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.     

Repair mechanisms of bone marrow mesenchymal stem cells in myocardial infarction

The prognosis of patients with myocardial infarction (MI) and resultant chronic heart failure remains extremely poor despite advances in optimal medical therapy and interventional procedures. Animal experiments and clinical trials using adult stem cell therapy following MI have shown a global improvement of myocardial function. Bone marrow-derived mesenchymal stem cells (MSCs) hold promise for cardiac repair following MI, due to their multilineage, self-renewal and proliferation potential. In addition, MSCs can be easily isolated, expanded in culture, and have immunoprivileged properties to the host tissue. Experimental studies and clinical trials have revealed that MSCs not only differentiate into cardiomyocytes and vascular cells, but also secrete amounts of growth factors and cytokines which may mediate endogenous regeneration via activation of resident cardiac stem cells and other stem cells, as well as induce neovascularization, anti-inflammation, anti-apoptosis, anti-remodelling and cardiac contractility in a paracrine manner. It has also been postulated that the anti-arrhythmic and cardiac nerve sprouting potential of MSCs may contribute to their beneficial effects in cardiac repair. Most molecular and cellular mechanisms involved in the MSC-based therapy after MI are still unclear at present. This article reviews the potential repair mechanisms of MSCs in the setting of MI.     

A Plant-Derived Remedy for Repair of Infarcted Heart

Background

Myocardial infarction (MI) due to coronary artery disease remains one of the leading causes of premature death. Replacement of infarcted heart tissue with regenerating myocardium from endogenous progenitor pools or exogenously introduced stem cells remains a therapeutic ideal. Their impracticality mainly lies in their low efficiency in cardiogenic differentiation (CD). Our recent studies with an acute MI animal model have already demonstrated the therapeutic effect of the MeOH extract of Geum japonicum (EGJ), providing clear evidence of myocardial regeneration.

Methods and Findings

The present study further isolated the active component contained in EGJ using bioassay-guided isolation and investigated its efficacy in the treatment of infarcted heart in animal MI models. We demonstrated that substantial repair of infarcted heart in animal MI models by EGJ can be mimicked by the isolated candidate compound (cardiogenin) in MI animal models. Clear evidence of newly regenerated endogenous mesenchymal stem cells (MSCs) derived cardiomyocytes was observed throughout the infarct zone, accompanied by significantly improved functional performance of the heart. Transplantation of MSCs pretreated with EGJ or cardiogenin into a MI animal model also resulted in substantial regeneration of functional myocardium, implying that the activated MSCs carry all the necessary blueprints for myocardial regeneration. Signaling pathways specific to cell survival, CD identified in embryonic heart induction and angiogenesis were activated in both cardiogenin-treated MSCs and cardiogenin-induced regenerating myocardium.

Conclusions

This study has demonstrated the therapeutic effects of cardiogenin in infarcted heart repair, and identified the associated signalling pathways for effective cardiogenic differentiation of MSCs, cell survival and angiogenesis. These findings should enable new treatment strategies for MI to be developed immediately.     

Mesenchymal stem cells modified with angiopoietin-1 improve remodeling in a rat model of acute myocardial infarction

We used human angiopoietin-1 (hAng1)-modified mesenchymal stem cells (MSCs) to treat acute myocardial infarction (AMI) in rats. The hAng1 gene was transfected into cultured rat MSCs using an adenoviral vector. Five million hAng-transfected MSCs (MSC(Ang1)) or green fluorescent protein transfected MSCs (MSC(GFP)) or PBS only (PBS group) were injected intramyocardially into the inbred Lewis rat hearts immediately after myocardial infarction. MSC(Ang1) survived in the infarcted myocardium, and expressed hAng1 at both mRNA and protein levels. The vascular density was higher in the MSC(Ang1) and MSC(GFP) groups than in the PBS group. The measurements of infarcted ventricular wall thickness, infarction area, and left ventricular diameter indicated that heart remodeling was inhibited and heart function was improved in both the MSC(Ang1) and MSC(GFP) groups. However, in contrast to the MSC(GFP) group, the MSC(Ang1) group showed enhanced angiogenesis and arteriogenesis (by 11-35%), infarction area was reduced by 30% and the left ventricular wall was 46% thicker (P<0.05). The results indicated that hAng1-modified MSCs improved heart function, followed by angiogenic effects in salvaging ischemic myocardium and reduced cardiac remodeling.     

Mesenchymal stem cell therapy: A promising cell‐based therapy for treatment of myocardial infarction

For decades, mesenchymal stem (MSCs) cells have been used for cardiovascular diseases as regenerative therapy. This review is an attempt to summarize the types of MSCs involved in myocardial infarction (MI) therapy, as well as its possible mechanisms effects, especially the paracrine one in MI focusing on the studies (human and animal) conducted within the last 10 years. Recently, reports showed that MSC therapy could have infarct‐limiting effects after MI in both experimental and clinical trials. In this context, various types of MSCs can help cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Furthermore, MSCs could produce paracrine growth factors that increase the survival of nearby cardiomyocytes, as well as increase angiogenesis through recruitment of stem cell from bone marrow or inducing vessel growth from existing capillaries. Recent research suggests that the paracrine effects of MSCs could be mediated by extracellular vesicles including exosomes. Exosomal microRNAs (miRNAs) released by MSCs are promising therapeutic hotspot target for MI. This could be attributed to the role of miRNA in cardiac biology, including cardiac regeneration, stem cell differentiation, apoptosis, neovascularization, cardiac contractility and cardiac remodeling. Furthermore, gene‐modified MSCs could be a recent promising therapy for MI to enhance the paracrine effects of MSCs, including better homing and effective cell targeted tissue regeneration. Although MSC therapy has achieved considerable attention and progress, there are critical challenges that remains to be overcome to achieve the most effective successful cell‐based therapy in MI.     

Pretreatment of adult bone marrow mesenchymal stem cells with cardiomyogenic growth factors and repair of the chronically infarcted myocardium

The in vivo cardiac differentiation and functional effects of unmodified adult bone marrow mesenchymal stem cells (MSCs) after myocardial infarction (MI) is controversial. We postulated that ex vivo pretreatment of autologous MSCs using cardiomyogenic growth factors will lead to cardiomyogenic specification and will result in superior biological and functional effects on cardiac regeneration of chronically infarcted myocardium. We used a chronic dog MI model generated by ligation of the coronary artery (n = 30). Autologous dog bone marrow MSCs were isolated, culture expanded, and specified into a cardiac lineage by adding growth factors, including basic FGF, IGF-1, and bone morphogenetic protein-2. Dogs underwent cell injection >8 wk after the infarction and were randomized into two groups. Group A dogs (n = 20) received MSCs specified with growth factors (147 +/- 96 x 10(6)), and group B (n = 10) received unmodified MSCs (168 +/- 24 x 10(6)). After the growth factor treatment, MSCs stained positive for the early muscle and cardiac markers desmin, antimyocyte enhancer factor-2, and Nkx2-5. In group A dogs, prespecified MSCs colocalized with troponin I and cardiac myosin. At 12 wk, group A dogs showed a significantly larger increase in regional wall thickening of the infarcted territory (from 22 +/- 8 to 32 +/- 6% in group A; P < 0.05 vs. baseline and group B, and from 19 +/- 7 to 21 +/- 7% in group B, respectively) and a decrease in the wall motion score index (from 1.60 +/- 0.05 to 1.35 +/- 0.03 in group A; P < 0.05 vs. baseline and group B, and from 1.58 +/- 0.07 vs. 1.56 +/- 0.08 in group B, respectively). The biological ex vivo cardiomyogenic specification of adult MSCs before their transplantation is feasible and appears to improve their in vivo cardiac differentiation as well as the functional recovery in a dog model of the chronically infarcted myocardium.     

Mineralocorticoid receptor deficiency improves the therapeutic effects of mesenchymal stem cells for myocardial infarction via enhanced cell survival

The poor survival of stem cells seriously limits their therapeutic efficacy for myocardial infarction (MI). Mineralocorticoid receptor (MR) activation plays an important role in the pathogenesis of multiple cardiovascular diseases. Here, we examined whether MR silencing in bone marrow derived mesenchymal stem cells (MSCs) could improve MSCs’ survival and enhance their cardioprotective effects in MI. MSCs from male Sprague‐Dawley rats were transfected with adenoviral small interfering RNA to silence MR (siRNA‐MR). MR silencing decreased hypoxia‐induced MSCs’ apoptosis, as demonstrated by Annexin V/7‐AAD staining. The mechanisms contributing to the beneficial effects of MR depletion were associated with inhibiting intracellular reactive oxygen species production and increased Bcl‐2/Bax ratio. In vivo study, 1 × 10⁶ of MSCs with or without siRNA‐MR were injected into rat hearts immediately after MI. Depletion of MR could improve the MSCs’ survival significantly in infarcted myocardium, associated with more cardiac function improvement and smaller infarct size. Capillary density were also significantly higher in siRNA group with increased expression of vascular endothelial growth factor. Our study demonstrated that silencing MR promoted MSCs’ survival and repair efficacy in ischaemic hearts. MR might be a potential target for enhancing the efficacy of cell therapy in ischaemic heart disease.     

Mesenchymal stem cell‐loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium

Cardiac patch is considered a promising strategy for enhancing stem cell therapy of myocardial infarction (MI). However, the underlying mechanisms for cardiac patch repairing infarcted myocardium remain unclear. In this study, we investigated the mechanisms of PCL/gelatin patch loaded with MSCs on activating endogenous cardiac repair. PCL/gelatin patch was fabricated by electrospun. The patch enhanced the survival of the seeded MSCs and their HIF‐1α, Tβ4, VEGF and SDF‐1 expression and decreased CXCL14 expression in hypoxic and serum‐deprived conditions. In murine MI models, the survival and distribution of the engrafted MSCs and the activation of the epicardium were examined, respectively. At 4 weeks after transplantation of the cell patch, the cardiac functions were significantly improved. The engrafted MSCs migrated across the epicardium and into the myocardium. Tendency of HIF‐1α, Tβ4, VEGF, SDF‐1 and CXCL14 expression in the infarcted myocardium was similar with expression in vitro. The epicardium was activated and epicardial‐derived cells (EPDCs) migrated into deep tissue. The EPDCs differentiated into endothelial cells and smooth muscle cells, and some of EPDCs showed to have differentiated into cardiomyocytes. Density of blood and lymphatic capillaries increased significantly. More c‐kit⁺ cells were recruited into the infarcted myocardium after transplantation of the cell patch. The results suggest that epicardial transplantation of the cell patch promotes repair of the infarcted myocardium and improves cardiac functions by enhancing the survival of the transplanted cells, accelerating locality paracrine, and then activating the epicardium and recruiting endogenous c‐kit⁺ cells. Epicardial transplantation of the cell patch may be applied as a novel effective MI therapy.     

Effects of hepatocyte growth factor overexpressed bone marrow‐derived mesenchymal stem cells on prevention from left ventricular remodelling and functional improvement in infarcted rat hearts

Bone marrow‐derived mesenchymal stem cells (BM‐MSCs ) transplantation has been reported to be a promising therapy for myocardial infarction (MI). However, low survival rate of BM‐MSCs in infarcted heart is one of the major limitations for the perspective clinical application. In this study, we aimed to investigate the effect of hepatocyte growth factor (HGF) on left ventricular function improvement of HGF gene‐modified BM‐MSCs (HGF‐MSCs) after its delivery into the infarcted rat hearts. BM‐MSCs were isolated with fibroblast‐like morphology and expressed CD44+CD29+CD90+/CD34‐CD45‐CD31‐CD11a. After 5‐azacytidine induction in vitro, 20%–30% of the cells were positively stained for desmin, cardiac‐specific cardiac troponin I and connexin‐43. Histological staining revealed that 2 weeks after MI is an optimal time point with decreased neutrophil infiltration and increased vascular number. Minimal infarct size and best haemodynamic analysis were also observed after cell injection at 2 weeks compared with that of 1 h, 1 week or 4 weeks. Echocardiogram confirmed that transplantation with HGF‐MSCs significantly improved left ventricular function compared with other groups in rat MI models. MSCs and HGF‐MSCslabelled with DAPI were detected 4 weeks after MI in the infarcted area. Decreased infarcted scar area and increased angiogenesis formation could be found in HGF‐MSCs group than in other groups as demonstrated by hematoxylin and eosin (H&E) staining and factor VIII staining. These results indicate that HGF‐MSCs transplantation could enhance the contractile function and attenuate left ventricular remodelling efficiently in rats with MI. Copyright © 2012 John Wiley & Sons, Ltd.     

Granulocyte colony-stimulating factor treatment enhances the efficacy of cellular cardiomyoplasty with transplantation of embryonic stem cell-derived cardiomyocytes in infarcted myocardium

We tested the hypothesis that granulocyte colony-stimulating factor (G-CSF) administration would enhance the efficacy of cellular cardiomyoplasty with embryonic stem (ES) cell-derived cardiomyocytes in infarcted myocardium. Three weeks after myocardial infarction by cryoinjury, Sprague-Dawley rats were randomized to receive either an injection of medium, ES cell-derived cardiomyocyte transplantation, G-CSF administration, or a combination of G-CSF administration and ES cell-derived cardiomyocyte transplantation. Eight weeks after treatment, the cardiac tissue formation, neovascularization, and apoptotic activity in the infarct regions were evaluated by histology and immunohistochemistry. The left ventricular (LV) dimensions and function of the treated heart were evaluated by echocardiography. Transplanted ES cell-derived cardiomyocytes survived and participated in the myocardial regeneration in the infarcted heart. A combination of G-CSF treatment and ES cell-derived cardiomyocyte transplantation significantly promoted angiogenesis and reduced the infarct area and cell apoptosis in the infarcted myocardium compared with ES cell-derived cardiomyocyte transplantation alone. The combination therapy also attenuated LV dilation, as compared with ES cell-derived cardiomyocyte transplantation alone. G-CSF treatment can enhance the efficacy of cellular cardiomyoplasty by ES cell-derived cardiomyocyte transplantation to treat myocardial infarction.     

Lipopolysaccharide preconditioning enhances the efficacy of mesenchymal stem cells transplantation in a rat model of acute myocardial infarction

Background  

Mesenchymal stem cells (MSCs)-based regenerative therapy is currently regarded as an alternative approach to salvage the acute myocardial infarcted hearts. However, the efficiency of MSCs transplantation is limited by lower survival rate of engrafted MSCs. In previous study, we found that 1.0 μg/ml Lipopolysaccharide (LPS) could protect MSCs against apoptosis induced by oxidative stress and meanwhile enhance the proliferation of MSCs. Therefore, in the present study, we firstly preconditioned MSCs with 1.0 μg/ml LPS, then transplanted MSCs into ischemic myocardium, and observed the survival and cardiac protective capacity of MSCs in a rat model of acute myocardial infarction. Furthermore, we tried to explore the underlying mechanisms and the role of Toll-like receptor-4 (TLR4) in the signal pathway of LPS-induced cardiac protection.     

The bifunctional SDF‐1‐AnxA5 fusion protein protects cardiac function after myocardial infarction

Stromal cell‐derived factor‐1 (SDF‐1) is a well‐characterized cytokine that protects heart from ischaemic injury. However, the beneficial effects of native SDF‐1, in terms of promoting myocardial repair, are limited by its low concentration in the ischaemic myocardium. Annexin V (AnxA5) can precisely detect dead cells in vivo. As massive cardiomyocytes die after MI, we hypothesize that AnxA5 can be used as an anchor to carry SDF‐1 to the ischaemic myocardium. In this study, we constructed a fusion protein consisting of SDF‐1 and AnxA5 domains. The receptor competition assay revealed that SDF‐1‐AnxA5 had high binding affinity to SDF‐1 receptor CXCR4. The treatment of SDF‐1‐AnxA5 could significantly promote phosphorylation of AKT and ERK and induce chemotactic response, angiogenesis and cell survival in vitro. The binding membrane assay and immunofluorescence revealed that AnxA5 domain had the ability to specifically recognize and bind to cells injured by hypoxia. Furthermore, SDF‐1‐AnxA5 administered via peripheral vein could accumulate at the infarcted myocardium in vivo. The treatment with SDF‐1‐AnxA5 attenuated cell apoptosis, enhanced angiogenesis, reduced infarcted size and improved cardiac function after mouse myocardial infarction. Our results suggest that the bifunctional SDF‐1‐AnxA5 can specifically bind to dead cells. The systemic administration of bifunctional SDF‐1‐AnxA5 effectively provides cardioprotection after myocardial infarction.     

Chemical and physical stimuli induce cardiomyocyte differentiation from stem cells

In this study we investigated cardiomyocyte differentiation of rat bone marrow-mesenchymal stem cells (BM-MSCs) by treating the stem cells with conditions mimicking that of myocardial infarction. The extract from infarcted rat myocardium contained the biochemical factors arising after infarction. The cardiac contraction and relaxation were simulated by applying 4% strain at 1 Hz to the stem cells. We found that the extract from infarcted myocardium or 4% strain each alone could induce cardiomyocyte differentiation of BM-MSCs, as shown by expression of cardiomyocyte-specific genes including α-actin, connexin 43, Nkx2.5, MEF2c, GATA4, α-MHC, and Troponin I. Furthermore, a combination of the extract and 4% strain had stronger effects on cardiomyocyte differentiation than what either treatment alone had. Our results suggest that this in vitro model system simulates the local cardiac environment cues after infarction and may be useful in identifying the biochemical and physical factors involved in cardiomyocyte differentiation.     

Microvascular transport model predicts oxygenation changes in the infarcted heart after treatment

Chronic heart failure is most commonly due to ischemic cardiomyopathy after a previous myocardial infarction (MI). Rebuilding lost myocardium to prevent heart failure mandates a neovasculature able to nourish new cardiomyocytes. Previously we have used a series of novel techniques to directly measure the ability of the scar neovasculature to deliver and exchange oxygen at 1-4 wk after MI in rats following left coronary artery ligation. In this study, we have developed a morphologically realistic mathematical model of oxygen transport in cardiac tissue to help in deciding what angiogenic strategies should be used to rebuild the vasculature. The model utilizes microvascular morphology of cardiac tissue based on available morphometric images and is used to simulate experimentally measured oxygen levels after MI. Model simulations of relative oxygenation match experimental measurements closely and can be used to simulate distributions of oxygen concentration in normal and infarcted rat hearts. Our findings indicate that both vascular density and vascular spatial distribution play important roles in cardiac tissue oxygenation after MI. Furthermore, the model can simulate relative changes in tissue oxygen levels in infarcted tissue treated with proangiogenic compounds such as losartan. From the minimum oxygen concentration myocytes need to maintain their normal function, we estimate that 2 wk after MI 29% of the myocardium is severely hypoxic and that the vascular density of the infarcted tissue should reach 75% of normal tissue to ensure that no areas of the myocardium are critically hypoxic.     

Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype

Fibrotic remodeling is an adverse consequence of immune response-driven phenotypic modulation of cardiac cells following myocardial infarction(Ml).MicroRNA-146b(miR-146b)is an active regulator of immunomodulation,but its function in the cardiac inflammatory cascade and its clinical implication in fibrotic remodeling following Ml remain largely unknown.Herein,miR-146b-5p was found to be upregulated in the infarcted myocardium of mice and the serum of myocardial ischemia patients.Gain-and loss-of-function experiments demonstrated that miR-146b-5p was a hypoxia-induced regulator that governed the pro-fibrotic phenotype transition of cardiac cells.Overexpression of miR-146b-5p activated fibroblast proliferation,migration,and fibroblast-to-myofibroblast transition,impaired endothelial cell function and stress survival,and disturbed macrophage paracrine signaling.Interestingly,the opposite effects were observed when miR-146b-5p expression was inhibited.Luciferase assays and rescue studies demonstrated that the miR-146b-5p target genes mediating the above phenotypic modulations included interleukin 1 receptor associated kinase 1(IRAKI)and carcinoembryonic antigen related cell adhesion molecule 1(CEACAM1).Local delivery of a miR-146b-5p antagomir significantly reduced fibrosis and cell death,and upregulated capillary and reparative macrophages in the infarcted myocardium to restore cardiac remodeling and function in both mouse and porcine Ml models.Local inhibition of miR-146b-5p may represent a novel therapeutic approach to treat cardiac fibrotic remodeling and dysfunction following Ml.     

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.     

Use of human embryonic stem cell derived-mesenchymal cells for cardiac repair

Human mesenchymal stem cells (hMSC) have proven beneficial in the repair and preservation of infarcted myocardium. Unfortunately, MSCs represent a small portion of the bone marrow and require ex vivo expansion. To further advance the clinical usefulness of cellular cardiomyoplasty, derivation of "MSC-like" cells that can be made available "off-the-shelf" are desirable. Recently, human embryonic stem cell-derived mesenchymal cells (hESC-MC) were described. We investigated the efficacy of hESC-MC for cardiac repair after myocardial infarction (MI) compared to hMSC. Because of increased efficacy of cell delivery, cells were embedded into collagen patches and delivered to infarcted myocardium. Culture of hMSC and hESC-MCs in collagen patches did not induce differentiation or significant loss in viability. Transplantation of hMSC and hES-MC patches onto infarcted myocardium of athymic nude rats prevented adverse changes in infarct wall thickness and fractional area change compared to a non-viable patch control. Hemodynamic assessment showed that hMSCs and hES-MC patch application improved end diastolic pressure equivalently. There were no changes in systolic function. hES-MC and hMSC construct application enhanced neovessel formation compared to a non-viable control, and each cell type had similar efficacy in stimulating endothelial cell growth in vitro. In summary, the use of hES-MC provides similar efficacy for cellular cardiomyoplasty as compared to hMSC and may be considered a suitable alternative for cell therapy.     

Cardiac telocytes were decreased during myocardial infarction and their therapeutic effects for ischaemic heart in rat

Recently, cardiac telocytes were found in the myocardium. However, the functional role of cardiac telocytes and possible changes in the cardiac telocyte population during myocardial infarction in the myocardium are not known. In this study, the role of the recently identified cardiac telocytes in myocardial infarction (MI) was investigated. Cardiac telocytes were distributed longitudinally and within the cross network of the myocardium, which was impaired during MI. Cardiac telocytes in the infarction zone were undetectable from approximately 4 days to 4 weeks after an experimental coronary occlusion was used to induce MI. Although cardiac telocytes in the non‐ischaemic area of the ischaemic heart experienced cell death, the cell density increased approximately 2 weeks after experimental coronary occlusion. The cell density was then maintained at a level similar to that observed 1–4 days after left anterior descending coronary artery (LAD)‐ligation, but was still lower than normal after 2 weeks. We also found that simultaneous transplantation of cardiac telocytes in the infarcted and border zones of the heart decreased the infarction size and improved myocardial function. These data indicate that cardiac telocytes, their secreted factors and microvesicles, and the microenvironment may be structurally and functionally important for maintenance of the physiological integrity of the myocardium. Rebuilding the cardiac telocyte network in the infarcted zone following MI may be beneficial for functional regeneration of the infarcted myocardium.     

StemBell therapy stabilizes atherosclerotic plaques after myocardial infarction

Background aims. After a myocardial infarction (MI) atherosclerosis is accelerated leading to destabilization of the atherosclerotic plaque. mesenchymal stromal cells are a promising therapeutic option for atherosclerosis. Previously, we demonstrated a novel stem cell delivery technique, with adipose stem cells coupled to microbubbles (i.e., StemBells) as therapy after MI. In this study, we aim to investigate the effect of StemBell therapy on atherosclerotic plaques in an atherosclerotic mouse model after MI. Methods. MI was induced in atherosclerotic Apolipoprotein E–deficient mice that were fed a high-fat Western diet. Six days post-MI, the mice received either 5?×?10⁵/100 µL StemBells or vehicle intravenously. The effects of StemBell treatment on the size and stability of aortic root atherosclerotic plaques and the infarcted heart were determined 28 days post-MI via (immuno)histological analyses. Moreover, monocyte subtypes and lipids in the blood were studied. Results. StemBell treatment resulted in significantly increased cap thickness, decreased intra-plaque macrophage density and increased percentage of intra-plaque anti-inflammatory macrophages and chemokines, without affecting plaque size and serum cholesterol/triglycerides. Furthermore, StemBell treatment significantly increased the percentage of anti-inflammatory macrophages within the infarcted myocardium but did not affect cardiac function nor infarct size. Finally, also the average percentage of anti-inflammatory monocytes in the circulation was increased after StemBell therapy. Discussion. StemBell therapy increased cap thickness and decreased intra-plaque inflammation after MI, indicative of stabilized atherosclerotic plaque. It also induced a shift of circulating monocytes and intra-plaque and intra-cardiac macrophages towards anti-inflammatory phenotypes. Hence, StemBell therapy may be a therapeutic option to prevent atherosclerosis acceleration after MI.     

The effect of hydrogel injection on cardiac function and myocardial mechanics in a computational post-infarction model

An emerging therapy to limit adverse heart remodelling following myocardial infarction (MI) is the injection of polymers into the infarcted left ventricle (LV). In the few numerical studies carried out in this field, the definition and distribution of the hydrogel in the infarcted myocardium were simplified. In this computational study, a more realistic biomaterial distribution was simulated after which the effect on cardiac function and mechanics was studied. A validated finite element heart model was used in which an antero-apical infarct was defined. Four infarct models were created representing different temporal phases in the progression of a MI. Hydrogel layers were simulated in the infarcted myocardium in each model. Biomechanical and functional improvement of the LV was found after hydrogel inclusion in the ischaemic models representing the early phases of MI. In contrast, only functional but no mechanical restitution was shown in the scar model due to hydrogel presence.