Cardiac Stem Cells Research Articles

Cardiac amyloidosis secondary to multiple myeloma: successful sequential cardiac and autologous stem cell transplantations with excellent outcome.

Cardiac amyloidosis secondary to multiple myeloma: successful sequential cardiac and autologous stem cell transplantations with excellent outcome.

Physical Exercise and Cardiac Repair: The Potential Role of Nitric Oxide in Boosting Stem Cell Regenerative Biology.

Over the years strong evidence has been accumulated showing that aerobic physical exercise exerts beneficial effects on the prevention and reduction of cardiovascular risk. Exercise in healthy subjects fosters physiological remodeling of the adult heart. Concurrently, physical training can significantly slow-down or even reverse the maladaptive pathologic cardiac remodeling in cardiac diseases, improving heart function. The underlying cellular and molecular mechanisms of the beneficial effects of physical exercise on the heart are still a subject of intensive study. Aerobic activity increases cardiovascular nitric oxide (NO) released mainly through nitric oxidase synthase 3 activity, promoting endothelium-dependent vasodilation, reducing vascular resistance, and lowering blood pressure. On the reverse, an imbalance between increasing free radical production and decreased NO generation characterizes pathologic remodeling, which has been termed the “nitroso-redox imbalance”. Besides these classical evidence on the role of NO in cardiac physiology and pathology, accumulating data show that NO regulate different aspects of stem cell biology, including survival, proliferation, migration, differentiation, and secretion of pro-regenerative factors. Concurrently, it has been shown that physical exercise generates physiological remodeling while antagonizes pathologic remodeling also by fostering cardiac regeneration, including new cardiomyocyte formation. This review is therefore focused on the possible link between physical exercise, NO, and stem cell biology in the cardiac regenerative/reparative response to physiological or pathological load. Cellular and molecular mechanisms that generate an exercise-induced cardioprotective phenotype are discussed in regards with myocardial repair and regeneration. Aerobic training can benefit cells implicated in cardiovascular homeostasis and response to damage by NO-mediated pathways that protect stem cells in the hostile environment, enhance their activation and differentiation and, in turn, translate to more efficient myocardial tissue regeneration. Moreover, stem cell preconditioning by and/or local potentiation of NO signaling can be envisioned as promising approaches to improve the post-transplantation stem cell survival and the efficacy of cardiac stem cell therapy.

The baby and the bath water: adult cardiac stem cells revisited.

The baby and the bath water: adult cardiac stem cells revisited.

Bioengineering Technologies for Cardiac Regenerative Medicine.

Cardiac regenerative medicine faces big challenges such as a lack of adult cardiac stem cells, low turnover of mature cardiomyocytes, and difficulty in therapeutic delivery to the injured heart. The interaction of bioengineering and cardiac regenerative medicine offers innovative solutions to this field. For example, cell reprogramming technology has been applied by both direct and indirect routes to generate patient-specific cardiomyocytes. Various viral and non-viral vectors have been utilized for gene editing to intervene gene expression patterns during the cardiac remodeling process. Cell-derived protein factors, exosomes, and miRNAs have been isolated and delivered through engineered particles to overcome many innate limitations of live cell therapy. Protein decoration, antibody modification, and platelet membranes have been used for targeting and precision medicine. Cardiac patches have been used for transferring therapeutics with better retention and integration. Other technologies such as 3D printing and 3D culture have been used to create replaceable cardiac tissue. In this review, we discuss recent advancements in bioengineering and biotechnologies for cardiac regenerative medicine.

Tumor necrosis factor alpha induces platelet‐derived growth factor receptor expression in cardiac mesenchymal stem cells that guides their myofibroblast differentiation

Heart failure (HF) is a global health problem. Analogous to inflammation, failing hearts also exhibit progressive fibrosis. Stem cells hold significant promise for ischemic heart diseases. However, there has not been clinical success so far. Understanding the effect of failing myocardium on stem cells is thus essential for devising efficient cell-based therapies. In addition to fibroblasts, mesenchymal stem cells (MSCs) can also differentiate into pro-fibrotic myofibroblasts. Platelet derived growth factors (PDGF) and PDGF-receptors (PDGFRs) are known regulators of fibrosis. We have discovered that cardiac MSCs (cMSCs) from failing hearts exhibit increased PDGFRβ (Rβ) expression and PDGFR-dependent myofibroblast differentiation. We hypothesize that inflammatory microenvironment in failing hearts promotes cMSC-Rβ expression and their subsequent myofibroblast differentiation. Wild type mouse cMSCs (Sca1+CD31-DDR2-) when exposed to pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) significantly increased their Rβ-expression that is mediated by JNK and Erk MAPK-activation but not NF-kB activation. More importantly, TNF-induced Rβ-expression in cMSCs is independent of Rβ-promoter transactivation. Evaluation of Rβ-promoter identified a putative CpG island which when deleted significantly increased basal Rβ-promoter activity suggesting role of DNA-methylation in modulating TNF-induced Rβ-expression in cMSCs. DNA-methylation is known to correlate directly with promotor activation and gene expression. Indeed, compared to HF cMSCs (with increased Rβ-expression), CpG island within Rβ-promoter in sham cMSCs (with decreased Rβ-expression) is predominantly methylated, and acute TNF exposure (24h) promotes its de-methylation that correlates with increased Rβ-expression. We conclude that regulating cMSC-localized Rβ expression could therapeutically be used to prevent cMSC-myofibroblast differentiation and attenuate overt fibrotic responses in HF.

Effects of Cardiotoxins on Cardiac Stem and Progenitor Cell Populations.

As research and understanding of the cardiotoxic side-effects of anticancer therapy expands further and the affected patient population grows, notably the long-term survivors of childhood cancers, it is important to consider the full range of myocardial cell types affected. While the direct impacts of these toxins on cardiac myocytes constitute the most immediate damage, over the longer term, the myocardial ability to repair, or adapt to this damage becomes an ever greater component of the disease phenotype. One aspect is the potential for endogenous myocardial repair and renewal and how this may be limited by cardiotoxins depleting the cells that contribute to these processes. Clear evidence exists of new cardiomyocyte formation in adult human myocardium, along with the identification in the myocardium of endogenous stem/progenitor cell populations with pro-regenerative properties. Any effects of cardiotoxins on either of these processes will worsen long-term prognosis. While the role of cardiac stem/progenitor cells in cardiomyocyte renewal appears at best limited (although with stronger evidence of this process in response to diffuse cardiomyocyte loss), there are strong indications of a pro-regenerative function through the support of injured cell survival. A number of recent studies have identified detrimental impacts of anticancer therapies on cardiac stem/progenitor cells, with negative effects seen from both long-established chemotherapy agents such as, doxorubicin and from newer, less overtly cardiotoxic agents such as tyrosine kinase inhibitors. Damaging impacts are seen both directly, on cell numbers and viability, but also on these cells' ability to maintain the myocardium through generation of pro-survival secretome and differentiated cells. We here present a review of the identified impacts of cardiotoxins on cardiac stem and progenitor cells, considered in the context of the likely role played by these cells in the maintenance of myocardial tissue homeostasis.

MATERNAL OBESITY NEGATIVELY IMPACT HEART DEVELOPMENT IN OFFSPRING

<h3>Background</h3> The development of the heart is a sensitive and dependent process of stem cells present during its maturation. Changes in the population of these cells through modifications in the intrauterine environment due to a metabolic program, such as during pregnancy of obese women is something of concern. It is estimated that 30% of pregnant women are obese and that 40% of women gain excessive weight during pregnancy. Thus, the objective of this work is to analyze the impacts of maternal obesity on the heart of the offspring in neonate Swiss mice. <h3>Methods</h3> After birth, litters were adjusted to nine pups and divided into overfeeding Group - nine pups until the 3rd day, when the litter was reduced to three female pups, and control Group with nine pups. Three months old females of both groups were mated to healthy males and their offspring were euthanized at the day of birth, resulting in the Offspring Control Group (OCG) and Offspring Overfed Group (OOG). Biometric parameters were analyzed, and fragments of the heart were used to analyze fibrosis by Picro-Sirius Red stanning and to analyze the population of c-kit and sca-1 cells. The results were expressed as mean ± SEM, analyzed by t-student test. <h3>Results</h3> OOG showed, at birth, 25% increased body mass compared to OCG. However, there was no difference in naso-anal length between groups, reflecting an increase of 93% in the Lee Index of OOG compared to OCG. Although the cardiac mass was 35% decreased in OOG, the analysis of collagen deposition in the heart showed an increased interstitial fibrosis (196%) in this group compared to the OCG. In addition, the quantification of cardiac stem cells demonstrated an increase of 229% in the c-kit+ cells and an increase of 218% in the sca-1+ cells when compared to the OCG. <h3>Conclusion</h3> Together, results demonstrate that maternal metabolic programming negatively impacts offspring at birth, altering cardiac development, making the heart more immature at birth, as well as increasing adverse remodeling, which may be related to the development of cardiovascular diseases in adulthood.

Polymers and Nanoparticles for Statin Delivery: Current Use and Future Perspectives in Cardiovascular Disease.

Atherosclerosis-related coronary artery disease (CAD) is one of the leading sources of mortality and morbidity in the world. Primary and secondary prevention appear crucial to reduce CAD-related complications. In this scenario, statin treatment was shown to be clinically effective in the reduction of adverse events, but systemic administration provides suboptimal results. As an attempt to improve bioavailability and effectiveness, polymers and nanoparticles for statin delivery were recently investigated. Polymers and nanoparticles can help statin delivery and their effects by increasing oral bioavailability or enhancing target-specific interaction, leading to reduced vascular endothelial dysfunction, reduced intimal hyperplasia, reduced ischemia-reperfusion injury, increased cardiac regeneration, positive remodeling in the extracellular matrix, reduced neointimal growth and increased re-endothelization. Moreover, some innovative aspects described in other cardiovascular fields could be translated into the CAD scenario. Recent preclinical studies are underlining the effect of statins in the stimulation and differentiation of endogenous cardiac stem cells, as well as in targeting of local adverse conditions implicated in atherosclerosis, and statin delivery through poly-lactic-co-glycolic acid (PLGA) appears the most promising aspect of current research to enhance drug activity. The present review intends to summarize the current evidence about polymers and nanoparticles for statin delivery in the field of cardiovascular disease, trying to shed light on this topic and identify new avenues for future studies.

Cellular signaling cross-talk between different cardiac cell populations: an insight into the role of exosomes in the heart diseases and therapy.

Exosomes are a subgroup of extracellular bilayer membrane nanovesicles that are enriched in a variety of bioactive lipids, receptors, transcription factors, surface proteins, DNA, and noncoding RNAs. They have been well recognized to play essential roles in mediating intercellular signaling by delivering bioactive molecules from host cells to regulate the physiological processes of recipient cells. In the context of heart diseases, accumulating studies have indicated that exosome-carried cellular proteins and noncoding RNA derived from different types of cardiac cells, including cardiomyocytes, fibroblasts, endothelial cells, immune cells, adipocytes, and resident stem cells, have pivotal roles in cardiac remodeling under disease conditions such as cardiac hypertrophy, diabetic cardiomyopathy, and myocardial infarction. In addition, exosomal contents derived from stem cells have been shown to be beneficial for regenerative potential of the heart. In this review, we discuss current understanding of the role of exosomes in cardiac communication, with a focus on cardiovascular pathophysiology and perspectives for their potential uses as cardiac therapies.

Two Stem Cell Populations Including VSELs and CSCs Detected in the Pericardium of Adult Mouse Heart.

Adult mammalian heart is considered to be one of the least regenerative organs as it is not able to initiate endogenous regeneration in response to injury unlike in lower vertebrates and neonatal mammals. Evidence is now accumulating to suggest normal renewal and replacement of cardiomyocytes occurs even in middle-aged and old individuals. But underlying mechanisms leading to this are not yet clear. Do tissue-resident stem cells exist or somatic cells dedifferentiate leading to regeneration? Lot of attention is currently being focused on epicardium as it is involved in cardiac development, lodges multipotent progenitors and is a source of growth factors. Present study was undertaken to study the presence of stem cells in the pericardium. Intact adult mouse heart was subjected to partial enzymatic digestion to collect the pericardialcells dislodged from the surface. Pericardial cells suspension was processed to enrich the stem cells using our recently published protocol. Two populations of stem cells were successfully enriched from the pericardium of adult mouse heart along with distinct 'cardiospheres' with cytoplasmic continuity (formed by rapid proliferation and incomplete cytokinesis). These included very small embryonic-like stem cells (VSELs) and slightly bigger 'progenitors' cardiac stem cells (CSCs). Expression of pluripotent (Oct-4A, Sox-2, Nanog), primordial germ cells (Stella, Fragilis) and CSCs (Oct-4, Sca-1) specific transcripts was studied by RT-PCR. Stem cells expressed OCT-4, NANOG, SSEA-1, SCA-1 and c-KIT. c-KIT was expressed by cells of different sizes but only smaller CD45-c-KIT+ VSELs possess regenerative potential. Inadvertent loss of stem cells while processing for different experiments has led to misperceptions & controversies existing in the field of cardiac stem cells and requires urgent rectification. VSELs/CSCs have the potential to regenerate damaged cardiac tissue in the presence of paracrine support provided by the mesenchymal stromal cells.

Estrogen is required for maintaining the quality of cardiac stem cells.

Compared to the age-matched men, the incidence of cardiovascular diseases is lower in premenopausal but higher in postmenopausal women, suggesting the cardio-protective role of estrogen in females. Although cardiac stem cells (CSCs) express estrogen receptors, yet the effects of estrogen on CSCs remain unclear. In this study, we investigated the potential role of estrogen in maintaining the quality of CSCs by in vivo and in vitro experiments. For the in vivo study, estrogen deficiency was induced by ovariectomy in 6-weeks-old C57BL/6 female mice, and then randomly given 17β-estradiol (E2) replacements at a low dose (0.01 mg/60 days) and high dose (0.18 mg/60 days), or vehicle treatment. All mice were killed 2 months after treatments, and heart tissues were collected for ex vivo expansion of CSCs. Compared to age-matched healthy controls, estrogen deficiency slightly decreased the yield of CSCs with significantly lower telomerase activity and more DNA damage. Interestingly, E2 replacements at low and high doses significantly increased the yield of CSCs and reversed the quality impairment of CSCs following estrogen deficiency. For the in vitro study, twice-passaged CSCs from the hearts of adult healthy female mice were cultured with the supplement of 0.01, 0.1, and 1 μM E2 in the medium for 3 days. We found that E2 supplement increased c-kit expression, increased proliferative activity, improved telomerase activity, and reduced DNA damage of CSCs in a dose-dependent manner. Our data suggested the potential role of estrogen in maintaining the quality of CSCs, providing new insight into the cardio-protective effects of estrogen.

The Potential Properties of Natural Compounds in Cardiac Stem Cell Activation: Their Role in Myocardial Regeneration.

Cardiovascular diseases (CVDs), which include congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, and many other cardiac disorders, cause about 30% of deaths globally; representing one of the main health problems worldwide. Among CVDs, ischemic heart diseases (IHDs) are one of the major causes of morbidity and mortality in the world. The onset of IHDs is essentially due to an unbalance between the metabolic demands of the myocardium and its supply of oxygen and nutrients, coupled with a low regenerative capacity of the heart, which leads to great cardiomyocyte (CM) loss; promoting heart failure (HF) and myocardial infarction (MI). To date, the first strategy recommended to avoid IHDs is prevention in order to reduce the underlying risk factors. In the management of IHDs, traditional therapeutic options are widely used to improve symptoms, attenuate adverse cardiac remodeling, and reduce early mortality rate. However, there are no available treatments that aim to improve cardiac performance by replacing the irreversible damaged cardiomyocytes (CMs). Currently, heart transplantation is the only treatment being carried out for irreversibly damaged CMs. Hence, the discovery of new therapeutic options seems to be necessary. Interestingly, recent experimental evidence suggests that regenerative stem cell medicine could be a useful therapeutic approach to counteract cardiac damage and promote tissue regeneration. To this end, researchers are tasked with answering one main question: how can myocardial regeneration be stimulated? In this regard, natural compounds from plant extracts seem to play a particularly promising role. The present review will summarize the recent advances in our knowledge of stem cell therapy in the management of CVDs; focusing on the main properties and potential mechanisms of natural compounds in stimulating and activating stem cells for myocardial regeneration.

Pathophysiological Basis for Nutraceutical Supplementation in Heart Failure: A Comprehensive Review.

There is evidence demonstrating that heart failure (HF) occurs in 1–2% of the global population and is often accompanied by comorbidities which contribute to increasing the prevalence of the disease, the rate of hospitalization and the mortality. Although recent advances in both pharmacological and non-pharmacological approaches have led to a significant improvement in clinical outcomes in patients affected by HF, residual unmet needs remain, mostly related to the occurrence of poorly defined strategies in the early stages of myocardial dysfunction. Nutritional support in patients developing HF and nutraceutical supplementation have recently been shown to possibly contribute to protection of the failing myocardium, although their place in the treatment of HF requires further assessment, in order to find better therapeutic solutions. In this context, the Optimal Nutraceutical Supplementation in Heart Failure (ONUS-HF) working group aimed to assess the optimal nutraceutical approach to HF in the early phases of the disease, in order to counteract selected pathways that are imbalanced in the failing myocardium. In particular, we reviewed several of the most relevant pathophysiological and molecular changes occurring during the early stages of myocardial dysfunction. These include mitochondrial and sarcoplasmic reticulum stress, insufficient nitric oxide (NO) release, impaired cardiac stem cell mobilization and an imbalanced regulation of metalloproteinases. Moreover, we reviewed the potential of the nutraceutical supplementation of several natural products, such as coenzyme Q10 (CoQ10), a grape seed extract, Olea Europea L.-related antioxidants, a sodium–glucose cotransporter (SGLT2) inhibitor-rich apple extract and a bergamot polyphenolic fraction, in addition to their support in cardiomyocyte protection, in HF. Such an approach should contribute to optimising the use of nutraceuticals in HF, and the effect needs to be confirmed by means of more targeted clinical trials exploring the efficacy and safety of these compounds.

Intracellular matrix metalloproteinase-9 mediates epigenetic modifications and autophagy to regulate differentiation in human cardiac stem cells

Abstract Epigenetic reprogramming and autophagy have critical roles in differentiation of stem cells. However, very little is known about how epigenetic modifications are mediated and how they contribute to autophagy and differentiation in human cardiac stem cells (hCSCs). Previously, we have reported that intracellular matrix metalloproteinase-9 (MMP9), a collagenase, mediates cell death in hCSCs. Here, we investigated whether intracellular MMP9 mediates epigenetic modifications and autophagy in hCSCs. We created MMP9KO hCSCs and treated them with 5-azacytidine, an inhibitor of DNA methylation, and bafilomycin A1, an inhibitor of autophagosome degradation, and evaluated epigenetic modifications, autophagic flux, and differentiation. Our results showed compromised epigenetic modifications, reduced autophagy, and impaired differentiation in MMP9KO hCSCs. Remarkably, paracrine MMP9 supplementation restored epigenetic modifications but further reduced autophagy in MMP9KO hCSCs. We conclude that intracellular MMP9 is a critical mediator of epigenetic modifications and autophagy in hCSCs. Furthermore, the endocrine and paracrine effects of MMP9 vary for regulating autophagy in hCSCs. These novel roles of MMP9 are valuable for stem cell therapy.

Cardiac Adipose Tissue Contributes to Cardiac Repair: a Review

Cardiac adipose tissue is a metabolically active adipose tissue in close proximity to heart. Recent studies emphasized the benefits of cardiac adipose tissue in heart remodeling, such as reducing infarction size, enhancing neovascularization and regulating immune response, through a series of cellular mechanisms. In the present manuscript, we provide a comprehensive review regarding the role of cardiac adipose tissue in cardiac repair. We focus on different cardiac adipose tissues according to their distinguished anatomical structures. This review summarizes the latest evidence on the relationship between cardiac adipose tissue and cardiac repair. Cardiac adipose tissues (CAT) were systematically reviewed in the current manuscript which focused on the components of CAT, debates about cardiac adipose stem cells and their effect on heart.

Cardiac Mesenchymal Stem Cells Promote Fibrosis and Remodeling in Heart Failure: Role of PDGF Signaling

Objective: To characterize cardiac mesenchymal stem cells (cMSCs) and define the role of platelet derived growth factor receptor (PDGFR) signaling on cMSC-myofibroblast differentiation. To evaluate the in vivo effects of PDGFR inhibition on the outcomes of post-myocardial infraction (MI) cardiac remodeling, function and inflammation. Background: Heart failure (HF) is characterized by chronic inflammation, fibrosis, and activation of pro-fibrotic myofibroblasts. PDGF is a known regulator of fibrosis while PDGFR is a marker of MSCs. In addition to fibroblasts, tissue MSCs also differentiate into myofibroblasts; however, the contribution of cMSCs and cMSC-localized PDGFR to fibrosis in the failing heart is unknown. Methods: Flow cytometry was used to quantitate cMSCs in failing hearts. Multiple in vitro experiments were used to characterize cMSCs. Permanent coronary ligation in mice was used to induce myocardial infarction and failure while echocardiography was used asses cardiac function. Results: We demonstrate that; 1) cMSCs temporally expand post-MI and acquire a pro-inflammatory and a pro-fibrotic cell fate, 2) pro-inflammatory macrophages promote a PDGFR-dependent pro-fibrotic myofibroblast differentiation fate specifically in HF-derived cMSCs, and that, 3) inhibition of PDGFR signaling in vivo attenuates post-MI LV remodeling and function. These in vivo effects occurred concomitantly with decreased myocardial fibrosis, myocyte hypertrophy and reduced myocardial infiltration of pro-inflammatory macrophages. Conclusion: Our findings suggest that restoring or maintaining a normal cMSC phenotype by modulating PDGFR expression and/or activation may represent a novel approach for both combating pathological fibrosis in the failing heart as well as potentially enhancing cardiac repair upon exogenous cMSC transplantation in HF.

Molecular neural crest cell markers enable discrimination of organophosphates in the murine cardiac embryonic stem cell test.

The cardiac embryonic stem cell test (ESTc) originally used the differentiation of beating cardiomyocytes for embryotoxicity screenings of compounds. However, the ESTc consists of a heterogeneous cell population, including neural crest (NC) cells, which are important contributors to heart development in vivo. Molecular markers for NC cells were investigated to explore if this approach improved discrimination between structurally related chemicals, using the three organophosphates (OP): chlorpyrifos (CPF), malathion (MLT), and triphenyl phosphate (TPP). To decrease the test duration and to improve the objective quantification of the assay read-out, gene transcript biomarkers were measured on study day 4 instead of the traditional cardiomyocyte beating assessment at day 10. Gene expression profiling and immunocytochemistry were performed using markers for pluripotency, proliferation and cardiomyocyte and NC differentiation. Cell proliferation was also assessed by measurements of embryoid body (EB) size and total protein quantification (day 7). Exposure to the OPs resulted in similar patterns of inhibition of beating cardiomyocyte differentiation and of myosin protein expression on day 10. However, these three chemically related compounds induced distinctive effects on NC cell differentiation, indicated by changes in expression levels of the NC precursor (Msx2), NC marker (Ap2α), and epithelial to mesenchymal transition (EMT; Snai2) gene transcripts. This study shows that investigating NC markers can provide added value for ESTc outcome profiling and may enhance the applicability of this assay for the screening of structurally related test chemicals.

Nanotechnology in cardiac stem cell therapy: cell modulation, imaging and gene delivery.

The wide arena of applications opened by nanotechnology is multidimensional. It is already been proven that its prominence can continuously influence human life. The role of stem cells in curing degenerative diseases is another major area of research. Cardiovascular diseases are one of the major causes of death globally. Nanotechnology-assisted stem cell therapy could be used to tackle the challenges faced in the management of cardiovascular diseases. In spite of the positive indications and proven potential of stem cells to differentiate into cardiomyocytes for cardiac repair and regeneration during myocardial infarction, this therapeutic approach still remains in its infancy due to several factors such as non-specificity of injected cells, insignificant survival rate, and low cell retention. Attempts to improve stem cell therapy using nanoparticles have shown some interest among researchers. This review focuses on the major hurdles associated with cardiac stem cell therapy and the role of nanoparticles to overcome the major challenges in this field, including cell modulation, imaging, tracking and gene delivery.

BMI1 in the heart: Novel functions beyond tumorigenesis.

The BMI1 protein, a member of the PRC1 family, is a well recognised transcriptional suppressor and has the capability of maintaining the self-renewal and proliferation of tissue-specific stem cells. Numerous studies have established that BMI1 is highly expressed in a variety of malignant cancers and serves as a key regulator in the tumorigenesis process. However, our understanding of BMI1 in terminally differentiated organs, such as the heart, is relatively nascent. Importantly, emerging data support that, beyond the tumor, BMI1 is also expressed in the heart tissue and indeed exerts profound effects in various cardiac pathological conditions. This review gives a summary of the novel functions of BMI1 in the heart, including BMI1-positive cardiac stem cells and BMI1-mediated signaling pathways, which are involved in the response to various cardiac pathological stimuli. Besides, we summarize the recent progress of BMI1 in some novel and rapidly developing cardiovascular therapies. Furtherly, we highlight the properties of BMI1, a therapeutic target proved effective in cancer treatment, as a promising target to alleviate cardiovascular diseases.

ROLE OF MESENCHYMAL STEM CELLS IN CARDIOVASCULAR DISEASE

In recent years, globally there is an incredible boost in stem cell research has kindled the expectations of both patients and physicians. Mesenchymal stem cells (MSCs) seem to represent a future powerful tool in regenerative medicine, owing to their availability, ease of manipulation, and therapeutic potential, therefore they are particularly important in medical research. Mesenchymal stem cells (MSCs) are capable self-renewing, multipotent progenitor cells with multilineage potential to differentiate into cell types, such as adipocytes, cardiomyocytes, endothelial cells and vascular smooth muscle cells, although the relative contribution of trilineage differentiation and paracrine effectors on cardiac repair. MSCs shows to have the beneficial effects of MSC-based therapies offers most attractive options to treatment of wide range of diseases from cartilage defects to cardiac disorders. Cardiovascular diseases (CVDs) are an important cause of death and disease worldwide. Because injured cardiac tissue cannot be repaired itself, it is urgent to develop other alternate therapies. Stem cells can be differentiated into cardiomyocytes, endothelial cells, and vascular smooth muscle cells for the treatment of CVDs. In addition to cardiac stem cells, mesenchymal stem cells represent another multipotent cell population in the heart; these cells are located in regions near pericytes and exhibit regenerative, angiogenic, antiapoptotic, and immunosuppressive properties.