable of differentiating into cardiomyocytes, vascular endothelium, and smooth muscle. In this study, we hypothesized that transplanted CPCs will preserve function of the infarcted heart by participating in both muscle replacement and neovascularization. Differentiated CPCs formed functional electromechanical junctions with cardiomyocytes in vitro and conducted action potentials over cm-scale distances. When transplanted into infarcted mouse hearts, CPCs engrafted long-term in the infarct zone and surrounding myocardium without causing teratomas or arrhythmias. The grafted cells differentiated into cross-striated cardiomyocytes forming gap junctions with the host cells, while also contributing to neovascularization. Serial echocardiography and pressure-volume catheterization demonstrated attenuated ventricular dilatation and preserved left ventricular fractional shortening, systolic and diastolic function. Our results demonstrate that CPCs can engraft, differentiate, and preserve the functional output of the infarcted heart.
... A second resident progenitor population comprises c-Kit (also known as CD117) positive cells, which are located in small clusters within the adult heart [147]. Isolated c-Kit+ cells do not differentiate into cardiovascular cell types in culture but showed impressive regenerative potential in some studies after transplantation into the injured rat heart, where they gave rise to cardiomyocytes, endothelial cells, and smooth muscle cells, while also improving ventricular function147148149150. However, these results have not been reproduced in all studies [55] . ...
Acute ischemic injury and chronic cardiomyopathies can cause irreversible loss of cardiac tissue leading to heart failure. Cellular therapy offers a new paradigm for treatment of heart disease. Stem cell therapies in animal models show that transplantation of various cell preparations improves ventricular function after injury. The first clinical trials in patients produced some encouraging results, despite limited evidence for the long-term survival of transplanted cells. Ongoing research at the bench and the bedside aims to compare sources of donor cells, test methods of cell delivery, improve myocardial homing, bolster cell survival, and promote cardiomyocyte differentiation. This article reviews progress toward these goals.
Exosomes are a pluripotent group of extracellular nanovesicles secreted by all cells that mediate intercellular communications. The effective information within exosomes is primarily reflected in exosomal cargos, including proteins, lipids, DNAs, and non-coding RNAs (ncRNAs), the most intensively studied molecules. Cardiac resident cells (cardiomyocytes, fibroblasts, and endothelial cells) and foreign cells (infiltrated immune cells, cardiac progenitor cells, cardiosphere-derived cells, and mesenchymal stem cells) are involved in the progress of ventricular remodeling (VR) following myocardial infarction (MI) via transferring exosomes into target cells. Here, we summarize the pathological mechanisms of VR following MI, including cardiac myocyte hypertrophy, cardiac fibrosis, inflammation, pyroptosis, apoptosis, autophagy, angiogenesis, and metabolic disorders, and the roles of exosomal cargos in these processes, with a focus on proteins and ncRNAs. Continued research in this field reveals a novel diagnostic and therapeutic strategy for VR.
Cell therapies have the potential to bring a paradigm shift to the treatment of heart failure (HF). Since the initial report of cell therapy with skeletal myoblasts in HF, a number of preclinical and clinical studies have been conducted, which support the ability of various stem cell populations to improve cardiac function and reduce the infarct size in HF. However, it is still too early in this new era of regenerative cell therapy as the novel modality. To address the fact that no cell therapy has been conclusively shown to be effective, the important issues involved have been discussed. First, the types of stem cells to be clinically investigated in HF have been reviewed; skeletal myoblasts, bone marrow-derived mononuclear and mesenchymal stem cells, adipose tissue-derived cells, and pluripotent stem cells have been discussed with their cell characteristics. Second, differentiation into cardiac lineage or paracrine effects as potential modes of action of stem cells in HF has been discussed. Finally, the routes of administration, cell dose and cell survival, and long-term engraftment have been discussed as current challenges and future directions. The purpose of this chapter is to review the preclinical and clinical studies carried out with respect to the use of stem cells in HF, and to discuss current unresolved issues and future directions.
Research has demonstrated that hypoxic preconditioning (HP) can enhance the survival and proliferation of cardiac progenitor cells (CPCs); however, the underlying mechanisms are not fully understood. Here, we report that HP of c-kit (+) CPCs inhibits p53 via the PI3K/Akt-DNMT1 pathway. First, CPCs were isolated from the hearts of C57BL/6 mice and further purified by magnetic-activated cell sorting. Next, these cells were cultured under either normoxia (H0) or HP for 6 hours (H6) followed by oxygen–serum deprivation for 24 hours (24h). Flow cytometric analysis and MTT assays revealed that hypoxia-preconditioned CPCs exhibited an increased survival rate. Western blot and quantitative real-time PCR assays showed that p53 was obviously inhibited, while DNMT1 and DNMT3β were both significantly up-regulated by HP. Bisulphite sequencing analysis indicated that DNMT1 and DNMT3β did not cause p53 promoter hypermethylation. A reporter gene assay and chromatin immunoprecipitation analysis further demonstrated that DNMT1 bound to the promoter locus of p53 in hypoxia-preconditioned CPCs. Together, these observations suggest that HP of CPCs could lead to p53 inhibition by up-regulating DNMT1 and DNMT3β, which does not result in p53 promoter hypermethylation, and that DNMT1 might directly repress p53, at least in part, by binding to the p53 promoter locus.
c-kit(pos) Cardiac Progenitor Cells (CPCs) represent a successful approach in healing the infarcted heart and rescuing its mechanical function while electrophysiological consequences are uncertain. CPC mobilization promoted by hepatocyte growth factor (HGF) and IGF-1 improved electrogenesis in myocardial infarction (MI). We hypothesized that locally delivered CPCs supplemented with HGF+IGF-1 (GFs) can concur in ameliorating electrical stability of the regenerated heart. One hundred and thirty-nine adult male Wistar rats with four-week old MI or sham operated were randomized to receive intra-myocardial injection of GFs, CPCs, CPCs+GFs, or vehicle (V). Enhanced Green-fluorescent-protein-tagged CPCs were used for cell tracking. Vulnerability to stress-induced arrhythmia was assessed by telemetry-ECG. Basic cardiac electrophysiological properties were examined by epicardial multiple-lead recording. Hemodynamic function was measured invasively. Hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. In comparison with V and at variance with individual CPCs, CPCs+GFs approximately halved arrhythmias in all animals, restoring cardiac anisotropy towards sham values. GFs alone reduced arrhythmias by less than CPCs+GFs, prolonging ventricular refractoriness without affecting conduction velocity. Concomitantly, CPCs+GFs reactivated the expression levels of Connexin-43 and Connexin-40 as well as channel proteins of key depolarizing and repolarizing ion currents differently than sole GFs. Mechanical function and anatomical remodeling were equally improved by all regenerative treatments, thus exhibiting a divergent behavior relative to electrical aspects. Conclusively, we provided evidence of distinctive anti-arrhythmic action of locally injected GF-supplemented CPCs, likely attributable to retrieval of Cx43, Cx40, and Cav1.2 expression, favoring intercellular coupling and spread of excitation in mended heart.
Stem cell therapy is a promising treatment for diseases such as Duchenne muscular dystrophy (DMD) and ischemic heart failure. However, low survival and differentiation of transplanted cells hinders therapy. In this study, we examined ways to enhance the effectiveness of muscle cells for cardiomyoplasty by increasing antioxidant levels, explored the role of vascular endothelial growth factor (VEGF) in mechanical stimulation pre-treatment and characterized muscle derived stem cells (MDSCs) from normal and dystrophic mice.
First we demonstrated that increasing antioxidant levels positively correlated with the early survival of myoblasts after implantation into infarcted hearts, but did not result in long term functional benefits, indicating that early survival does not necessarily correlate with long term regeneration and repair.
Next we aimed to determine the effect of VEGF on mechanically stimulated MDSCs transplanted into dystrophic muscle. MDSCs were transduced with vectors carrying the LacZ reporter gene (lacZ-MDSCs), the soluble VEGF receptor Flt1 (sFlt1-MDSCs) or short hairpin RNA targeting VEGF messenger RNA (shRNA_VEGF MDSCs). They were subjected to 24 hours of cyclic strain and injected into the gastrocnemius muscles of dystrophic mdx/SCID mice. After 2 weeks, there was an increase in angiogenesis in muscles transplanted with mechanically stimulated lacZ-MDSCs compared to non-stimulated lacZ-MDSCs and sFlt1-MDSCs. Dystrophin positive myofiber regeneration and in vitro myotube differentiation were significantly lower in the shRNA_VEGF-MDSC group compared to the lacZ-MDSC and sFlt1-MDSC groups. Thus, the beneficial effects of mechanical stimulation on MDSC mediated muscle repair were lost by inhibiting VEGF.
Finally, we aimed to compare wild-type (wt) MDSCs with MDSCs obtained from mdx and dystrophin/utrophin double knock out (DKO) mice, which are models of muscular dystrophy. We demonstrated that wt and mdx MDSCs did not have differences in proliferation, differentiation, or VEGF secretion. We compared DKO homozygous MDSCs and DKO heterozygous MDSCs and found that DKO homo MDSCs had decreased proliferation, differentiation, and cell survival capabilities compared to DKO het MDSCs. Finally, we pre-treated DKO MDSCs with mechanical stimulation and increased their proliferation rates. In conclusion, efforts to optimize cell therapy are necessary to improve transplantation outcomes for both ischemic cardiac repair and muscular diseases.
Introduction:
We investigated whether attachment of gelatin hydrogel microsphere (GHM) sheet impregnated with antagomir-92a on the infarcted heart promotes angiogenesis and cardiomyogenesis, and improves cardiac function after myocardial infarction (MI) in rats.
Methods:
GHM sheet impregnated with antagomir-92a, its scramble sequence antagomir-control sheet or the sheet alone was attached on the area at risk of MI after the left anterior descending coronary artery ligation. Bromodeoxyuridine (BrdU) was included in the sheet to trace proliferating cells.
Results:
The antagomir-92a sheet significantly increased capillary density in the infarct border zone 14 days after MI compared to the antagomir-control sheet or the sheet alone, associated with an increase in endothelial cells incorporated with BrdU. The antagomir-92a sheet significantly increased cardiac stem cells incorporated with BrdU 3 days after MI in the infarct border zone. This was associated with an increase in cardiomyocytes incorporated with BrdU 14 days after MI. Scar area was significantly reduced by the antagomir-92a sheet compared to the antagomir-control sheet or the sheet alone (12.8 ± 1.3 vs 25.2 ± 2.2, 24.0 ± 1.7% LV area, respectively) 14 days after MI. LV dilatation was inhibited, and LV wall motion was improved 14 days after MI in rats with the antagomir-92a sheet compared to the antagomir-control sheet or the sheet alone.
Conclusions:
These results suggest that attachment of the GHM sheet impregnated with antagomir-92a on the area at risk of MI enhances angiogenesis, promotes cardiomyogenesis, and ameliorates LV function.
Cardiac- (CSC) and mesenchymal-derived (MSC) CD117+ isolated stem cells improve cardiac function after injury. However, no study has compared the therapeutic benefit of these cells when used autologously.
MSCs and CSCs were isolated on day 0. Cardiomyopathy was induced (day 28) by infusion of L-isoproterenol (1,100 ug/kg/hour) from Alzet minipumps for 10 days. Bromodeoxyuridine (BrdU) was infused via minipumps (50 mg/mL) to identify proliferative cells during the injury phase. Following injury (day 38), autologous CSC (n = 7) and MSC (n = 4) were delivered by intracoronary injection. These animals were compared to those receiving sham injections by echocardiography, invasive hemodynamics, and immunohistochemistry.
Fractional shortening improved with CSC (26.9 ± 1.1% vs. 16.1 ± 0.2%, p = 0.01) and MSC (25.1 ± 0.2% vs. 12.1 ± 0.5%, p = 0.01) as compared to shams. MSC were superior to CSC in improving left ventricle end-diastolic (LVED) volume (37.7 ± 3.1% vs. 19.9 ± 9.4%, p = 0.03) and ejection fraction (27.7 ± 0.1% vs. 19.9 ± 0.4%, p = 0.02). LVED pressure was less in MSC (6.3 ± 1.3 mmHg) as compared to CSC (9.3 ± 0.7 mmHg) and sham (13.3 ± 0.7); p = 0.01. LV BrdU+ myocytes were higher in MSC (0.17 ± 0.03%) than CSC (0.09 ± 0.01%) and sham (0.06 ± 01%); p < 0.001.
Both CD117+ isolated CSC and MSC therapy improve cardiac function and attenuate pathological remodeling. However, MSC appear to confer additional benefit.
© 2015 Wiley Periodicals, Inc.
A new problem has emerged with the ever-increasing number of breast cancer survivors. While early screening and advances in treatment have allowed these patients to overcome their cancer, these treatments often have adverse cardiovascular side effects that can produce abnormal cardiovascular function. Chemotherapeutic and radiation therapy have both been linked to cardiotoxicity; these therapeutics can cause a loss of cardiac muscle and deterioration of vascular structure that can eventually lead to heart failure (HF). This cardiomyocyte toxicity can leave the breast cancer survivor with a probable diagnosis of dilated or restrictive cardiomyopathy (DCM or RCM). While current HF standard of care can alleviate symptoms, other than heart transplantation, there is no therapy that replaces cardiac myocytes that are killed during cancer therapies. There is a need to develop novel therapeutics that can either prevent or reverse the cardiac injury caused by cancer therapeutics. These new therapeutics should promote the regeneration of lost or deteriorating myocardium. Over the last several decades, the therapeutic potential of cell-based therapy has been investigated for HF patients. In this review, we discuss the progress of pre-clinical and clinical stem cell research for the diseased heart and discuss the possibility of utilizing these novel therapies to combat cardiotoxicity observed in breast cancer survivors.
Abstract Diabetic cardiomyopathy consists of a series of structural and functional changes. Accumulating evidence supports the concept that a "cardiac stem cell compartment disease" plays an important role in the pathophysiology of diabetic cardiomyopathy. In diabetic hearts, human cardiac stem/progenitor cells (CSPC) are reduced and manifest defective proliferative capacity. Hyperglycaemia, hyperlipidemia, inflammation, and the consequent oxidative stress are enhanced in diabetes: these conditions can induce defects in both growth and survival of these cells with an imbalance between cell death and cell replacement, thus favouring the onset of diabetic cardiomyopathy and its progression towards heart failure. The preservation of CSPC compartment can contribute to counteract the negative impact of diabetes on the myocardium. The recent studies summarized in this review have improved our understanding of the development and stem cell biology within the cardiovascular system. However, several issues remain unsolved before cell therapy can become a clinical therapeutically relevant strategy.
Heart regeneration in lower vertebratesCardiomyocyte proliferationCardiac stem cell activationConclusions
Acknowledgments
The prognosis of patients with myocardial infarction (MI) and resultant chronic heart failure remains extremely poor despite continuous advancements in optimal medical therapy and interventional procedures. Animal experiments and clinical trials using adult stem cell therapy following MI have shown a global improvement of myocardial function. The emergence of stem cell transplantation approaches has recently represented promising alternatives to stimulate myocardial regeneration. Regarding their tissue-specific properties, cardiac stem cells (CSCs) residing within the heart have advantages over other stem cell types to be the best cell source for cell transplantation. However, time-consuming and costly procedures to expanse cells prior to cell transplantation and the reliability of cell culture and expansion may both be major obstacles in the clinical application of CSC-based transplantation therapy after MI. The recognition that the adult heart possesses endogenous CSCs that can regenerate cardiomyocytes and vascular cells has raised the unique therapeutic strategy to reconstitute dead myocardium via activating these cells post-MI. Several strategies, such as growth factors, mircoRNAs and drugs, may be implemented to potentiate endogenous CSCs to repair infarcted heart without cell transplantation. Most molecular and cellular mechanism involved in the process of CSC-based endogenous regeneration after MI is far from understood. This article reviews current knowledge opening up the possibilities of cardiac repair through CSCs activation in situ in the setting of MI. © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
Stem cell therapy is an emerging therapeutic approach for the treatment of cardiovascular diseases. Experimental studies have demonstrated that different types of stem cells, including bone marrow-derived cells, mesenchymal stem cells, skeletal myoblasts, and cardiac progenitor cells and embryonic stem cells, can improve cardiac function after myocardial injuries. Nevertheless, the potential proarrhythmic risk after stem cell transplantation remains a major concern. Several mechanisms, including the immaturity of electrical phenotypes of the transplanted cardiomyocytes, poor cell-cell coupling and cardiac nerve sprouting, may contribute to arrhythmogenic risk after stem cell transplantation. This review summarizes the potential theoretical arrhythmogenic mechanisms associated with different types of stem cells for the treatment of cardiovascular diseases. Nevertheless, current experimental and clinical data on the proarrhythmic risk for different types of stem cell transplantation are limited, and await further experimental and clinical investigation.
For nearly a century, the human heart has been viewed as a terminally differentiated postmitotic organ in which the number of cardiomyocytes is established at birth, and these cells persist throughout the lifespan of the organ and organism. However, the discovery that cardiac stem cells live in the heart and differentiate into the various cardiac cell lineages has changed profoundly our understanding of myocardial biology. Cardiac stem cells regulate myocyte turnover and condition myocardial recovery after injury. This novel information imposes a reconsideration of the mechanisms involved in myocardial aging and the progression of cardiac hypertrophy to heart failure. Similarly, the processes implicated in the adaptation of the infarcted heart have to be dissected in terms of the critical role that cardiac stem cells and myocyte regeneration play in the restoration of myocardial mass and ventricular function. Several categories of cardiac progenitors have been described but, thus far, the c-kit–positive cell is the only class of resident cells with the biological and functional properties of tissue specific adult stem cells.
Cardiosphere-derived stem cell (CDC) transplantation can improve global left ventricular ejection fraction (LVEF) after myocardial infarction (MI). The aim of this study was to examine the effects of CDC transplantation on regional function and dyssynchrony after MI.
Two million rat CDCs (n = 7) or phosphate-buffered saline (n = 7) was injected into the infarct regions of Wistar Kyoto rats. Infarct size and CDC localization were evaluated by positron emission tomography (n = 7). Two-dimensional and strain echocardiography were performed at 1 and 4 weeks after MI. LVEF, circumferential strain, and time to peak circumferential strain were measured in the basal and apical short-axis views. Dyssynchrony was defined as the maximal difference of time to peak circumferential strain of opposing segments in each short-axis view. Engraftment was measured by quantitative polymerase chain reaction.
Positron emission tomography revealed that infarct size was 15.4 ± 3.6% of the left ventricle and that CDCs were localized to the infarct and border zone. CDC transplantation improved mean LVEF (45 ± 8% to 52 ± 7%, P = .02), mean circumferential strain (-7 ± 2% to -10 ± 1%, P = .02), and mean dyssynchrony (45 ± 10 to 28 ± 11 m sec, P = .04) of the infarct/peri-infarct zone from 1 to 4 weeks after MI, despite CDC engraftment of only 2.4 ± 3%. In contrast, mean LVEF (48 ± 5% to 40 ± 4%, P = .03) and mean circumferential strain (-8 ± 2% to -7 ± 1%, P = .02) of the infarcted region deteriorated, with no significant change in dyssynchrony (42 ± 12 vs 46 ± 13 m sec, P = .60) in the saline group during the same time period. Change in LVEF was correlated with change in circumferential strain (r = -0.8, P = .002) and dyssynchrony (r = 0.6, P = .02) of the infarct/peri-infarct region at 4 weeks after MI.
CDC therapy enhanced LVEF by improving circumferential strain and decreasing dyssynchrony of the infarct/peri-infarct region at 4 weeks, but not 1 week, after MI. Cellular resynchronization therapy using CDCs may be an alternative to traditional electrical cellular resynchronization therapy in post-MI dyssynchrony.
The focus of this review is on translational studies utilizing large-animal models and clinical studies that provide fundamental insight into cellular and extracellular pathways contributing to post-myocardial infarction (MI) left ventricle (LV) remodeling. Specifically, both large-animal and clinical studies have examined the potential role of endogenous and exogenous stem cells to alter the course of LV remodeling. Interestingly, there have been alterations in LV remodeling with stem cell treatment despite a lack of long-term cell engraftment. The translation of the full potential of stem cell treatments to clinical studies has yet to be realized. The modulation of proteolytic pathways that contribute to the post-MI remodeling process has also been examined. On the basis of recent large-animal studies, there appears to be a relationship between stem cell treatment post-MI and the modification of proteolytic pathways, generating the hypothesis that stem cells leave an echo effect that moderates LV remodeling.
Bone marrow mesenchymal stromal cell (BMStC) transplantation into the infarcted heart improves left ventricular function and cardiac remodelling. However, it has been suggested that tissue-specific cells may be better for cardiac repair than cells from other sources. The objective of the present work has been the comparison of in vitro and in vivo properties of adult human cardiac stromal cells (CStC) to those of syngeneic BMStC.
Although CStC and BMStC exhibited a similar immunophenotype, their gene, microRNA, and protein expression profiles were remarkably different. Biologically, CStC, compared with BMStC, were less competent in acquiring the adipogenic and osteogenic phenotype but more efficiently expressed cardiovascular markers. When injected into the heart, in rat a model of chronic myocardial infarction, CStC persisted longer within the tissue, migrated into the scar, and differentiated into adult cardiomyocytes better than BMStC.
Our findings demonstrate that although CStC and BMStC share a common stromal phenotype, CStC present cardiovascular-associated features and may represent an important cell source for more efficient cardiac repair.
Introduction
Stem cell therapy
Regeneration of myocardium 28 days after myocardial infarction
Concluding remarks
To study the efficiency of maintaining the reduced tissue environment via pre‐treatment with natural antioxidant resveratrol in stem cell therapy, we pre‐treated male Sprague‐Dawley rats with resveratrol (2.5 mg/kg/day gavaged for 2 weeks). After occlusion of the left anterior descending coronary artery (LAD), adult cardiac stem cells stably expressing EGFP were injected into the border zone of the myocardium. One week after the LAD occlusion, the cardiac reduced environment was confirmed in resveratrol‐treated rat hearts by the enhanced expression of nuclear factor‐E2‐related factor‐2 (Nrf2) and redox effector factor‐1 (Ref‐1). In concert, cardiac functional parameters (left ventricular ejection fraction and fractional shortening) were significantly improved. The improvement of cardiac function was accompanied by the enhanced stem cell survival and proliferation as demonstrated by the expression of cell proliferation marker Ki67 and differentiation of stem cells towards the regeneration of the myocardium as demonstrated by the enhanced expression of EGFP 28 days after LAD occlusion in the resveratrol‐treated hearts. Our results demonstrate that resveratrol maintained a reduced tissue environment by overexpressing Nrf2 and Ref‐1 in rats resulting in an enhancement of the cardiac regeneration of the adult cardiac stem cells as demonstrated by increased cell survival and differentiation leading to cardiac function.
Chronic heart rate reduction (HRR) therapy following myocardial infarction, using either the pure HRR agent ivabradine or the beta-blocker atenolol, has been shown to preserve maximal coronary perfusion, via reduction of perivascular collagen and a decrease in renin-angiotensin system activation. In addition ivabradine, but not atenolol, treatment attenuated the decline in ejection fraction and decreased left ventricular wall stress. In this study, we tested the hypothesis that cell survival within the infarct region was enhanced by these two pharmacological agents. Four weeks after ligating the left anterior descending coronary artery, the percentage of the LV that contained the infarct was similar in the untreated (MI) rats and those chronically treated with ivabradine (MI + IVA) or atenolol (MI + ATEN). However, the mean thickness (mm) of the ventricular wall containing the scar was significantly greater in the MI + IVA, 1.54 (P < or = 0.01) and the MI + ATEN 1.32, compared to 1.1 in the MI group, due to a 2-fold greater area of surviving cardiomyocytes (P < or = 0.01) in the treated rats compared to the untreated group. Regions of cell survival were usually in the subepicardium, with cardiomyocytes surrounding veins or venules. However, some hearts displayed surviving cells along the endocardium. These data suggest that HRR by either ivabradine or atenolol facilitates a more favorable O2 microenvironment via improved venous flow and decreased O2 demand. We conclude that chronic HRR by these agents may serve to limit infarct expansion and wall thinning and may serve to reduce the potential for ventricular rupture.
From 4 to 5 April 2008, international experts met for the second time in Tubingen, Germany, to present and discuss the latest proceedings in research on non-hematopoietic stem cells (NHSC). This report presents issues of basic research including characterization, isolation, good manufacturing practice (GMP)-like production and imaging as well as clinical applications focusing on the regenerative and immunomodulatory capacities of NHSC.
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