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bFGF-PLGA promotes the expression and secretion of elastin and collagen in differentiated BMSCs. BMSCs with or without elastin transduction were differentiated in the presence of either bFGF or bFGF-PLGA for 7 days. Levels of mRNA a and protein b, and concentration in medium c of elastin and collagen were examined by RT-PCR, western blot, and ELISA assays. Values are mean ± SD. *P <0.05 vs BMSC + bFGF and BMSC + bFGF-PLGA. #P <0.05 vs elastin-BMSC + bFGF. bFGF basic fibroblast growth factor, BMSC bone marrow-derived mesenchymal stem cell, PLGA poly(lactic-co-glycolic acid)
Source publication
Background
Pelvic floor dysfunction (PFD) is a group of clinical conditions including stress urinary incontinence (SUI) and pelvic organ prolapse (POP). The abnormality of collagen and elastin metabolism in pelvic connective tissues is implicated in SUI and POP.
Methods
To reconstitute the connective tissues with normal distribution of collagen an...
Contexts in source publication
Context 1
... of elastin and collagen into cul- ture media using ELISA. In both RT-PCR and western blotting analysis, significantly increased expressions of elastin and collagen were observed in both groups of elastin-expressing BMSCs, compared with those from BMSCs not expressing elastin, regardless of incubation with either free bFGF or bFGF-loaded PLGA (Fig. 4a, b). In addition, administration of bFGF-loaded PLGA NPs to the elastin-expressing BMSCs further upregulated the expression of elastin and collagen, compared with the same cells incubated with free bFGF. Consistently, co- culture of elastin-expressing BMSCs with bFGF-loaded PLGA exhibited a higher extent of stimulation on the se- cretion ...
Context 2
... BMSCs further upregulated the expression of elastin and collagen, compared with the same cells incubated with free bFGF. Consistently, co- culture of elastin-expressing BMSCs with bFGF-loaded PLGA exhibited a higher extent of stimulation on the se- cretion of elastin and collagen, compared with the same cells cocultured with free bFGF (Fig. 4c). These results indicated that overexpressing elastin in the BMSCs not only upregulated the expression of elastin itself, but also stimulated the intracellular production of collagen as well as extracellular secretion of both elastin and ...
Similar publications
Background
Pelvic floor dysfunction (PFD) is a condition affecting many women worldwide, with symptoms including stress urinary incontinence (SUI) and pelvic organ prolapse (POP). We have previously demonstrated stable elastin-expressing bone marrow-derived mesenchymal stem cells (BMSCs) attenuated PFD in rats, and aim to further study the effect o...
Citations
... The rat model of vaginal distention, previously documented,19,20 was employed to simulate childbirth injury. In brief, a Foley balloon filledwith 2.5-3.0 mL water was introduced into the rat vagina on Day 0, connected to a pressure transducer to exert pressure (approximately 0.15 kg) on the pelvic floor tissue. ...
Exosomes derived from bone marrow‐derived mesenchymal stem cells (BMSCs) can alleviate the symptoms of pelvic floor dysfunction (PFD) in rats. However, the potential therapeutical effects of exosomes derived from BMSCs treated with tumour necrosis factor (TNF)‐α on the symptoms of PFD in rats are unknown. Exosomes extracted from BMSCs treated with or without TNF‐α were applied to treat PFD rats. Our findings revealed a significant elevation in interleukin (IL)‐6 and TNF‐α, and matrix metalloproteinase‐2 (MMP2) levels in the vaginal wall tissues of patients with pelvic organ prolapse (POP) compared with the control group. Daily administration of exosomes derived from BMSCs, treated either with or without TNF‐α (referred to as Exo and TNF‐Exo), resulted in increased void volume and bladder void pressure, along with reduced peak bladder pressure and leak point pressure in PFD rats. Notably, TNF‐Exo treatment demonstrated superior efficacy in restoring void volume, bladder void pressure and the mentioned parameters compared with Exo treatment. Importantly, TNF‐Exo exhibited greater potency than Exo in restoring the levels of multiple proteins (Elastin, Collagen I, Collagen III, IL‐6, TNF‐α and MMP2) in the anterior vaginal walls of PFD rats. The application of exosomes derived from TNF‐α‐treated BMSCs holds promise as a novel therapeutic approach for treating PFD.
... A promising strategy is tissue engineering, which uses the combination of cells, biomaterials, and biomechanical and biochemical cues to regenerate tissues. 6 Multiple cell types have been investigated regarding pelvic tissue regeneration, such as fibroblasts, 7 bone marrow-derived stem cells, 8 adipose-derived stem cells (ADSCs), 9 endometrial mesenchymal stem cells (MSCs), 10,11 and skeletal muscle-derived stem cells. 12 Biomaterials such as polycaprolactone, 13 polylactic acid, 14,15 and polylactic-co-glycolic acid 9 have shown promise in triggering a regenerative pelvic tissue response. ...
... Of Jin et al., only the in vitro section was included in the systematic review as the in vivo experiments did not include an appropriate control. 8 Basic fibroblast growth factor (bFGF) is the most reported growth factor (six studies), followed by connective tissue growth factor (CTGF) (two studies) and epidermal growth factor (EGF) (one study). ...
Surgical outcomes of pelvic organ prolapse surgery are poor, resulting in a 20% recurrence risk. Following the hypothesis that impaired wound healing is the main determinant of recurrent pelvic organ prolapse, growth factors have the potential to promote wound healing and may improve surgical outcomes. Here, we systematically reviewed the effect of growth factors on vaginal wound healing in both in vitro and animal studies. For each independent comparison, the standardized mean difference and 95% CI were calculated using the Hedges' g correction. Of the 3,858 retrieved studies, seven studies were included of which six were included in meta-analysis (three in vitro studies and four in vivo studies). In vitro, basic fibroblast growth factor promotes proliferation, differentiation, and collagen types I and III production. Epidermal growth factor stimulates proliferation and connective tissue growth factor promotes Tenascin-C expression. These effects, however are less pronounced in vivo; only basic fibroblast growth factor slightly promotes collagen production. The review shows that growth factors, particularly basic fibroblast growth factor, are able to promote vaginal wound healing in vitro. The uncertain in vivo findings suggest that pre-clinical models should be improved. The ultimate goal is to develop effective growth factor-supplemented therapies that improve surgical outcomes for pelvic organ prolapse.
... For example, the miR-29 family of miRs downregulates the expression of elastin (Sudo et al., 2015;Zhang et al., 2015). More precisely, miR-29a-3p downregulates the endogenous expression of elastin in BMSCs (Jin et al., 2016a). The inhibition of miR-29a-3p in BMSCs markedly increases the expression and secretion of elastin, consequently enhancing the therapeutic effect of BMSCs following injection into PFD rats. ...
Stress urinary incontinence (SUI) adversely affects the quality of life of patients, while the currently available surgical and non-surgical therapies are not effective in all patients. Application of mesenchymal stem cells (MSCs) for regaining the ability to control urination has attracted interest. Herein, we reviewed the literature and analyzed recent studies on MSC-based therapies for SUI, summarized recent treatment strategies and their underlying mechanisms of action, while assessing their safety, effectiveness, and prospects. In addition, we traced and sorted the root literature and, from an experimental design perspective, divided the obtained results into four categories namely single MSC type therapy for SUI, MSC-based combination therapy for SUI, treatment of SUI with the MSC secretome, and other factors influencing MSC therapy. Although evidence demonstrates that the treatment strategies are safe and effective, the underlying mechanisms of action remain nebulous, hence more clinical trials are warranted. Therefore, future studies should focus on designing clinical trials of MSC-based therapies to determine the indications for treatment, cell dosage, appropriate surgical strategies, and optimal cell sources, and develop clinically relevant animal models to elucidate the molecular mechanisms underlying stem cell therapies improvement of SUI.
... It has been proposed that these cells could function as natural tissue restorers and therefore can be used to restore various cell populations after transplantation. Not only their differentiation potential makes them an ideal candidate for this purpose, but several trophic properties that promote regeneration in the surrounding tissue, including 1) secretion action [17]- [22], 2) migration capacity [23]- [33] and 3) immunomodulatory action [12] [34]. ...
Mesenchymal stem cells (MSCs) are self-renewing cells found in almost all postnatal organs and tissues in the perivascular region. These cells have a high capacity for mesodermal differentiation; however, numerous studies have shown that MSCs can also differentiate into cells of endodermal and ectodermal lineages. Due to this multilineage differentiation capacity, these cells could function as restoratives of various cell populations after transplantation. However, not only their differentiation potential makes them ideal candidates for this, but also a series of trophic properties that promote regeneration in the surrounding tissue, such as their migratory capacity, secretory and immunomodulatory actions. This review analyzes several MSC transplantation trials to treat neurological diseases such as demyelinating injury, spinal cord injury, paraplegia, Parkinson's disease, cochlear injury, and Alzheimer's disease. These cells could facilitate functional recovery in multiple models of neurodegenerative diseases and nervous system injuries by using their trophic capacities, reducing inflammation in the injured area, reducing apoptosis, and enhancing endogenous neurogenesis through the secretion of bioactive factors. Furthermore, since cells derived from patients have demonstrated disease-associated differences in various brain diseases, these cells represent an excellent candidate for the study of these diseases, functioning as "a window to the brain."
... POP affects people's quality of life because of its Genes 2022, 13, 829 2 of 13 high operation cost [3], many postoperative complications [3,4], symptoms affecting the quality of life [5,6], unsatisfactory conservative treatment effect [7][8][9], and so on. Among the existing studies, there are few basic studies related to the pathological process of POP, such as cell behavior [10], histological characteristics [11], protein expression changes [12,13] and cell therapy [14]. Mitofusin 2 (Mfn2), also known as the hyperplasia suppression gene (HSG), mediates mitochondrial fusion and signal transduction, and its abnormal expression affects the process of aging [15,16]. ...
... Compared with traditional gene regulation methods, stem cells are safer and more conducive to clinical transformation. There have been preliminary explorations of the treatment of POP using stem cells [14,25], but these studies focused more on the combination of stem cells and biodegradable scaffolds, and there are few studies on the targeted regulation of pathogenic genes at the stem cell level, especially regarding the treatment of POP after the regulation of stem cell Mfn2 expression. ...
... The rats were randomly divided into the POP (n = 48) and non-pelvic organ prolapse (NPOP, n = 48) groups after entering the animal center. As POP is a disease associated with middle and old age, all of the rats were castrated to mimic the hormone levels in POP patients [14]. In brief, after anesthesia with intraperitoneally administered ketamine (120 mg/kg), a longitudinal incision was made 0.5-1 cm from both sides the midline of the back, located roughly 0.5-1 cm downward at the angle between the costal arch and the spinal edge of the rat. ...
Background:
The relationship between pelvic organ prolapse (POP), an aging-related disease, and the senescence-related protein mitofusin 2 (Mfn2) has rarely been studied. The aim of the present study was to explore the therapeutic effects of the downregulation of Mfn2 expression by stem cells on POP through animal experiments.
Methods:
First, a rat POP model was constructed by ovariectomy and traction. The rats in the non-pelvic organ prolapse (NPOP) and POP groups were divided into four groups for negative controls (N1-N4, N1: NPOP-normal saline; N2: NPOP-untransfected stem cells; N3: NPOP-short hairpin negative control (NPOP-sh-NC); N4: NPOP-short hairpin-Mfn2 (NPOP-sh-Mfn2)), and four groups for prolapse (P1-P4, P1: POP-normal saline; P2: POP-untransfected stem cells; P3: POP-sh-NC; P4: POP-sh-Mfn2), respectively. Stem cells were then cultured and isolated. The expression of Mfn2 was inhibited by lentivirus transfection, and the stem cells were injected into the uterosacral ligament of the rats in each group. The expression levels of Mfn2 and procollagen 1A1/1A2/3A1 in the uterosacral ligaments of the rats were observed at 0, 7, 14, and 21 days after injection.
Results:
Compared to the rats in the NPOP group, the POP rats had significant prolapse. The Mfn2 expression in the uterosacral ligaments of the POP rats was significantly increased (p < 0.05, all), and the expression of procollagen 1A1/1A2/3A1 was significantly decreased (p < 0.001, all). The POP rat model maintained the same trend after 21 days (without stem cell injection). At day 14, compared to the rats in the N1 group, the Mfn2 expression in the uterosacral ligament of the rats in the N4 group was significantly decreased (p < 0.05, all), and the expression of procollagens was significantly increased (p < 0.05, all). Similarly, compared to the rats in the P1 group, the Mfn2 expression in the uterosacral ligament of the rats in the P4 group was significantly decreased (p < 0.05, all), and the expression of procollagens was significantly increased (p < 0.05, all). Similarly, on day 21, the Mfn2 mRNA and protein expression in the uterosacral ligament of the POP and NPOP rats was significantly decreased (p < 0.05, all), and the expression of procollagens was significantly increased (p < 0.05, all) in the rats in the sh-Mfn2 group (N4, P4) compared to the rats in the saline group (N1, P1).
Conclusions:
The downregulation of Mfn2 expression by stem cells decreased the expression of Mfn2 and increased the expression of procollagen1A1/1A2/3A1 in the uterosacral ligament of the POP rats; this effect was significant 14-21 days after the injection. Thus, Mfn2 may be a new target for POP control.
... It has been proposed that these cells could function as natural tissue restorers and therefore can be used to restore various cell populations after transplantation. Not only their differentiation potential makes them an ideal candidate for this purpose, but several trophic properties that promote regeneration in the surrounding tissue, including 1) secretion action [17]- [22], 2) migration capacity [23]- [33] and 3) immunomodulatory action [12] [34]. ...
Mesenchymal stem cells (MSCs) are self-renewing cells found in almost all postnatal organs and tissues in the perivascular region. These cells present multiple characteristics that make them candidates to be applied in cell therapy for neurodegenerative diseases, such as their secretory action, migration to the lesion area, and immunomodulatory potential. These cells have a high capacity for mesodermal differentiation; however, numerous studies have shown that MSCs can also differentiate into neurons. However, despite positive results in multiple trials in which undifferentiated MSCs transplanted into animal models of neurodegenerative diseases, some studies suggest that the therapeutic effects obtained are enhanced by the use of MSCs differentiated towards the neuronal lineage before transplant. In this sense, there are several methods to induce in vitro reprogramming of MSCs towards the neu-ronal lineage, including chemical substances, growth factors, cocultures with neural lineage cells, transfection of genes, miRNAs, etc., and small molecules stand out. Therefore, this article compares multiple experimental tests in which these inducers promote neuronal differentiation of MSCs and identify those methods that originate an optimal neuronal differentiation. The analysis includes the percentage of differentiation, maturation, expression of neuronal markers, functionality, and cell survival considering the intrinsic characteristics of the MSCs used as the tissue of origin and the species from which they were isolated.
... It has been proposed that these cells could function as natural tissue restorers and therefore can be used to restore various cell populations after transplantation. Not only their differentiation potential makes them an ideal candidate for this purpose, but several trophic properties that promote regeneration in the surrounding tissue, including 1) secretion action [17]- [22], 2) migration capacity [23]- [33] and 3) immunomodulatory action [12] [34]. ...
Mesenchymal stem cells (MSCs) are self-renewing cells found in almost all postnatal organs and tissues in the perivascular region. These cells present multiple characteristics that make them candidates to be applied in cell therapy for neurodegenerative diseases, such as their secretory action, migration to the lesion area, and immunomodulatory potential. These cells have a high capacity for mesodermal differentiation; however, numerous studies have shown that MSCs can also differentiate into neurons. However, despite positive results in multiple trials in which undifferentiated MSCs transplanted into animal models of neurodegenerative diseases, some studies suggest that the therapeutic effects obtained are enhanced by the use of MSCs differentiated towards the neuronal lineage before transplant. In this sense, there are several methods to induce in vitro reprogramming of MSCs towards the neu-ronal lineage, including chemical substances, growth factors, cocultures with neural lineage cells, transfection of genes, miRNAs, etc., and small molecules stand out. Therefore, this article compares multiple experimental tests in which these inducers promote neuronal differentiation of MSCs and identify those methods that originate an optimal neuronal differentiation. The analysis includes the percentage of differentiation, maturation, expression of neuronal markers, functionality, and cell survival considering the intrinsic characteristics of the MSCs used as the tissue of origin and the species from which they were isolated.
... This is critical for translating a promising achievement from the laboratory bench to the patient's bedside, and later into a specific treatment of clinical daily routine [50]. Many studies have explored the preclinical and clinical application of stem cells isolated from various origins that have promising results for the treatment of SUI [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] and were summoned up as part of the several reviews articles. Hart and colleagues summarized the mainly preclinical published literature on cell therapy models for the regeneration of smooth and striated urethral sphincter muscles, but also the regeneration of nerves and neuromuscular synapses [47]. ...
Urinary incontinence (UI) is a major problem in health care and more than 400 million people worldwide suffer from involuntary loss of urine. With an increase in the aging population, UI is likely to become even more prominent over the next decades and the economic burden is substantial. Among the different subtypes of UI, stress urinary incontinence (SUI) is the most prevalent and focus of this review. The main underlying causes for SUI are pregnancy and childbirth, accidents with direct trauma to the pelvis or medical treatments that affect the pelvic floor, such as surgery or irradiation. Conservative approaches for the treatment of SUI are pelvic physiotherapy, behavioral and lifestyle changes, and the use of pessaries. Current surgical treatment options include slings, colposuspensions, bulking agents and artificial urinary sphincters. These treatments have limitations with effectiveness and bear the risk of long-term side effects. Furthermore, surgical options do not treat the underlying pathophysiological causes of SUI. Thus, there is an urgent need for alternative treatments, which are effective, minimally invasive and have only a limited risk for adverse effects. Regenerative medicine is an emerging field, focusing on the repair, replacement or regeneration of human tissues and organs using precursor cells and their components. This article critically reviews recent advances in the therapeutic strategies for the management of SUI and outlines future possibilities and challenges.
... In a study, injection of autologous BMSCs into the sub-endometrial zone resulted in endometrial thickness increase and successful menstruation (Queckbörner et al. 2019). Jin et al. (2016) also transduced primary BMSCs with a high-efficiency adenoviral vector expressing elastin and induced them to differentiate into fibroblasts under a certain condition in which bFGF was encapsulated in poly(lactide-co-glycolide-co-caprolactone) polymer nanoparticles (NPs). They reported a successful differentiation of BMSCs into fibroblasts with subsequent production of collagen and elastin after the injection of the aforementioned cells into the pelvis of pelvic floor dysfunctioned (PFD) rats (Jin et al. 2016). ...
... Jin et al. (2016) also transduced primary BMSCs with a high-efficiency adenoviral vector expressing elastin and induced them to differentiate into fibroblasts under a certain condition in which bFGF was encapsulated in poly(lactide-co-glycolide-co-caprolactone) polymer nanoparticles (NPs). They reported a successful differentiation of BMSCs into fibroblasts with subsequent production of collagen and elastin after the injection of the aforementioned cells into the pelvis of pelvic floor dysfunctioned (PFD) rats (Jin et al. 2016). ...
... They found that the electrospinning technique can be applied to develop biodegradable scaffolds with different mechanical properties and potential for extracellular matrix organization towards human-like fascia. Recently, newly developed cell-based approaches opened a promising era in the treatment of POP (Emmerson and Gargett 2016) and different cell types such as mesenchymal stem cells (MSCs) have been proposed (Emmerson and Gargett 2016;Jin et al. 2016). In 2019, Paul et al. successfully bioprinted a plant-based aloe vera-sodium alginate (AV-Alg) hydrogel on a melt electrospinning (MES) poly ε-caprolactone (PCL) mesh, containing endometrial mesenchymal stem/stromal cells (eMSCs); they used this hydrogel for POP therapy in mice. ...
Endometrial-related disorders including Asherman’s syndrome, thin endometrium, pelvic organ prolapse, and cesarean scar pregnancies can be accompanied by different symptoms such as amenorrhea, infertility, abnormal placental implantation and recurrent miscarriage. Different methods have been introduced to overcome these problems such as surgery and hormonal therapy but none of them has shown promising outcomes. On the other hand, the development of novel regenerative therapeutic strategies has opened new avenues for the treatment of endometrial-related deficiencies. In this regard, different types of scaffolds, acellular matrices and also cell therapy with adult or stem cells have been investigated for the treatment of endometrial-related deficiencies. In this paper, we review the current status of cell-based endometrium regeneration using scaffold dependent and scaffold-free methods and future perspectives in this field. Moreover, we discuss the endometrial diseases that can be candidates for cell-based treatments. Also, the cells with the potential for endometrial regeneration are explained.
... Pelvic floor dysfunction (PFD) refers to a group of clinical conditions, which include stress urinary incontinence, pelvic organ prolapse (POP), overactive bladder syndrome, and fecal incontinence [1]. POP entails the descent of one or more of the female pelvic organs (uterus, bladder, rectum) into the vagina [2]. ...
... Cells were then trypsinized, replated, and cultured until passage two. The plastic-adhering fibroblast-like cells obtained from these two passages were regarded as MSCs, and were stored for use in subsequent experiments [1]. ...
Nondegradable transvaginal polypropylene meshes for treating pelvic organ prolapse (POP) are now generally unavailable or banned due to serious adverse events. New tissue engineering approaches combine degradable scaffolds with mesenchymal stem/stromal cells from human endometrium (eMSC). In this study, we investigate effect of microRNA-138 (miR-138) regulation on bone marrow-derived mesenchymal stem cells (BMSCs) and the efficacy of BMSC transplantation therapy in a rat POP model. We first identified FBLN5 as a target of miR-138. miR-138, fibulin-5 (FBLN5), interleukin-1β (IL-1β), and elastin expression in uterosacral ligament of POP patients and controls were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. After isolation and identification, BMSCs were treated to alter their expression of miR-138 or FBLN5. Proliferation of BMSCs was analyzed by CCK-8. After establishing the rat pelvic floor dysfunction (PFD) model, we evaluated efficacy of BMSC injection by applying leak point pressure (LPP) and the conscious cystometry (CMG) tests. miR-138 inhibition resulted in increased viability of BMSCs and elevated their secretion of elastin, while downregulating IL-1β expression. BMSCs with inhibited miR-138 improved LPP and conscious CMG results in vivo. Taken together, miR-138 could be a potential therapeutic target for treating POP in conjunction with tissue engineering.
