Wnt11 preserves mitochondrial membrane potential and protects cardiomyocytes against hypoxia through paracrine signaling

We investigated the effect of Wnt11 on mitochondrial membrane integrity in cardiomyocytes (CMs) and the underlying mechanism of Wnt11-mediated CM protection against hypoxic injury. A rat mesenchymal stem cell (MSC) line that overexpresses Wnt11 (MSC^Wnt11) and a control cell line transduced with empty vector (MSC^Null) were established to determine the cardioprotective role of Wnt11 in response to hypoxia. Mitochondrial membrane integrity in MSC^Wnt11 cells was assessed using fluorescence assays. The role of paracrine signaling mediated by vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), and insulin-like growth factor 1 (IGF-1) in protecting CMs against hypoxia were investigated using cocultures of primary CMs from neonatal rats with conditioned medium (CdM) from MSC^Wnt11. MSC^Wnt11 cells exposed to hypoxia reduced lactate dehydrogenase release from CMs and increased CM survival under hypoxia. In addition, CMs cocultured with CdM that were exposed to hypoxia showed reduced CM apoptosis and necrosis. There was significantly higher VEGF and IGF-1 release in the MSC^Wnt11 group compared with the MSC^Null group, and the addition of anti-VEGF and anti-IGF-1 antibodies inhibited secretion. Moreover, mitochondrial membrane integrity was maintained in the MSC^Wnt11 cell line. In conclusion, overexpression of Wnt11 in MSCs promotes IGF-1 and VEGF release, thereby protecting CMs against hypoxia.     

Molecular Strategy to Reduce In Vivo Collagen Barrier Promotes Entry of NCX1 Positive Inducible Pluripotent Stem Cells (iPSCNCX1+) into Ischemic (or Injured) Myocardium

Objective

The purpose of this study was to assess the effect of collagen composition on engraftment of progenitor cells within infarcted myocardium.

Background

We previously reported that intramyocardial penetration of stem/progenitor cells in epicardial patches was enhanced when collagen was reduced in hearts overexpressing adenylyl cyclase-6 (AC6). In this study we hypothesized an alternative strategy wherein overexpression of microRNA-29b (miR-29b), inhibiting mRNAs that encode cardiac fibroblast proteins involved in fibrosis, would similarly facilitate progenitor cell migration into infarcted rat myocardium.

Methods

In vitro: A tri-cell patch (Tri-P) consisting of cardiac sodium-calcium exchanger-1 (NCX1) positive iPSC (iPSC^NCX1+), endothelial cells (EC), and mouse embryonic fibroblasts (MEF) was created, co-cultured, and seeded on isolated peritoneum. The expression of fibrosis-related genes was analyzed in cardiac fibroblasts (CFb) by qPCR and Western blot. In vivo: Nude rat hearts were administered mimic miRNA-29b (miR-29b), miRNA-29b inhibitor (Anti-29b), or negative mimic (Ctrl) before creation of an ischemically induced regional myocardial infarction (MI). The Tri-P was placed over the infarcted region 7 days later. Angiomyogenesis was analyzed by micro-CT imaging and immunofluorescent staining. Echocardiography was performed weekly.

Results

The number of green fluorescent protein positive (GFP⁺) cells, capillary density, and heart function were significantly increased in hearts overexpressing miR-29b as compared with Ctrl and Anti-29b groups. Conversely, down-regulation of miR-29b with anti-29b in vitro and in vivo induced interstitial fibrosis and cardiac remodeling.

Conclusion

Overexpression of miR-29b significantly reduced scar formation after MI and facilitated iPSC^NCX1+ penetration from the cell patch into the infarcted area, resulting in restoration of heart function after MI.     

Enhanced mesenchymal stem cell survival induced by GATA-4 overexpression is partially mediated by regulation of the miR-15 family

We reported previously that pre-programming mesenchymal stem cells with the GATA-4 gene increases significantly cell survival in an ischemic environment. In this study, we tested whether regulation of microRNAs and their target proteins was associated with the cytoprotective effects of GATA-4.Methods and resultsMesenchymal stem cells were harvested from adult rat bone marrow and transduced with GATA-4 (MSC^GATA-4) using the murine stem cell virus retroviral expression system. Cells transfected with empty vector (MSC^Null) were used as controls. Quantitative real-time PCR data showed that the expression levels of miR-15 family members (miR-15b, miR-16, and miR-195) were significantly down-regulated in MSC^GATA-4. The protein expression of Bcl-w (Bcl-2-like-2), an anti-apoptotic Bcl-2 family protein, was increased in MSC^GATA-4. Hypoxic culture (low glucose and low oxygen) induced the release of lactate dehydrogenase from mesenchymal stem cells and reduced cell survival. Compared to MSC^Null, MSC^GATA-4 showed less lactate dehydrogenase release and greater cell survival following 72 h hypoxia exposure. The mitochondrial membrane potential, detected with the dye JC-1, was well maintained, and mitochondrial membrane permeability, expressed as caspase 3 and 7 activities in response to the ischemic environment was lower in MSC^GATA-4. Moreover, transfection with miR-195 significantly down-regulated Bcl-w expression in mesenchymal stem cells through a binding site in the 3′-UTR of the Bcl-w mRNA and reduced mesenchymal stem cell resistance to ischemic injury.ConclusionsThe overexpression of GATA-4 in mesenchymal stem cells down-regulates miR-15 family members, causing increased resistance to ischemia through the up-regulation of anti-apoptotic proteins in the Bcl-2 family.     

In vivo therapy of myocardial infarction with mesenchymal stem cells modified with prostaglandin I synthase gene improves cardiac performance in mice

AimIntra-myocardial injection of adult bone marrow-derived stem cells (MSC) has recently been proposed as a therapy to repair damaged cardiomyocytes after acute myocardial infarction (AMI). PGI₂ has vasodilatation effects; however, the effects of combining both MSC and PGI₂ therapy on AMI have never been evaluated.Main methodsWe genetically enhanced prostaglandin I synthase (PGIS) gene expression in mouse mesenchymal stem cells (MSC) using lentiviral vector transduction (MSC_PGIS). Mice were subjected to an AMI model and injected (intra-myocardially) with either 5 × 10⁴ MSCs or MSC_PGIS before surgery. Fourteen days post AMI, mice were analyzed with echocardiography, immunohistochemistry, and apoptotic, and traditional tissue assays.Key findingsLenti-PGIS transduction did not change any characteristic of the MSCs. PGIS over-expressed MSCs secreted 6-keto-PGF1α in the culture medium and decreased free radical damage during hypoxia/re-oxygenation and H₂O₂ treatment. Furthermore, splenocyte proliferation was significantly suppressed with MSC_PGIS as compared with MSCs alone. Fourteen days post AMI, echocardiography showed more improvement in cardiac function of the MSC_PGIS group than the MSC alone group, sham-operated group, or artery ligation only group. The histology of MSC_PGIS treated hearts revealed MSCs in the infarcted region and decreased myocardial fibrosis/apoptosis with limited cardiac remodeling. Furthermore, the level of the vascular endothelial growth factor was elevated in the MSC_PGIS group as compared to the other three groups.SignificanceIn summary, our results provide both in vitro and in vivo evidence for the beneficial role of MSC_PGIS in limiting the process of detrimental cardiac remodeling in a mouse AMI model during early stages of the disease.     

Paracrine effect of CXCR4‐overexpressing mesenchymal stem cells on ischemic heart injury

It has been reported that CXCR4‐overexpressing mesenchymal stem cells (MSC^CX4) can repair heart tissue post myocardial infarction. This study aims to investigate the MSCCX4‐derived paracrine cardio‐protective signaling in the presence of myocardial infarction. Mesenchymal stem cells (MSCs) were divided into 3 groups: MSC only, MSC^CX4, and CXCR4 gene‐specific siRNA‐transduced MSC. Mesenchymal stem cells were exposed to hypoxia, and then MSCs‐conditioned culture medium was incubated with neonatal and adult cardiomyocytes, respectively. Cell proliferation–regulating genes were assessed by real‐time polymerase chain reaction (RT‐PCR). In vitro: The number of cardiomyocytes undergoing DNA synthesis, cytokinesis, and mitosis was increased to a greater extent in MSC^CX4 medium‐treated group than control group, while this proproliferative effect was reduced in CXCR4 gene‐specific siRNA‐transduced MSC–treated cells. Accordingly, the maximal enhancement of vascular endothelial growth factor, cyclin 2, and transforming growth factor‐β2 was observed in hypoxia‐exposed MSC^CX4. In vivo: MSCs were labeled with enhanced green fluorescent protein (EGFP) and engrafted into injured myocardium in rats. The number of EGFP and CD31 positive cells in the MSC^CX4 group was significantly increased than other 2 groups, associated with the reduced left ventricular (LV) fibrosis, the increased LV free wall thickness, the enhanced angiogenesis, and the improved contractile function. CXCR4 overexpression can mobilize MSCs into ischemic area, whereby these cells can promoted angiogenesis and alleviate LV remodeling via paracrine signaling mechanism.     

Over-expression of HO-1 on mesenchymal stem cells promotes angiogenesis and improves myocardial function in infarcted myocardium

Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with diverse cytoprotective effects, and reported to have an important role in angiogenesis recently. Here we investigated whether HO-1 transduced by mesenchymal stem cells (MSCs) can induce angiogenic effects in infarcted myocardium. HO-1 was transfected into cultured MSCs using an adenoviral vector. 1 × 10⁶ Ad-HO-1-transfected MSCs (HO-1-MSCs) or Ad-Null-transfected MSCs (Null-MSCs) or PBS was respectively injected into rat hearts intramyocardially at 1 h post-myocardial infarction. The results showed that HO-1-MSCs were able to induce stable expression of HO-1 in vitro and in vivo. The capillary density and expression of angiogenic growth factors, VEGF and FGF2 were significantly enhanced in HO-1-MSCs-treated hearts compared with Null-MSCs-treated and PBS-treated hearts. However, the angiogenic effects of HO-1 were abolished by treating the animals with HO inhibitor, zinc protoporphyrin. The myocardial apoptosis was marked reduced with significantly reduced fibrotic area in HO-1-MSCs-treated hearts; Furthermore, the cardiac function and remodeling were also significantly improved in HO-1-MSCs-treated hearts. Our current findings support the premise that HO-1 transduced by MSCs can induce angiogenic effects and improve heart function after acute myocardial infarction.     

Blocking exosomal miRNA-153-3p derived from bone marrow mesenchymal stem cells ameliorates hypoxia-induced myocardial and microvascular damage by targeting the ANGPT1-mediated VEGF/PI3k/Akt/eNOS pathway

It has been widely reported that exosomes derived from mesenchymal stem cells (MSCs) have a protective effect on myocardial infarction (MI). However, the specific molecules which play a damaging role in MSCs shuttled miRNAs are much less explored. MiRNA-153-3p (miR-153-3p) is a vital miRNA which has been proved to modulate cell proliferation, apoptosis, angiogenesis, peritoneal fibrosis and aortic calcification. Here, we aim to study the effect and mechanism of miR-153-3p in MSC-derived exosomes on hypoxia-induced myocardial and microvascular damage. The exosomes of MSCs were isolated and identified, and the MSCs-exosomes with low expression of miR-153-3p (exo-miR-153-3p⁻) were constructed to interfere with the endothelial cells and cardiomyocytes in the oxygen-glucose deprivation (OGD) model. The viability, apoptosis, angiogenesis of endothelial cells and cardiomyocytes were determined. Additionally, ANGPT1/VEGF/VEGFR2/PI3K/Akt/eNOS pathway was detected by ELISA and/or western blot. The results illustrated that exo-miR-153-3p⁻ significantly reduced the apoptosis of endothelial cells and cardiomyocytes and promoted their viability. Meanwhile, exo-miR-153-3p⁻ can promote the angiogenesis of endothelial cells. Mechanistically, miR-153-3p regulates the VEGF/VEGFR2/PI3K/Akt/eNOS pathways by targeting ANGPT1. Intervention with VEGFR2 inhibitor (SU1498, 1 μM) remarkably reversed the protective effect of exo-miR-153-3p⁻ in vascular endothelial cells and cardiomyocytes treated by OGD. Collectively, MSCs-derived exosomes with low-expressed miR-153-3p notably promotes the activation of ANGPT1 and the VEGF/VEGFR2 /PI3K/Akt/eNOS pathways, thereby preventing the damages endothelial cells and cardiomyocytes against hypoxia.     

Cardiomyocyte Protection by GATA-4 Gene Engineered Mesenchymal Stem Cells Is Partially Mediated by Translocation of miR-221 in Microvesicles

Introduction

microRNAs (miRs), a novel class of small non-coding RNAs, are involved in cell proliferation, differentiation, development, and death. In this study, we found that miR-221 translocation by microvesicles (MVs) plays an important role in cardioprotection mediated by GATA-4 overexpressed mesenchymal stem cells (MSC).

Methods and Results

Adult rat bone marrow MSC and neonatal rat ventricle cardiomyocytes (CM) were harvested as primary cultures. MSC were transduced with GATA-4 (MSC^GATA-4) using the murine stem cell virus (pMSCV) retroviral expression system. Empty vector transfection was used as a control (MSC^Null). The expression of miRs was assessed by real-time PCR and localized using in situ hybridization (ISH). MVs collected from MSC cultures were characterized by expression of CD9, CD63, and HSP70, and photographed with electron microscopy. Cardioprotection during hypoxia afforded by conditioned medium (CdM) from MSC cultures was evaluated by lactate dehydrogenase (LDH) release, MTS uptake by CM, and caspase 3/7 activity. Expression of miR-221/222 was significantly higher in MSC than in CM and miR-221 was upregulated in MSC^GATA-4. MSC overexpression of miR-221 significantly enhanced cardioprotection by reducing the expression of p53 upregulated modulator of apoptosis (PUMA). Moreover, expression of PUMA was significantly decreased in CM co-cultured with MSC. MVs derived from MSC expressed high levels of miR-221, and were internalized quickly by CM as documented in images obtained from a Time-Lapse Imaging System.

Conclusions

Our results demonstrate that cardioprotection by MSC^GATA-4 may be regulated in part by a transfer of anti-apoptotic miRs contained within MVs.     

Vascular Endothelial Cell-specific MicroRNA-15a Inhibits Angiogenesis in Hindlimb Ischemia

The effects and potential mechanisms of the vascular endothelial cell (EC)-enriched microRNA-15a (miR-15a) on angiogenesis remain unclear. Here, we show a novel finding that EC-selective miR-15a transgenic overexpression leads to reduced blood vessel formation and local blood flow perfusion in mouse hindlimbs at 1-3 weeks after hindlimb ischemia. Mechanistically, gain- or loss-of-miR-15a function by lentiviral infection in ECs significantly reduces or increases tube formation, cell migration, and cell differentiation, respectively. By FGF2 and VEGF 3'-UTR luciferase reporter assays, Real-time PCR, and immunoassays, we further identified that the miR-15a directly targets FGF2 and VEGF to facilitate its anti-angiogenic effects. Our data suggest that the miR-15a in ECs can significantly suppress cell-autonomous angiogenesis through direct inhibition of endogenous endothelial FGF2 and VEGF activities. Pharmacological modulation of miR-15a function may provide a new therapeutic strategy to intervene against angiogenesis in a variety of pathological conditions.     

The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis

Endothelial cells play essential roles in maintenance of vascular integrity, angiogenesis, and wound repair. We show that an endothelial cell-restricted microRNA (miR-126) mediates developmental angiogenesis in vivo. Targeted deletion of miR-126 in mice causes leaky vessels, hemorrhaging, and partial embryonic lethality, due to a loss of vascular integrity and defects in endothelial cell proliferation, migration, and angiogenesis. The subset of mutant animals that survives displays defective cardiac neovascularization following myocardial infarction. The vascular abnormalities of miR-126 mutant mice resemble the consequences of diminished signaling by angiogenic growth factors, such as VEGF and FGF. Accordingly, miR-126 enhances the proangiogenic actions of VEGF and FGF and promotes blood vessel formation by repressing the expression of Spred-1, an intracellular inhibitor of angiogenic signaling. These findings have important therapeutic implications for a variety of disorders involving abnormal angiogenesis and vascular leakage.     

Down-Regulation of miR-92 in Human Plasma Is a Novel Marker for Acute Leukemia Patients

Background

MicroRNAs are a family of 19- to 25-nucleotides noncoding small RNAs that primarily function as gene regulators. Aberrant microRNA expression has been described for several human malignancies, and this new class of small regulatory RNAs has both oncogenic and tumor suppressor functions. Despite this knowledge, there is little information regarding microRNAs in plasma especially because microRNAs in plasma, if exist, were thought to be digested by RNase. Recent studies, however, have revealed that microRNAs exist and escape digestion in plasma.

Methodology/Principal Findings

We performed microRNA microaray to obtain insight into microRNA deregulation in the plasma of a leukemia patient. We have revealed that microRNA-638 (miR-638) is stably present in human plasmas, and microRNA-92a (miR-92a) dramatically decreased in the plasmas of acute leukemia patients. Especially, the ratio of miR-92a/miR-638 in plasma was very useful for distinguishing leukemia patients from healthy body.

Conclusions/Significance

The ratio of miR-92a/miR-638 in plasma has strong potential for clinical application as a novel biomarker for detection of leukemia.     

Protein Kinase G1 α Overexpression Increases Stem Cell Survival and Cardiac Function after Myocardial Infarction

Background

We hypothesized that overexpression of cGMP-dependent protein kinase type 1α (PKG1α) could mimic the effect of tadalafil on the survival of bone marrow derived mesenchymal stem cells (MSCs) contributing to regeneration of the ischemic heart.

Methods and Results

MSCs from male rats were transduced with adenoviral vector encoding for PKG1α (^PKG1αMSCs).Controls included native MSCs (^NatMSCs) and MSCs transduced with an empty vector (^NullMSCs). PKG1α activity was increased approximately 20, 5 and 16 fold respectively in ^PKG1αMSCs. ^PKG1αMSCs showed improved survival under oxygen and glucose deprivation (OGD) which was evidenced by lower LDH release, caspase-3/7 activity and number of positive TUNEL cells. Anti-apoptotic proteins pAkt, pGSK3β, and Bcl-2 were significantly increased in ^PKG1αMSCs compared to ^NatMSCs and ^NullMSCs. Higher release of multiple prosurvival and angiogenic factors such as HGF, bFGF, SDF-1 and Ang-1 was observed in ^PKG1αMSCs before and after OGD. In a female rat model of acute myocardial infarction, ^PKG1αMSCs group showed higher survival compared with ^NullMSCs group at 3 and 7 days after transplantation as determined by TUNEL staining and sry-gene quantitation by real-time PCR. Increased anti-apoptotic proteins and paracrine factors in vitro were also identified. Immunostaining for cardiac troponin I combined with GFP showed increased myogenic differentiation of ^PKG1αMSCs. At 4 weeks after transplantation, compared to DMEM group and ^NullMSCs group, ^PKG1αMSCs group showed increased blood vessel density in infarct and peri-infarct areas (62.5±7.7; 68.8±7.3 per microscopic view, p<0.05) and attenuated infarct size (27.2±2.5%, p<0.01). Heart function indices including ejection fraction (52.1±2.2%, p<0.01) and fractional shortening (24.8%±1.3%, p<0.01) were improved significantly in ^PKG1αMSCs group.

Conclusion

Overexpression of PKG1α transgene could be a powerful approach to improve MSCs survival and their angiomyogenic potential in the infarcted heart.     

Growth differentiation factor 11 promotes differentiation of MSCs into endothelial‐like cells for angiogenesis

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor‐β super family. It has multiple effects on development, physiology and diseases. However, the role of GDF11 in the development of mesenchymal stem cells (MSCs) is not clear. To explore the effects of GDF11 on the differentiation and pro‐angiogenic activities of MSCs, mouse bone marrow–derived MSCs were engineered to overexpress GDF11 (MSC^GDF11) and their capacity for differentiation and paracrine actions were examined both in vitro and in vivo. Expression of endothelial markers CD31 and VEGFR2 at the levels of both mRNA and protein was significantly higher in MSC^GDF11 than control MSCs (MSC^Vector) during differentiation. More tube formation was observed in MSC^GDF11 as compared with controls. In an in vivo angiogenesis assay with Matrigel plug, MSC^GDF11 showed more differentiation into CD31⁺ endothelial‐like cells and better pro‐angiogenic activity as compared with MSC^Vector. Mechanistically, the enhanced differentiation by GDF11 involved activation of extracellular‐signal‐related kinase (ERK) and eukaryotic translation initiation factor 4E (EIF4E). Inhibition of either TGF‐β receptor or ERK diminished the effect of GDF11 on MSC differentiation. In summary, our study unveils the function of GDF11 in the pro‐angiogenic activities of MSCs by enhancing endothelial differentiation via the TGFβ‐R/ERK/EIF4E pathway.     

Clusterin/Akt Up-Regulation Is Critical for GATA-4 Mediated Cytoprotection of Mesenchymal Stem Cells against Ischemia Injury

Background

Clusterin (Clu) is a stress-responding protein with multiple biological functions. Our preliminary microarray studies show that clusterin was prominently upregulated in mesenchymal stem cells (MSCs) overexpressing GATA-4 (MSC^GATA-4). We hypothesized that the upregulation of clusterin is involved in overexpression of GATA-4 mediated cytoprotection.

Methods

MSCs harvested from bone marrow of rats were transduced with GATA-4. The expression of clusterin in MSCs was further confirmed by real-time PCR and western blotting. Simulation of ischemia was achieved by exposure of MSCs to a hypoxic environment. Lactate dehydrogenase (LDH) released from MSCs was served as a biomarker of cell injury and MTs uptake was used to estimate cell viability. Mitochondrial function was evaluated by measuring mitochondrial membrane potential (ΔΨm) and caspase 3/7 activity.

Results

(1) Clusterin expression was up-regulated in MSC^GATA-4 compared to control MSCs transfected with empty-vector (MSC^Null). MSC^GATA-4 were tolerant to 72 h hypoxia exposure as shown by reduced LDH release and higher MTs uptake. This protection was abrogated by transfecting Clu-siRNA into MSC^GATA-4. (2) Exogenous clusterin significantly decreased LDH release and increased MSC survival in hypoxic environment. Moreover, ΔΨm was maintained and caspase 3/7 activity was reduced by clusterin in a concentration-dependent manner. (3) p-Akt expression in MSCs was upregulated following pre-treatment with clusterin, with no change in total Akt. Moreover, cytoprotection mediated by clusterin was partially abrogated by Akt inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002.

Conclusions

Clusterin/Akt signaling pathway is involved in GATA-4 mediated cytoprotection against hypoxia stress. It is suggested that clusterin may be therapeutically exploited in MSC based therapy for cardiovascular diseases.     

VEGF improves survival of mesenchymal stem cells in infarcted hearts

Bone marrow-derived mesenchymal stem cells (MSC) are a promising source for cell-based treatment of myocardial infarction (MI), but existing strategies are restricted by low cell survival and engraftment. We examined whether vascular endothelial growth factor (VEGF) improve MSC viability in infracted hearts. We found long-term culture increased MSC-cellular stress: expressing more cell cycle inhibitors, p16^INK, p21 and p19^ARF. VEGF treatment reduced cellular stress, increased pro-survival factors, phosphorylated-Akt and Bcl-xL expression and cell proliferation. Co-injection of MSCs with VEGF to MI hearts increased cell engraftment and resulted in better improvement of cardiac function than that injected with MSCs or VEGF alone. In conclusion, VEGF protects MSCs from culture-induce cellular stress and improves their viability in ischemic myocardium, which results in improvements of their therapeutic effect for the treatment of MI.     

miR-126 regulates angiogenic signaling and vascular integrity

Precise regulation of the formation, maintenance, and remodeling of the vasculature is required for normal development, tissue response to injury, and tumor progression. How specific microRNAs intersect with and modulate angiogenic signaling cascades is unknown. Here, we identified microRNAs that were enriched in endothelial cells derived from mouse embryonic stem (ES) cells and in developing mouse embryos. We found that miR-126 regulated the response of endothelial cells to VEGF. Additionally, knockdown of miR-126 in zebrafish resulted in loss of vascular integrity and hemorrhage during embryonic development. miR-126 functioned in part by directly repressing negative regulators of the VEGF pathway, including the Sprouty-related protein SPRED1 and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-beta). Increased expression of Spred1 or inhibition of VEGF signaling in zebrafish resulted in defects similar to miR-126 knockdown. These findings illustrate that a single miRNA can regulate vascular integrity and angiogenesis, providing a new target for modulating vascular formation and function.     

Bone marrow mesenchymal stem cells for post-myocardial infarction cardiac repair: microRNAs as novel regulators

Transplantation of bone marrow-derived mesenchymal stem cells (MSCs) is safe and may improve cardiac function and structural remodelling in patients following myocardial infarction (MI). Cardiovascular cell differentiation and paracrine effects to promote endogenous cardiac regeneration, neovascularization, anti-inflammation, anti-apoptosis, anti-remodelling and cardiac contractility, may contribute to MSC-based cardiac repair following MI. However, current evidence indicates that the efficacy of MSC transplantation was unsatisfactory, due to the poor viability and massive death of the engrafted MSCs in the infarcted myocardium. MicroRNAs are short endogenous, conserved, non-coding RNAs and important regulators involved in numerous facets of cardiac pathophysiologic processes. There is an obvious involvement of microRNAs in almost every facet of putative repair mechanisms of MSC-based therapy in MI, such as stem cell differentiation, neovascularization, apoptosis, cardiac remodelling, cardiac contractility and arrhythmias, and others. It is proposed that therapeutic modulation of individual cardiovascular microRNA of MSCs, either mimicking or antagonizing microRNA actions, will hopefully enhance MSC therapeutic efficacy. In addition, MSCs may be manipulated to enhance functional microRNA expression or to inhibit aberrant microRNA levels in a paracrine manner. We hypothesize that microRNAs may be used as novel regulators in MSC-based therapy in MI and MSC transplantation by microRNA regulation may represent promising therapeutic strategy for MI patients in the future.