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Secretion of G-CSF by MSCs. Levels of G-CSF were assayed after treating cells from different donors (n = 3 experiments/donor) with different concentrations of TNF-α (a) and IFN-γ (b) for 24 h, which had no significant effect on the secretion of G-CSF. Treatments with IL-1α (c) and IL-1β (d) for 24 h induced a strong increase in the secretion of G-CSF. The youngest donor presented the highest increase in secretion, as measured by ELISA (*p < 0.05, **p < 0.01, ***p < 0.001 vs untreated from same donor), despite all donors showing an increase in the secreted levels of G-CSF. The increased secretion of G-CSF in response to priming with IL-1α (e) and IL-1β (f) is completely inhibited when IL1-Ra (100 μg/ml) is added 10 min prior to the treatment. *p < 0.05, ***p < 0.001 vs untreated; ++ p < 0.05, +++ p < 0.001 IL-1Ra condition vs cytokine treatment only. Cells from donor 3 were used in the inhibition experiment. G-CSF granulocyte-colony stimulating factor, IFN-γ interferon gamma, IL interleukin, IL-1Ra interleukin-1 receptor antagonist, nd not detectable, TNF-α tumour necrosis factor alpha
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Background
Inflammation is a key contributor to central nervous system (CNS) injury such as stroke, and is a major target for therapeutic intervention. Effective treatments for CNS injuries are limited and applicable to only a minority of patients. Stem cell-based therapies are increasingly considered for the treatment of CNS disease, because they...
Citations
... 172 Conversely, in the case of high levels of inflammation, MSCs can inhibit the activation and proliferation of T lymphocytes. 173 In addition to the above-mentioned inflammatory factors, alarmins like IL-1α, 174 IL-33, 175 and heat shock proteins 176 all have an impact on MSC biology and show a potent ability in tissue repair and showed positive promoting effects on MSCs. MSCs also produce a large number of cytokines such as IDO, PGE2, and TGF-β, which are directly involved in the activation of Treg cells. ...
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.
... In addition, recent studies have provided important mechanistic insights of BM-MSC biology in the vicinity of inflammation and its ability to decrease the intra cellular levels of IL1β, and TNFα as well as their levels in macrophages thus reducing M1 macrophages activation and consequently iNOS expression which have essential roles in mediating DCM (Jin et al. 2022). This priming effect has been demonstrated in healing of wounds, liver tissues, corneal epithelium, and nervous tissue, while not yet demonstrated in cardiac tissues (Redondo-Castro et al. 2017;Vander Beken et al. 2019;Harrell et al. 2020). Furthermore, preconditioning of BM-MSCs by IL1β selectively promotes their migration to various target organs and improved stem cell induced M2 polarization and M1 reduction (Saparov et al. 2016;Philipp et al. 2018;Jesmin et al. 2006;Wang et al. 2022). ...
Diabetic cardiomyopathy (DCM) is a serious common complication of diabetes. Unfortunately, there is no satisfied treatment for those patients and more studies are in critical need to cure them. Therefore, we aimed to carry out our current research to explore the role of two novel therapeutic approaches: one a biological drug aimed to block inflammatory signaling of the IL 1beta (IL1β) axis, namely, anakinra; the other is provision of anti-inflammatory regenerative stem cells. Wistar male rats were allocated into four groups: control group: type 2 diabetes mellitus (DM) induced by 6-week high-fat diet (HFD) followed by a single-dose streptozotocin (STZ) 35 mg/kg i.p., then rats were allocated into: DM: untreated; DM BM-MSCs: received a single dose of BM-MSCs (1 × 10⁶ cell/rat) into rat tail vein; DM-Anak received Anak 0.5 μg/kg/day i.p. for 2 weeks. Both therapeutic approaches improved cardiac performance, fibrosis, and hypertrophy. In addition, blood glucose and insulin resistance decreased, while the antioxidant parameter, nuclear factor erythroid 2–related factor 2 (Nrf2) and interleukin 10 (IL10), and anti-inflammatory agent increased. Furthermore, there is a significant reduction in tumor necrosis factor alpha (TNFα), IL1β, caspase1, macrophage marker CD 11b, inducible nitric oxide synthase (iNOS), and T-cell marker CD 8. Both Anak and BM-MSCs effectively ameliorated inflammatory markers and cardiac performance as compared to non-treated diabetics. Improvement is mostly due to anti-inflammatory, antioxidant, anti-apoptotic properties, and regulation of TNFα/IL1β/caspase1 and Nrf2/IL10 pathways.
... Curiously, this effect was not observed in cells pretreated with 3-MA (autophagy inhibitor) [20]. In addition, Redondo-Castro and colleagues (2017) also observed that preconditioning human BM-MSCs with inflammatory factors (IL-1α, IL-1β, TNF-α, and INF-γ) increased the release of anti-inflammatory factors by BM-MSCs [39]. Moreover, the addition of conditioned medium from BM-MSCs preconditioned with IL-1 to an immortalized microglial cell line (BV2) stimulated with LPS reduced the release of pro-inflammatory factors and increased anti-inflammatory IL-10 secretion, promoting a less reactive state in microglial cells [39]. ...
... In addition, Redondo-Castro and colleagues (2017) also observed that preconditioning human BM-MSCs with inflammatory factors (IL-1α, IL-1β, TNF-α, and INF-γ) increased the release of anti-inflammatory factors by BM-MSCs [39]. Moreover, the addition of conditioned medium from BM-MSCs preconditioned with IL-1 to an immortalized microglial cell line (BV2) stimulated with LPS reduced the release of pro-inflammatory factors and increased anti-inflammatory IL-10 secretion, promoting a less reactive state in microglial cells [39]. Another studied strategy was the pretreatment of UC-MSCs with IFN-γ. ...
This systematic review aims to gather evidence on the mechanisms triggered by diverse preconditioning strategies for mesenchymal stem cells (MSCs) and their impact on their potential to treat ischemic and traumatic injuries affecting the nervous system. The 52 studies included in this review report nine different types of preconditioning, namely, manipulation of oxygen pressure, exposure to chemical substances, lesion mediators or inflammatory factors, usage of ultrasound, magnetic fields or biomechanical forces, and culture in scaffolds or 3D cultures. All these preconditioning strategies were reported to interfere with cellular pathways that influence MSCs’ survival and migration, alter MSCs’ phenotype, and modulate the secretome and proteome of these cells, among others. The effects on MSCs’ phenotype and characteristics influenced MSCs’ performance in models of injury, namely by increasing the homing and integration of the cells in the lesioned area and inducing the secretion of growth factors and cytokines. The administration of preconditioned MSCs promoted tissue regeneration, reduced neuroinflammation, and increased angiogenesis and myelinization in rodent models of stroke, traumatic brain injury, and spinal cord injury. These effects were also translated into improved cognitive and motor functions, suggesting an increased therapeutic potential of MSCs after preconditioning. Importantly, none of the studies reported adverse effects or less therapeutic potential with these strategies. Overall, we can conclude that all the preconditioning strategies included in this review can stimulate pathways that relate to the therapeutic effects of MSCs. Thus, it would be interesting to explore whether combining different preconditioning strategies can further boost the reparative effects of MSCs, solving some limitations of MSCs’ therapy, namely donor-associated variability.
... Priming of MSCs can be accomplished with bioactive substances such as cytokines, growth factors, hormones, and vitamins, along with hypoxia, biomaterials, pharmacological agents, and chemical factors to augment their therapeutic potential by modulating their secretory behavior [10][11][12]. Prior investigations have explored the beneficial effects of MSC priming through various biofactors, including IFN-γ, TNF-α, IL-1α-β, FGF-2, LPS, IL-17A, TLR3 and IGF-1 [10,11,[13][14][15][16][17]. The results of these studies indicate promising enhancements in the treatment profiles of MSCs for a variety of diseases. ...
... The therapeutic effectiveness of MSCs was enhanced by priming them with biofactors and chemical factors, which controlled their secretion [10,12] (Table 2). Previous works have investigated the potential roles of MSC priming by a variety of biofactors, such as IFN-γ [13,31,32], TNF-α [14,33], IL-1α-β [15,34], FGF-2 [16], LPS [35], IL-17A [17], TLR3 [36], IGF-1 [37,38], IL-6 [39], IL-8 [40,41], IL-3 [42,43], IL-25 [44], even gaseous signal molecule nitric oxide [45][46][47]. Their findings showed promise in enhancing MSC treatment profiles for various diseases. ...
Mesenchymal stem cells (MSCs) have gained substantial attention in regenerative medicine due to their multi-lineage differentiation potential and immunomodulatory capabilities. MSCs have demonstrated therapeutic promise in numerous preclinical and clinical studies across a variety of diseases, including neurodegenerative disorders, cardiovascular diseases, and autoimmune conditions. Recently, priming MSCs has emerged as a novel strategy to enhance their therapeutic efficacy by preconditioning them for optimal survival and function in challenging in vivo environments. This study presented a comprehensive bibliometric analysis of research activity in the field of priming mesenchymal stem cells (MSCs) from 2003 to 2023. Utilizing a dataset of 585 documents, we explored research trends, leading authors and countries, productive journals, and frequently used keywords. We also explored priming strategies to augment the therapeutic efficacy of MSCs. Our findings show increasing research productivity with a peak in 2019, identified the United States as the leading contributor, and highlighted WANG JA as the most prolific author. The most published journal was Stem Cell Research & Therapy. Keyword analysis revealed core research areas emerging hotspots, while coword and cited sources visualizations elucidated the conceptual framework and key information sources. Further studies are crucial to advance the translation of primed MSCs from bench to bedside, potentially revolutionizing the landscape of regenerative medicine.
... Interleukins also impact the immunomodulatory ability of MSCs. Preconditioning of MSCs with IL-1, significantly enhances their immune-regulatory function, and induces a reduction in the secretion of inflammatory mediators (REDONDO-CASTRO et al., 2017;WONG et al., 2023). ...
The jawbone, a unique structure in the human body, undergoes faster remodeling than other bones due to the presence of stem cells and its distinct immune microenvironment. Long-term exposure of jawbones to an oral environment rich in microbes results in a complex immune balance, as shown by the higher proportion of activated macrophage in the jaw. Stem cells derived from the jawbone have a higher propensity to differentiate into osteoblasts than those derived from other bones. The unique immune microenvironment of the jaw also promotes osteogenic differentiation of jaw stem cells. Here, we summarize the various types of stem cells and immune cells involved in jawbone reconstruction. We describe the mechanism relationship between immune cells and stem cells, including through the production of inflammatory bodies, secretion of cytokines, activation of signaling pathways, etc. In addition, we also comb out cellular interaction of immune cells and stem cells within the jaw under jaw development, homeostasis maintenance and pathological conditions. This review aims to eclucidate the uniqueness of jawbone in the context of stem cell within immune microenvironment, hopefully advancing clinical regeneration of the jawbone.
... Careful experimental design and clinical trials of stem cell therapies are likely to usher in a new era of treatment for stroke by promoting neurogenesis, rebuilding neural networks, and boosting axonal growth and synaptogenesis [1,99]. Additionally, amelioration and inhibition of one or more of the earlier mentioned overarching components of IS constitute the mechanism of neuroprotection and neurorepair properties of SCT [100][101][102] (Table 1). Neural repair is an alternative therapy to neuroprotection. ...
The majority of approved therapies for many diseases are developed to target their underlying pathophysiology. Understanding disease pathophysiology has thus proven vital to the successful development of clinically useful medications. Stroke is generally accepted as the leading cause of adult disability globally and ischemic stroke accounts for the most common form of the two main stroke types. Despite its health and socioeconomic burden, there is still minimal availability of effective pharmacological therapies for its treatment. In this review, we take an in-depth look at the etiology and pathophysiology of ischemic stroke, including molecular and cellular changes. This is followed by a highlight of drugs, cellular therapies, and complementary medicines that are approved or undergoing clinical trials for the treatment and management of ischemic stroke. We also identify unexplored potential targets in stroke pathogenesis that can be exploited to increase the pool of effective anti-stroke and neuroprotective agents through de novo drug development and drug repurposing.
... Although neuron expresses higher level of IL-1R1 compared with microglia, IL-1R1 on both cells were involved in the neuroinflammation and neurodegenerative diseases [40][41][42][43][44][45]. ...
Microglia regulate synaptic function in various ways, including the microglial displacement of the surrounding GABAergic synapses, which provides important neuroprotection from certain diseases. However, the physiological role and underlying mechanisms of microglial synaptic displacement remain unclear. In this study, we observed that microglia exhibited heterogeneity during the displacement of GABAergic synapses surrounding neuronal soma in different cortical regions under physiological conditions. Through three-dimensional reconstruction, in vitro co-culture, two-photon calcium imaging, and local field potentials recording, we found that IL-1β negatively modulated microglial synaptic displacement to coordinate regional heterogeneity in the motor cortex, which impacted the homeostasis of the neural network and improved motor learning ability. We used the Cre-Loxp system and found that IL-1R1 on glutamatergic neurons, rather than that on microglia or GABAergic neurons, mediated the negative effect of IL-1β on synaptic displacement. This study demonstrates that IL-1β is critical for the regional heterogeneity of synaptic displacement by coordinating different actions of neurons and microglia via IL-1R1, which impacts both neural network homeostasis and motor learning ability. It provides a theoretical basis for elucidating the physiological role and mechanism of microglial displacement of GABAergic synapses.
... 25,26 The human umbilical cord MSCs (hUC-MSCs) are a promising candidate for cell-based therapy owing to its excellent advantages in regulating innate and adaptive immune systems to improve inflammation. 27,28 The immunomodulatory and anti-inflammatory capabilities of hUC-MSCs have also been recognized to improve neurological disorders, including LPS-induced neuroinflammation and brain injury, 29 CUMS-induced depression, and stress-related neurodegenerative disorders. 30,31 Numerous studies have revealed that the anti-inflammatory action of hUC-MSCs is accomplished through inhibiting the expression of inflammatory factors. ...
Background
Inflammation and oxidative stress are considered crucial to the pathogenesis of depression. Rat models of depression can be created by combined treatments of chronic unpredictable mild stress (CUMS) and lipopolysaccharide (LPS). Behaviors associated with depression could be improved by treatment with mesenchymal stem cells (MSCs) owing to immunomodulatory functions of the cells. Therapeutic potentials of the MSCs to reverse pro‐inflammatory cytokines, proteins, and metabolites were identified by transcriptomic, proteomic, and metabolomic analysis, respectively.
Methods
A depression model was established in male SD rats by 2 weeks of CUMS combined with LPS. The models were verified by behavioral tests, namely SPT, OFT, EPM, and qRT‐PCR for pro‐inflammatory cytokines. Such depressed rats were administered human umbilical cord MSCs (hUC‐MSCs) via the tail vein once a week for 2 and 4 weeks. The homing capacity was confirmed by detection of the fluorescent dye on day 7 after the hUC‐MSCs were labeled with CM‐Dil and administered. The expression of GFAP in astrocytes serves as a biomarker of CNS disorders and IBA1 in microglia serves as a marker of microglia activation were detected by immunohistochemistry at 2 and 4 weeks after final administration of hUC‐MSCs. At the same time, transcriptomics of rat hippocampal tissue, proteomic and metabolomic analysis of the serum from the normal, depressed, and treated rats were also compared.
Results
Reliable models of rat depression were successfully induced by treatments of CUMS combined with LPS. Rat depression behaviors, pro‐inflammatory cytokines, and morphological disorders of the hippocampus associated with depression were reversed in 4 weeks by hUC‐MSC treatment. hUC‐MSCs could reach the hippocampus CA1 region through the blood circulation on day 7 after administration owing to the disruption of blood brain barrier (BBB) by microglial activation from depression. Differentiations of whole‐genome expression, protein, and metabolite profiles between the normal and depression‐modeled rats, which were analyzed by transcriptomic, proteomics, and metabolomics, further verified the high association with depression behaviors.
Conclusions
Rat depression can be reversed or recovered by treatment with hUC‐MSCs.
... This cytokine also enhanced homing following intramuscular administration of the activated MSC and promoted tissue repair through the release of pro-angiogenic cytokines [113]. In 2017, Redondo-Castro and colleagues reported an increase in the production of the trophic factor granulocyte colony-stimulating factor (G-CSF) and anti-inflammatory cytokine IL-10 by BM-MSCs following IL-1 activation [114]. Similarly, IL-1β-priming of BM-MSCs activated the genes responsible for cell survival, migration, and adhesion. ...
... The authors also observed an increase in the production of chemokines, growth factors, MMPs (1 and 3) and adhesion molecule ICAM-1 [115]. Secretome from IL-1-primed MSCs were also able to significantly reduce infarct volume in MCAO model of stroke in mice [114,116]. ...
Promising preclinical stroke research has not yielded meaningful and significant success in clinical trials. This lack of success has prompted the need for refinement of preclinical studies with the intent to optimize the chances of clinical success. Regenerative medicine, especially using mesenchymal stem/stromal cells (MSCs), has gained popularity in the last decade for treating many disorders, including central nervous system (CNS), such as stroke. In addition to less stringent ethical constraints, the ample availability of MSCs also makes them an attractive alternative to totipotent and other pluripotent stem cells. The ability of MSCs to differentiate into neurons and other brain parenchymal and immune cells makes them a promising therapy for stroke. However, these cells also have some drawbacks that, if not addressed, will render MSCs unfit for treating ischaemic stroke. In this review, we highlighted the molecular and cellular changes that occur following an ischaemic stroke (IS) incidence and discussed the physiological properties of MSCs suitable for tackling these changes. We also went further to discuss the major drawbacks of utilizing MSCs in IS and how adequate priming using both hypoxia and interleukin-1 can optimize the beneficial properties of MSCs while eliminating these drawbacks.
... G-CSF is secreted mainly by monocytes and macrophages, and also to some degree by MSCs. 71,72 Both could be responsible for the increased levels of G-CSF in the SF, as an increase was observed over time in both groups, but more so in the treated group. MSCs are known to recruit resident progenitor cells or stem cells potentially through G-CSF secretion 73,[74][75][76] and in vivo studies have shown improved healing of cartilage defects in the presence of G-CSF. ...
Objective
Integrin α10β1-selected mesenchymal stem cells (integrin α10-MSCs) have previously shown potential in treating cartilage damage and osteoarthritis (OA) in vitro and in animal models in vivo. The aim of this study was to further investigate disease-modifying effects of integrin α10-MSCs.
Design
OA was surgically induced in 17 horses. Eighteen days after surgery, horses received 2 × 10 ⁷ integrin α10-MSCs intra-articularly or were left untreated. Lameness and response to carpal flexion was assessed weekly along with synovial fluid (SF) analysis. On day 52 after treatment, horses were euthanized, and carpi were evaluated by computed tomography (CT), MRI, histology, and for macroscopic pathology and integrin α10-MSCs were traced in the joint tissues.
Results
Lameness and response to carpal flexion significantly improved over time following integrin α10-MSC treatment. Treated horses had milder macroscopic cartilage pathology and lower cartilage histology scores than the untreated group. Prostaglandin E2 and interleukin-10 increased in the SF after integrin α10-MSC injection. Integrin α10-MSCs were found in SF from treated horses up to day 17 after treatment, and in the articular cartilage and subchondral bone from 5 of 8 treated horses after euthanasia at 52 days after treatment. The integrin α10-MSC injection did not cause joint flare.
Conclusion
This study demonstrates that intra-articular (IA) injection of integrin α10-MSCs appears to be safe, alleviate pathological changes in the joint, and improve joint function in an equine post-traumatic osteoarthritis (PTOA) model. The results suggest that integrin α10-MSCs hold promise as a disease-modifying osteoarthritis drug (DMOAD).
