Annexin A1-Loaded Alginate Hydrogel Promotes Cardiac Repair via Modulation of Macrophage Phenotypes after Myocardial Infarction.

Myocardial infarction (MI) is associated with inflammatory reaction, which is a pivotal component in MI pathogenesis. Moreover, excessive inflammation post-MI can lead to cardiac dysfunction and adverse remodeling, emphasizing the critical need for an effective inflammation-regulating treatment for cardiac repair. Macrophage polarization is crucial in the inflammation process, indicating its potential as an adjunct therapy for MI. In this study, we developed an injectable alginate hydrogel loaded with annexin A1 (AnxA1, an endogenous anti-inflammatory and pro-resolving mediator) for MI treatment. In vitro results showed that the composite hydrogel had good biocompatibility and consistently released AnxA1 for several days. Additionally, this hydrogel led to a reduced number of pro-inflammatory macrophages and an increased proportion of pro-healing macrophages via the adenosine monophosphate (AMP)-activated protein kinase (AMPK)-mammalian target of the rapamycin (mTOR) axis. Furthermore, the intramyocardial injection of this composite hydrogel into a mouse MI model effectively modulated macrophage transition to pro-healing phenotypes. This transition mitigated early inflammatory responses and cardiac fibrosis, promoted angiogenesis, and improved cardiac function. Therefore, our study findings suggest that combining biomaterials and endogenous proteins for MI treatment is a promising approach for limiting adverse cardiac remodeling, preventing cardiac damage, and preserving the function of infarcted hearts.

Research Progress on the Pathogenesis of Aortic Aneurysm and Dissection in Metabolism.

Aortic aneurysm and dissection are complicated diseases having both high prevalence and mortality. It is usually diagnosed at advanced stages and posing diagnostic and therapeutic challenges due to the limitations of current detecting methods for aortic dissection used in clinics. Metabonomics demonstrated its great potential capability in the early diagnosis and personalized treatment of several diseases. Emerging evidence suggests that metabolic disorders including amino acid metabolism, glycometabolism, and lipid metabolism disturbance are involved in the pathogenesis of aortic aneurysm and dissection by affecting multiple functional aortic cells. The purpose of this review is to provide new insights into the metabolism alterations and their related regulatory mechanisms with a focus on recent advances and findings and provide a theoretical basis for the diagnosis, prevention, and drug development for aortic aneurysm and dissection.

An immunometabolic patch facilitates mesenchymal stromal/stem cell therapy for myocardial infarction through a macrophage-dependent mechanism.

Mesenchymal stromal/stem cells (MSCs) have emerged as a promising approach against myocardial infarction. Due to hostile hyperinflammation, however, poor retention of transplanted cells seriously impedes their clinical applications. Proinflammatory M1 macrophages, which rely on glycolysis as their main energy source, aggravate hyperinflammatory response and cardiac injury in ischemic region. Here, we showed that the administration of an inhibitor of glycolysis, 2-deoxy-d-glucose (2-DG), blocked the hyperinflammatory response within the ischemic myocardium and subsequently extended effective retention of transplanted MSCs. Mechanistically, 2-DG blocked the proinflammatory polarization of macrophages and suppressed the production of inflammatory cytokines. Selective macrophage depletion abrogated this curative effect. Finally, to avoid potential organ toxicity caused by systemic inhibition of glycolysis, we developed a novel chitosan/gelatin-based 2-DG patch that directly adhered to the infarcted region and facilitated MSC-mediated cardiac healing with undetectable side effects. This study pioneered the application of an immunometabolic patch in MSC-based therapy and provided insights into the therapeutic mechanism and advantages of this innovative biomaterial.

Microneedle Patch Loaded with Exosomes Containing MicroRNA-29b Prevents Cardiac Fibrosis after Myocardial Infarction.

Myocardial infarction (MI) is a cardiovascular disease that poses a serious threat to human health. Uncontrolled and excessive cardiac fibrosis after MI has been recognized as a primary contributor to mortality by heart failure. Thus, prevention of fibrosis or alleviation of fibrosis progression is important for cardiac repair. To this end, a biocompatible microneedle (MN) patch based on gelatin is fabricated to load exosomes containing microRNA-29b (miR-29b) mimics with antifibrotic activity to prevent excessive cardiac fibrosis after MI. Exosomes are isolated from human umbilical cord mesenchymal stem cells and loaded with miR-29b mimics via electroporation, which can be internalized effectively in cardiac fibroblasts to upregulate the expression of miR-29b and downregulate the expression of fibrosis-related proteins. After being implanted in the infarcted heart of a mouse MI model, the MN patch can increase the retention of loaded exosomes in the infarcted myocardium, leading to alleviation of inflammation, reduction of the infarct size, inhibition of fibrosis, and improvement of cardiac function. This design explored the MN patch as a suitable platform to deliver exosomes containing antifibrotic biomolecules locally for the prevention of cardiac fibrosis, showing the potential for MI treatment in clinical applications.

Clinical Outcomes by Consolidation of Bone Marrow Stem Cell Therapy and Coronary Artery Bypass Graft in Patients With Heart Failure With Reduced Ejection Fraction: A Meta-analysis.

Bone marrow stem cell (BMSC) transplantation during coronary artery bypass graft (CABG) is an innovative treatment for ischemic heart disease (IHD). We conduct a meta-analysis to examine whether patients with IHD presenting heart failure with reduced ejection fraction (HFrEF) can be beneficent from CABG with additional BMSC transplantation. Electronic searches were performed on PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov from their inception to July 2021. The efficacy was based on left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic volume index (LVEDVi), left ventricular end-systolic volume index (LVESVi), and 6-min walk test (6MWT) change after treatment. Eight randomized-controlled trials (RCTs) were included in this meta-analysis, with a total of 350 patients. Results showed BMSC transplantation significantly improved the LVEF [mean difference (MD) = 6.23%, 95% confidence interval (CI): 3.22%-9.24%, P < 0.0001], LVEDVi (MD = -20.15 ml/m2, 95% CI: -30.49 to -9.82 ml/m2, P < 0.00001), and LVESVi (MD = -17.69 ml/m2, 95% CI: -25.24 to -10.14 ml/m2, P < 0.00001). There was no statistically significant difference in the improvement of LVEDD, LVEDV, and 6MWT between the cell transplantation group and control groups. Subgroup analysis revealed that the intervention for control group could affect the efficacy of BMSC transplantation. Sensitivity analysis found the conclusion of LVEDD, LVEDV, and 6MWT changes was not stable. Therefore, among patients with IHD presenting HFrEF, BMSC transplantation during CABG is promising to be beneficial for postoperative left ventricular (LV) function improvement. However, according to the unstable results of the sensitivity analysis, it cannot be concluded whether the extra step has a positive effect on left ventricular remodeling and exercise capacity. RCTs with larger cohorts and more strict protocols are needed to validate these conclusions.

Inflammation in myocardial infarction: roles of mesenchymal stem cells and their secretome.

Inflammation plays crucial roles in the regulation of pathophysiological processes involved in injury, repair and remodeling of the infarcted heart; hence, it has become a promising target to improve the prognosis of myocardial infarction (MI). Mesenchymal stem cells (MSCs) serve as an effective and innovative treatment option for cardiac repair owing to their paracrine effects and immunomodulatory functions. In fact, transplanted MSCs have been shown to accumulate at injury sites of heart, exerting multiple effects including immunomodulation, regulating macrophages polarization, modulating the activation of T cells, NK cells and dendritic cells and alleviating pyroptosis of non-immune cells. Many studies also proved that preconditioning of MSCs can enhance their inflammation-regulatory effects. In this review, we provide an overview on the current understanding of the mechanisms on MSCs and their secretome regulating inflammation and immune cells after myocardial infarction and shed light on the applications of MSCs in the treatment of cardiac infarction.

Generation of a human embryonic stem cell line targeted homozygous deletion of BMP10 (WAe007-A-2) by CRISPR/Cas9-dgRNA.

BMP10 signaling has been implicated in regulation of cardiovascular cell fate determination and diseases, while the underlying molecular mechanism still remains uncertain. Here, the human embryonic stem cell line (H7-BMP10del) with homozygous deletion of BMP10 was generated by CRISPR/Cas9 method. Thus, the crosstalk related to BMP10 signaling could be investigated in cell fate determination and the molecular pathogenesis of cardiovascular disease.

Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Attenuate Myocardial Infarction Injury via miR-24-3p-Promoted M2 Macrophage Polarization.

Exosomes derived from human umbilical cord mesenchymal stem cells (UMSC-Exos) have shown encouraging effects in regulating inflammation and attenuating myocardial injury. Macrophages are regulated dynamically in response to environmental cues. However, the underlying mechanisms by which UMSC-Exos regulate macrophage polarization are still not well understood. Herein, it is aimed to explore the effects of UMSC-Exos on macrophage polarization and their roles in cardiac repair after myocardial infarction (MI). These results show that UMSC-Exos improve cardiac function by increasing M2 macrophage polarization and reducing excessive inflammation. RNA-sequencing results identify Plcb3 as a key gene involved in UMSC-Exo-facilitated M2 macrophage polarization. Further bioinformatic analysis identifies exosomal miR-24-3p as a potential effector mediating Plcb3 downregulation in macrophages. Increasing miR-24-3p expression in macrophages effectively enhances M2 macrophage polarization by suppressing Plcb3 expression and NF-κB pathway activation in the inflammatory environment. Furthermore, reducing miR-24-3p expression in UMSC-Exos attenuates the effects of UMSC-Exos on M2 macrophage polarization. This study demonstrates that the cardiac therapeutic effects of UMSC-Exos are at least partially through promoting M2 macrophage polarization in an inflammatory microenvironment. Mechanistically, exosomal miR-24-3p is found to inhibit Plcb3 expression and NF-κB pathway activation to promote M2 macrophage polarization.

Generation of Marfan patient specific iPSCs (ICSSUi001-A) carrying a novel heterozygous mutation in FBN1 gene.

Marfan syndrome (MFS) is an autosomal genetic disorder caused by mutation in FBN1 gene, encoding the extracellular matrix protein fibrillin-1. Here, a MFS patient specific iPSC carrying a novel heterozygous mutation (c.7897 T > G) in FBN1 gene was generated. This iPSC line exhibited normal morphology and karyotype, and could differentiate into three germ layers in vivo and in vitro. Thus, the established iPSC line provided a precise platform for elucidating the molecular pathogenesis and personalized drug screening of MFS.

Generation of a Human iPSC (ICSSUi002-A) with MTHFR SNP (rs1801133, TT) from Thoracic Aortic Dissection Patient.

Thoracic aortic dissection is a devastating cardiovascular disease with an increasing annual incidence. The homozygous mutation in rs1801133 site has been accepted for decreased enzyme activity of mutant MTHFR protein, contributing to an accumulated homocysteine in blood. Recently, elevated homocysteine level is causally associated with an increased risk of cardiovascular disease. Conversely, the relationship between rs1801133 and thoracic aortic dissection is poorly understood. Here, the generated human induced pluripotent stem cell (iPSC) line provided a novel strategy for investigating the underlying mechanism of MTHFR mutation (rs1801133, TT) and its implication in the pathogenesis of thoracic aortic dissection.

Evaluation of Circulating Endothelial Progenitor Cells in Abdominal Aortic Aneurysms after Endovascular Aneurysm Repair.

Background and Objectives: Circulating endothelial progenitor cells (EPCs) participate in vascular repair and predict cardiovascular outcomes. The aim of this study was to investigate the correlation between EPCs and abdominal aortic aneurysms (AAAs). Methods and Results: Patients (age 67±9.41 years) suffering from AAAs (aortic diameters 58.09±11.24 mm) were prospectively enrolled in this study. All patients received endovascular aneurysm repair (EVAR). Blood samples were taken preoperatively and 14 days after surgery from patients with aortic aneurysms. Samples were also obtained from age-matched control subjects. Circulating EPCs were defined as those cells that were double positive for CD34 and CD309. Rat models of AAA formation were generated by the peri-adventitial elastase application of either saline solution (control; n=10), or porcine pancreatic elastase (PPE; n=14). The aortas were analyzed using an ultrasonic video system and immunohistochemistry. The levels of CD34＋/CD309＋ cells in the peripheral blood mononuclear cell populations were measured by flow cytometry. The baseline numbers of circulating EPCs (CD34＋/CD309＋) in the peripheral blood were significantly smaller in AAA patients compared with control subjects. The number of EPCs doubled by the 14th day after EVAR. A total of 78.57% of rats in the PPE group (11/14) formed AAAs (dilation ratio ＞150%). The numbers of EPCs from defined AAA rats were significantly decreased compared with the control group. Conclusions: EPC levels may be useful for monitoring abdominal aorta aneurysms and rise after EVAR in patients with aortic aneurysms, and might contribute to the rapid endothelialization of vessels.

The application of umbilical cord-derived MSCs in cardiovascular diseases.

Transplantation of stem cells is a promising, emerging treatment for cardiovascular diseases in the modern era. Mesenchymal stem cells (MSCs) derived from the umbilical cord are one of the most promising cell sources because of their capacity for differentiation into cardiomyocytes, endothelial cells and vascular smooth muscle cells in vitro/in vivo. In addition, umbilical cord-derived MSCs (UC-MSCs) secrete many effective molecules regulating apoptosis, fibrosis and neovascularization. Another important and specific characteristic of UC-MSCs is their low immunogenicity and immunomodulatory properties. However, the application of UC-MSCs still faces some challenges, such as low survivability and tissue retention in a harmful disease environment. Gene engineering and pharmacological studies have been implemented to overcome these difficulties. In this review, we summarize the differentiation ability, secretion function, immunoregulatory properties and preclinical/clinical studies of UC-MSCs, highlighting the advantages of UC-MSCs for the treatment of cardiovascular diseases.

Long non-coding RNA RP11-465L10.10 promotes vascular smooth muscle cells phenotype switching and MMP9 expression via the NF-κB pathway.

BACKGROUND: Thoracic aortic aneurysm/dissection (TAA/D) are complicated vascular disorders with rapid development and high mortality. Vascular smooth muscle cells (VSMCs) phenotype switching plays an important role in the pathological process of TAA/D. Previous studies have indicated a potential correlation between long non-coding RNA (lncRNA) RP11-465L10.10 and matrix metallopeptidase 9 (MMP9) involved in the development of TAA/D. This study aims to investigate the role of lncRNA RP11-465L10.10 in VSMCs phenotype switching and the molecular mechanism in regulating MMP9 expression. METHODS: The expression of RP11-465L10.10 in vascular tissues and in VMSCs was detected by RT-qPCR. To investigate the role of RP11-465L10.10 on VSMCs phenotype switching, an RP11-465L10.10-overexpressed lentiviral vector was constructed and transfected into VSMCs. Through EdU staining, migration assay, flow cytometry analysis, the roles of RP11-465L10.10 were estimated. Bioinformatics indicated that RP11-465L10.10 upregulating MMP9 expression via NF-κB signaling, and SN50 (a specific inhibitor of NF-κB pathway) was used to inhibit the NF-κB pathway activation, then the expression of MMP9 was detected in RP11-465L10.10 overexpressed VMSCs. RESULTS: In this study, we found RP11-465L10.10 and MMP9 were highly increased in TAD patient tissues, which was consistent in angiotensin II-induced VSMCs phenotype switching. RP11-465L10.10 overexpression facilitated VSMCs phenotype switching and MMP9 expression. Mechanismly, NF-κB signal pathway was involved in RP11-465L10.10 induced VSMCs phenotype switching and MMP9 expression by transcriptome data analysis and experimental confirm. CONCLUSION: This study demonstrated that RP11-465L10.10 induces VSMCs phenotype switching and MMP9 expression via the NF-κB signal pathway, suggesting that RP11-465L10.10 might be a potential therapeutic target for TAA/D treatment.

Adult Cardiomyocyte Proliferation: a New Insight for Myocardial Infarction Therapy.

Myocardial infarction leads to cardiomyocyte loss, ensuing ventricular pathological remodeling, dramatic impairment of cardiac function, and ultimately heart failure. Unfortunately, the existing therapeutical treatments cannot directly replenish the lost myocytes in the injured myocardium and the long-term prognosis of heart failure after myocardial infarction remains poor. Growing investigations have demonstrated that the adult mammalian cardiomyocytes possess very limited proliferation capacity, and that was not enough to restore the injured heart. Recently, many studies were targeting to promote cardiomyocyte proliferation via inducing cardiomyocyte cell cycle re-entry for cardiac repair after myocardial infarction. Indeed, these results showed it is a feasible way to stimulate terminally differentiated cardiomyocyte proliferation. Here, we reviewed the major mechanisms and the potential targets for stimulating mammalian adult cardiomyocyte proliferation specifically. This will provide a new therapeutic strategy for the clinical treatment of myocardial infarction by activating the endogenous regeneration. Graphical abstract.

HIF-1α overexpression in mesenchymal stem cell-derived exosomes mediates cardioprotection in myocardial infarction by enhanced angiogenesis.

BACKGROUND: Myocardial infarction (MI) is a severe disease that often associated with dysfunction of angiogenesis. Cell-based therapies for MI using mesenchymal stem cell (MSC)-derived exosomes have been well studied due to their strong proangiogenic effect. Genetic modification is one of the most common methods to enhance exosome therapy. This study investigated the proangiogenic and cardioprotective effect of exosomes derived from hypoxia-inducible factor 1-alpha (HIF-1α)-modified MSCs. METHODS: Lentivirus containing HIF-1α overexpressing vector was packaged and used to infect MSCs. Exosomes were isolated from MSC-conditioned medium by ultracentrifugation. Human umbilical vein endothelial cells (HUVECs) were treated under hypoxia condition for 48 h co-cultured with PBS, control exosomes, or HIF-1α-overexpressed exosomes, respectively. Then the preconditioned HUVECs were subjected to tube formation assay, Transwell assay, and EdU assay to evaluate the protective effect of exosomes. Meanwhile, mRNA and secretion levels of proangiogenic factors were measured by RT-qPCR and ELISA assays. In vivo assays were conducted using the rat myocardial infarction model. PBS, control exosomes, or HIF-1α-overexpressed exosomes were injected through tail vein after MI surgery. Heart function was assessed by echocardiography at days 3, 14, and 28. At day 7, mRNA and protein expression levels of proangiogenic factors in the peri-infarction area and circulation were evaluated, respectively. At day 28, hearts were collected and subjected to H&E staining, Masson's trichrome staining, and immunofluorescent staining. RESULTS: HIF-1α-overexpressed exosomes rescued the impaired angiogenic ability, migratory function, and proliferation of hypoxia-injured HUVECs. Simultaneously, HIF-1α-overexpressed exosomes preserved heart function by promoting neovessel formation and inhibiting fibrosis in the rat MI model. In addition, both in vitro and in vivo proangiogenic factors mRNA and protein expression levels were elevated after HIF-1α-overexpressed exosome application. CONCLUSION: HIF-1α-overexpressed exosomes could rescue the impaired angiogenic ability, migration, and proliferation of hypoxia-pretreated HUVECs in vitro and mediate cardioprotection by upregulating proangiogenic factors and enhancing neovessel formation.

Downregulation of MicroRNA-206 Alleviates the Sublethal Oxidative Stress-Induced Premature Senescence and Dysfunction in Mesenchymal Stem Cells via Targeting Alpl.

Bone marrow-derived mesenchymal stem cells (MSCs) have shown great promise in tissue engineering and regenerative medicine; however, the regenerative capacity of senescent MSCs is greatly reduced, thus exhibiting limited therapy potential. Previous studies uncovered that microRNA-206 (miR-206) could largely regulate cell functions, including cell proliferation, survival, and apoptosis, but whether miR-206 is involved in the senescent process of MSCs remains unknown. In this study, we mainly elucidated the effects of miR-206 on MSC senescence and the underlying mechanism. We discovered that miR-206 was upregulated in the senescent MSCs induced by H2O2, and abrogation of miR-206 could alleviate this tendency. Besides, we determined that by targeting Alpl, miR-206 could ameliorate the impaired migration and paracrine function in MSCs reduced by H2O2. In vivo study, we revealed that inhibition of miR-206 in senescent MSCs could effectively protect their potential for myocardial infarction treatment in a rat MI model. In summary, we examined that inhibition of miR-206 in MSCs can alleviate H2O2-induced senescence and dysfunction, thus protecting its therapeutic potential.

The protective effects of HMGA2 in the senescence process of bone marrow-derived mesenchymal stromal cells.

Bone marrow-derived mesenchymal stromal cells (MSCs) have been wildly applied to cell-based strategies for tissue engineering and regenerative medicine; however, they have to undergo the senescence process and thus appeared to be less therapeutic effective. HMGA2, a protein belonged to high mobility group A (HMGA) family, exhibits an inverse expression level related to embryonic development and acts as a developmental regulator in stem cell self-renewal progression. Therefore, we performed senescence-associated ß-galactosidase (SA-ß-gal) staining, transwell assay, to examine the changes of MSCs in different stages and then over-expressed HMGA2 in MSCs by lentivirus transfection. We found the percentage of SA-ß-gal staining positive cells in MSCs from 24-month-old Sprague-Dawley (SD) rats (O-MSCs) was significantly higher compared with MSCs from 2-week-old SD rats (Y-MSCs), and the expression levels of P21 and P53, two senescence-related molecules, were also significantly up-regulated in O-MSCs than in Y-MSCs. In contrast, the HMGA2 expression level in O-MSCs was dramatically down-regulated in contrast to Y-MSCs. In additional, the migration ability in O-MSCs was significantly attenuated than in Y-MSCs. After successfully over-expressed HMGA2 in O-MSCs, the percentage of SA-ß-gal staining positive cells and the expression levels of P21 and P53 were reduced, and the migration ability was improved compared with O-MSCs without treatment. Further, mRNA sequencing analysis revealed that overexpression of HMGA2 changed the expression of genes related to cell proliferation and senescence, such as Lyz2, Pf4, Rgs2, and Mstn. Knockdown of Rgs2 in HMGA2 overexpression O-MSCs could antagonize the protective effect of HMGA2 in the senescence process of O-MSCs.

Knockout of beta-2 microglobulin enhances cardiac repair by modulating exosome imprinting and inhibiting stem cell-induced immune rejection.

BACKGROUND AND AIMS: Allogeneic human umbilical mesenchymal stem cells (alloUMSC) are convenient cell source for stem cell-based therapy. However, immune rejection is a major obstacle for clinical application of alloUMSC for cardiac repair after myocardial infarction (MI). The immune rejection is due to the presence of human leukocyte antigen (HLA) class I molecule which is increased during MI. The aim of this study was to knockout HLA light chain ß2-microglobulin (B2M) in UMSC to enhance stem cell engraftment and survival after transplantation. METHODS AND RESULTS: We developed an innovative strategy using CRISPR/Cas9 to generate UMSC with B2M deletion (B2M-UMSC). AlloUMSC injection induced CD8+ T cell-mediated immune rejection in immune competent rats, whereas no CD8+ T cell-mediated killing against B2M-UMSC was observed even when the cells were treated with IFN-γ. Moreover, we demonstrate that UMSC-derived exosomes can inhibit cardiac fibrosis and restore cardiac function, and exosomes derived from B2M-UMSC are more efficient than those derived from UMSC, indicating that the beneficial effect of exosomes can be enhanced by modulating exosome's imprinting. Mechanistically, microRNA sequencing identifies miR-24 as a major component of the exosomes from B2M-UMSCs. Bioinformatics analysis identifies Bim as a putative target of miR-24. Loss-of-function studies at the cellular level and gain-of-function approaches in exosomes show that the beneficial effects of B2M-UMSCs are mediated by the exosome/miR-24/Bim pathway. CONCLUSION: Our findings demonstrate that modulation of exosome's imprinting via B2M knockout is an efficient strategy to prevent the immune rejection of alloUMSCs. This study paved the way to the development of new strategies for tissue repair and regeneration without the need for HLA matching.

Knockout of beta-2 microglobulin reduces stem cell-induced immune rejection and enhances ischaemic hindlimb repair via exosome/miR-24/Bim pathway.

Generating universal human umbilical mesenchymal stem cells (UMSCs) without immune rejection is desirable for clinical application. Here we developed an innovative strategy using CRISPR/Cas9 to generate B2M- UMSCs in which human leucocyte antigen (HLA) light chain ß2-microglobulin (B2M) was deleted. The therapeutic potential of B2M- UMSCs was examined in a mouse ischaemic hindlimb model. We show that B2M- UMSCs facilitated perfusion recovery and enhanced running capability, without inducing immune rejection. The beneficial effect was mediated by exosomes. Mechanistically, microRNA (miR) sequencing identified miR-24 as a major component of the exosomes originating from B2M- UMSCs. We identified Bim as a potential target of miR-24 through bioinformatics analysis, which was further confirmed by loss-of-function and gain-of-function approaches. Taken together, our data revealed that knockout of B2M is a convenient and efficient strategy to prevent UMSCs-induced immune rejection, and it provides a universal clinical-scale cell source for tissue repair and regeneration without the need for HLA matching in the future.

The enhanced effect and underlying mechanisms of mesenchymal stem cells with IL-33 overexpression on myocardial infarction.

BACKGROUND: Interleukin 33 is known to have an important influence in the process of myocardial infarction, and the immunoregulatory function of MSCs could be influenced by cell factors. In this study, we evaluated the therapeutic efficacy of IL-33-overexpressing bone marrow mesenchymal stem cells (IL33-MSCs) on myocardial infarction (MI) and detected the inflammatory level and cardiac function in rats. METHODS AND RESULTS: First, we evaluated the proliferation of T cells and polarization of macrophages that had been co-cultured with Vector-MSCs or IL33-MSCs. Co-culture experiments indicated that IL33-MSCs reduced T cell proliferation and enhanced CD206+ macrophage polarization. Second, we determined the inflammation level and cardiac function of PBS-, Vector-MSC-, and IL33-MSC-injected rats. Echocardiography indicated that left ventricular ejection fraction (LVEF) was enhanced in IL33-MSC-injected rats compared with Vector-MSC-injected rats. Postmortem analysis of rat heart tissue showed reduced fibrosis and less inflammation in IL33-MSC-injected rats. CONCLUSION: These studies indicated that the IL33-MSC injection improved heart function and reduces inflammation in rats with MI compared with PBS or Vector-MSC injections. IL-33 overexpression enhances the immunomodulatory function and therapeutic effects of MSCs on acute MI via enhancing the polarization of macrophages toward M2, enhancing the differentiation of CD4+ T cells toward CD4+IL4+Th2 cells, and finally, reducing heart inflammation and enhancing heart function.