Resident Cardiac Progenitor Cells Research Articles

Cardiac Progenitor Cells and their Therapeutic Application for Cardiac Repair

Heart disease is the principal cause of death in humans. Stem cell-based therapy for heart regeneration has long been seen as a potential application since the heart lacks adequate intrinsic regenerative potential. In the cardiovascular field, clinical trials have already been carried out by implantation of both bone marrow-derived stem cells and cardiac resident progenitor cells derived from the adult heart tissue into the injured myocardium to restore the functionality of the heart after damage. However, before a robust stem and progenitor cell-based therapy for cardiovascular diseases can be applied in the clinical setting, more research is necessary to generate sufficient quantities of functional cardiomyocytes from stem cells and to understand behavior of cardiomyocytes upon transplantation. A comprehensive understanding of the developmental processes involved in cardiogenesis might support further investigations in more efficient cell-based regeneration therapies. This review discusses the molecular aspects of cardiogenesis during early development and links the insights with the in vitro generation of cardiac progenitor cells as well as functional cardiomyocytes. Furthermore, we discuss the advantages of cardiac progenitor cells and cardiomyocytes derived from pluripotent stem cells, cardiac resident stem cells in regenerative applications to cope with the damaged heart.

Characterization of cardiac-resident progenitor cells expressing high aldehyde dehydrogenase activity.

High aldehyde dehydrogenase (ALDH) activity has been associated with stem and progenitor cells in various tissues. Human cord blood and bone marrow ALDH-bright (ALDHbr) cells have displayed angiogenic activity in preclinical studies and have been shown to be safe in clinical trials in patients with ischemic cardiovascular disease. The presence of ALDHbr cells in the heart has not been evaluated so far. We have characterized ALDHbr cells isolated from mouse hearts. One percent of nonmyocytic cells from neonatal and adult hearts were ALDHbr. ALDHvery-br cells were more frequent in neonatal hearts than adult. ALDHbr cells were more frequent in atria than ventricles. Expression of ALDH1A1 isozyme transcripts was highest in ALDHvery-br cells, intermediate in ALDHbr cells, and lowest in ALDHdim cells. ALDH1A2 expression was highest in ALDHvery-br cells, intermediate in ALDHdim cells, and lowest in ALDHbr cells. ALDH1A3 and ALDH2 expression was detectable in ALDHvery-br and ALDHbr cells, unlike ALDHdim cells, albeit at lower levels compared with ALDH1A1 and ALDH1A2. Freshly isolated ALDHbr cells were enriched for cells expressing stem cell antigen-1, CD34, CD90, CD44, and CD106. ALDHbr cells, unlike ALDHdim cells, could be grown in culture for more than 40 passages. They expressed sarcomeric α-actinin and could be differentiated along multiple mesenchymal lineages. However, the proportion of ALDHbr cells declined with cell passage. In conclusion, the cardiac-derived ALDHbr population is enriched for progenitor cells that exhibit mesenchymal progenitor-like characteristics and can be expanded in culture. The regenerative potential of cardiac-derived ALDHbr cells remains to be evaluated.

Erratum: Stimulation of adult resident cardiac progenitor cells by durable myocardial expression of thymosin beta 4 with ultrasound-targeted microbubble delivery

Correction to: Gene Therapy (2013) 20, 225–233; doi: 10.1038/gt.2012.89; published online 15 November 2012 Since the advance online publication of this article, the authors have noticed that an old version of Figures 1, 3, 4, 5, 6 and 7 was used. The correct figures, which include a 12-week bar, areincluded in the corrected article, which appears in this issue.

Stimulation of adult resident cardiac progenitor cells by durable myocardial expression of thymosin beta 4 with ultrasound-targeted microbubble delivery

It has been proposed that thymosin beta 4 (TB4)-protein delivery stimulates differentiation of resident adult WT1-positive cardiac progenitor cells, but with very low efficiency. We determined whether gene therapy with human TB4 stimulates proliferation of resident adult cardiac progenitor cells in normal rat heart. Ultrasound-targeted microbubble destruction (UTMD) was used to deliver the human TB4 gene under a piggybac transposon plasmid to normal rat heart. The rat hearts were assayed by quantitative reverse transcription-PCR and immunohistology with a confocal microscope at 1, 2, 3, 4 and 12 weeks after UTMD. Exogenous TB4 stimulation resulted in the presence of WT1-positive cardiac progenitor cells from epicardium to endocardium. TB4 stimulated angiogenesis and arteriogenesis. One month after TB4 gene therapy by UTMD, the percentage of NKX2.5-positive cardiomyocytes was 5.5±1.0% and NKX2.5 mRNA was 24-fold higher than in the control groups (P<0.001). Similar results were found for ISL-1, BrDu, Ki-67, PHH3 and aurora B (P<0.001). Cardiac-specific delivery of exogenous human TB4 gene efficiently stimulates proliferation and differentiation of resident WT1-positive adult cardiac progenitor cells into three intact cardiac cell lineages-vascular endothelial cells, coronary artery smooth muscle cells and cardiac muscle cells in normal adult rat heart.

‘Shovel-Ready’ applications of stem cell advances for pediatric heart disease

The past decade has seen remarkable advances in the field of stem cell biology. Many new technologies and applications are passing the translational phase and likely will soon be relevant for the clinical pediatric cardiologist. This review will focus on two advances in basic science that are now translating into clinical trials. The first advance is the recognition, characterization, and recent therapeutic application of resident cardiac progenitor cells (CPCs). Early results of adult trials and scattered case reports in pediatric patients support expanding CPC-based trials for end-stage heart failure in pediatric patients. The relative abundance of CPCs in the neonate and young child offers greater potential benefits in heart failure treatment than has been realized to date. The second advance is the technology of induced pluripotent stem cells (iPSCs), which reprograms differentiated somatic cells to an undifferentiated embryonic-like state. When iPSCs are differentiated into cardiomyocytes, they model a patient's specific disease, test pharmaceuticals, and potentially provide an autologous source for cell-based therapy. The therapeutic recruitment and/or replacement of CPCs has potential for enhancing cardiac repair and regeneration in children with heart failure. Use of iPSCs to model heart disease holds great potential to gain new insights into diagnosis, pathophysiology, and disease-specific management for genetic-based cardiovascular diseases that are prevalent in pediatric patients.

Sca-1 Knockout Impairs Myocardial and Cardiac Progenitor Cell Function

Cardiac progenitor cells are important for maintenance of myocardial structure and function, but molecular mechanisms governing these progenitor cells remain obscure and require elucidation to enhance regenerative therapeutic approaches. To understand consequences of stem cell antigen-1 (Sca-1) deletion on functional properties of c-kit+ cardiac progenitor cells and myocardial performance using a Sca-1 knock-out/green fluorescent protein knock-in reporter mouse (ScaKI). Genetic deletion of Sca-1 results in early-onset cardiac contractile deficiency as determined by echocardiography and hemodynamics as well as age-associated hypertrophy. Resident cardiac progenitor cells in ScaKI mice do not respond to pathological damage in vivo, consistent with observations of impaired growth and survival of ScaKI cardiac progenitor cells in vitro. The molecular basis of the defect in ScaKI cardiac progenitor cells is associated with increased canonical Wnt signaling pathway activation consistent with molecular characteristics of lineage commitment. Genetic deletion of Sca-1 causes primary cardiac defects in myocardial contractility and repair consistent with impairment of resident cardiac progenitor cell proliferative capacity associated with altered canonical Wnt signaling.

Cardiac resident progenitor cells: evidence and functional significance

This editorial refers to ‘Higher frequencies of BCRP+ cardiac resident cells in ischaemic human myocardium’, by M.Y. Emmert et al. , doi:10.1093/eurheartj/ehs156 It has been estimated that a serious myocardial infarction (MI) results in the loss of ∼1 billion functional cardiomyocytes, which are replaced with a fibrous scar, frequently leading to heart failure. Experimental data demonstrate that the mitotic renewal in the human myocardium exists but at a very low rate: 1% annually at the age of 25 and 0.45% at the age of 75.1 With this turnover rate, most cardiomyocytes will never be exchanged during a normal life span. Although the renewal rate may increase somewhat after injury, the heart itself is not able to effect large-scale cardiac regeneration. Thus, stem cell-based therapy may be a realistic strategy for providing a source of new functional cardiomyocytes. Additionally, stem cells may promote tissue healing through paracrine mechanisms. Regenerative stem cells may be derived from extracardiac sources as well as from the heart itself. Over the past decade, extensive studies have provided us with evidence that progenitor cells are present in the adult heart. In mice, cells expressing the stem cell factor receptor c-Kit,2 stem cell antigen-1 (Sca-1),3 and transcription factor islet-1 (Isl-1),4 as well as side population (SP) cells5 have been identified as cardiac resident progenitor cells (CRPCs) due to their ability to differentiate into cardiomyocytes both in vivo and in vitro . Following the animal studies, a series of studies by several independent groups have suggested that CRPCs also exist in adult or postnatal hearts of humans ( Figure 1 ),4,6–9 which are also identified by the expression of c-Kit, Sca-1, and Isl-1. In addition, cardiospheres cultured from human heart biopsies contain CRPCs and can proliferate in vitro (not addressed in …

Patient profile modulates cardiac c-kit+ progenitor cell availability and amplification potential

Human c-kit(+) cardiac progenitor cells (CPCs) are multipotent and may be used for cardiac repair. The effect of cardiovascular risk factors and medications on CPCs isolation efficiency, c-kit stem cell marker expression, and exvivo proliferative potential is unknown and was examined in the present work. Cells from human right atrial appendages (n = 50) were expanded in culture; after ∼16 days (T0), it was established the percentage of CPCs and c-kit protein mean fluorescence intensity (MFI) by fluorescence activated cell sorting (FACS). Thereafter, CPCs were isolated by high throughput sorting; after culturing for 4 passages CPCs-derived cells were re-analyzed to assess c-kit(+) cell percentage and enrichment vs T0. The association between 19 demographic and clinical variables to CPCs number and MFI at T0, and CPCs enrichment at P4, was determined by multiple linear regression analysis with stepwise selection procedure. The results revealed that (1) at T0, the number of isolated CPCs directly correlated to β-blocker treatment; (2) at T0, c-kit protein expression directly correlated to pulmonary hypertension (PH); (3) at P4, CPC's enrichment inversely correlated to smoke, atrial fibrillation (AF), a history of myocardial infarction, whereas it directly correlated to PH and statins. Patient clinical profile and medications differently modulate CPCs isolation and amplification potential exvivo. These results may provide new insights for the understanding of cardiac homeostasis and suggest both limitations and possible enhancing strategies for the therapeutic use of cardiac-resident progenitor cells.

OMICS-based exploration of the molecular phenotype of resident cardiac progenitor cells from adult murine heart

Resident cardiac progenitor cells have emerged as a potential source of adult stem cells for regeneration of damaged myocardium. Sca-1 cells, expressing Stem cell antigen-1 as a cell surface marker, are multipotent cells that were shown to differentiate into different cell types i.e. cardiomyocytes. Previous studies have reported that Sca-1 positive cells are able to home to the injured heart. However, the mechanism of improving cardiac function is still unclear. In the current study, we have profiled the proteome and transcriptome of Sca-1 positive cells in comparison with other endogenous heart cell types to unravel the molecular phenotype of the progenitor cells. Among the 861 proteins identified with high confidence in total, 331 non-redundant proteins were overrepresented in Sca-1 positive cells. Highly abundant candidates were mostly associated with cell growth and proliferation, cell migration and cytoskeletal organization. Transcriptional profiling disclosed significant expression of surface antigens such as CD31, CD36, CD38, CD66a, CD102, and CD202B. Growth factors like KITL, JAG2, PDGFB and VEGFC showed a higher expression in Sca-1 progenitor cells than in Sca-1 negative cells. Selective candidates were validated by Western blotting. These global findings provide a basis for the study of their capability to participate in the cardiac regeneration process.

Aging Kit Mutant Mice Develop Cardiomyopathy

Both bone marrow (BM) and myocardium contain progenitor cells expressing the c-Kit tyrosine kinase. The aims of this study were to determine the effects of c-Kit mutations on: i. myocardial c-Kit+ cells counts and ii. the stability of left ventricular (LV) contractile function and structure during aging. LV structure and contractile function were evaluated (echocardiography) in two groups of Kit mutant (W/Wv and W41/W42) and in wild type (WT) mice at 4 and 12 months of age and the effects of the mutations on LV mass, vascular density and the numbers of proliferating cells were also determined. In 4 month old Kit mutant and WT mice, LV ejection fractions (EF) and LV fractional shortening rates (FS) were comparable. At 12 months of age EF and FS were significantly decreased and LV mass was significantly increased only in W41/W42 mice. Myocardial vascular densities and c-Kit+ cell numbers were significantly reduced in both mutant groups when compared to WT hearts. Replacement of mutant BM with WT BM at 4 months of age did not prevent these abnormalities in either mutant group although they were somewhat attenuated in the W/Wv group. Notably BM transplantation did not prevent the development of cardiomyopathy in 12 month W41/W42 mice. The data suggest that decreased numbers and functional capacities of c-Kit+ cardiac resident progenitor cells may be the basis of the cardiomyopathy in W41/W42 mice and although defects in mutant BM progenitor cells may prove to be contributory, they are not causal.

Abstract 9107: Pim-1 Kinase Increases Non-Random Chromatid Segregation in Cardiac Progenitor Cells

Rationale: A cell has DNA strands of different replication ages because DNA replication is semi-conservative. Double-stranded DNA molecules possess one DNA strand that is one generation older than the other. Non-sister chromatids containing newly synthesized DNA and ‘old’ DNA strands are non-randomly partitioned between mother and daughter cells. Stem cells are presumed to non-randomly segregate chromatids to determine cell fate of daughter cells, although experimental evidence is lacking. Resident cardiac progenitor cells (CPC) present in the adult heart have been used for cell-based treatment of myocardial damage but the factors determining the stemness and lineage commitment of these cells are poorly understood. Cardio protective kinase Pim-1 increases asymmetric cell division in vivo, proliferation and commitment of CPCs after adaptive transfer in pathological injury model but its role in non-random segregation is unknown. Objective: Establish role of Pim-1 on non-random chromatid segregation and correlate with daughter cell fate determination in cardiac progenitor cells. Methods and Results: Non-random segregation was tracked by incorporation of bromodeoxyuridine (BrdU), a thymidine analogue labeling newly synthesized DNA strands. For label retention assay, cells were labeled for many generations and blocked in second cytokinesis during chase in BrdU free media. Two daughter nuclei within a cell body had different BrdU intensity. Density measurements showed that 4.6% of CPCs outside the 95% confidence interval for equal BrdU intensity between daughter nuclei indicating non-random segregation of BrdU labeled chromatids. Genetic engineering of CPCs to express Pim-1 kinase greatly enhanced non-random segregation (12.6% vs 5.6% GFP expressing cells). Non-random segregation was further confirmed by asymmetric BrdU segregation in anaphase cells from second mitotic shake off during chase. Conclusions: CPCs non-randomly segregate chromatids as demonstrated by selective segregation of BrdU labeled chromatids which is twofold increased in cells overexpressing Pim-1 kinase. Future Directions: The relationship of non-random chromatid segregation to identity of stem cells fate remains to be determined.

Low-dose Erythropoietin reduces risk of heart failure induced by anti-cancer therapy

Heart disease can be caused by many different insults and injuries and often terminates in death from heart failure, an inability of the heart muscle to adequately supply blood to the body. A major aim in today's research is to define novel therapeutic strategies to limit myocardial damage and to enhance the ability of the heart muscle to regenerate and to heal itself. The anti-cancer drug doxorubicin (DOX) is used to treat a broad range of cancers but is limited in its use by severe side effects, most notably heart failure [1]. STAT3 is an important factor that promotes survival and migration of many tumor cell types and its pharmacological blockade hold good promise as a novel anti-cancer strategy [2, 3]. However, likewise to DOX, blocking STAT3 in the heart has been associated with heart failure in various experimental models [4, 5]. In our latest work, we found that low-doses of erythropoietin (EPO), a cytokine with multiple functions best known for its role to control the production of red blood cells, reduces the risk of heart failure mediated by DOX treatment or STAT3 blockade [6]. Our findings suggest that treatment with low-doses (hematocrit-inactive) synthetic EPO (CERA) during DOX treatment or STAT3 blockade is able to preserve the ability of cardiac progenitor cells to repair the vasculature of the heart and thereby to attenuate myocardial injury [6]. Recent studies have shown that the heart possesses intrinsic cardiac stem or progenitor cells that can contribute to regeneration and healing during disease and aging [7]. Little is known about the molecules and pathways that regulate stem cell proliferation and differentiation. In order to obtain a better understanding how the cardiac microenvironment impacts on the endogenous regeneration system of the adult heart, we studied phenotypic alterations of resident cardiac progenitor cells (identified by the expression of Sca-1) in heart failure as a consequence of DOX treatment or genetic ablation of STAT3 in cardiac muscle cells. We observed that in both heart failure models, cardiac progenitor cells displayed an impaired ability to form new blood vessels essential for oxygen delivery to the heart muscle[6]. Both models also exhibited reduced production of EPO in the heart muscle[6]. Interestingly, we found that cardiac progenitor cells bind EPO within the cardiac microenvironment, a feature that seems to be required to maintain the ability to differentiate into new blood vessels[6]. Importantly, administration of the synthetic EPO derivative CERA at a low-dosage (hematocrit-inactive) restored or preserved the endothelial differentiation potential of cardiac progenitor cells in mice with depleted STAT3 or in mice obtaining DOX treatment. Moreover, CERA preserved heart blood vessels and cardiac function in both mouse models[6]. Our data imply that short-term EPO administration at low-doses seems an attractive avenue to pursue for protecting the heart against chemotherapy-induced failure and might even have broader applications in cardiac regeneration[6]. However, further evaluation of EPO in tumor research is required, especially with regard to its effect on tumor growth and anti-tumor treatment strategies.

397 Molecular signature of EX vivo proliferated resident cardiac progenitor cells

A number of laboratories have documented small reservoirs of resident cardiac progenitor cells (CPCs) within the post-natal heart. Because these cells reside within the heart and have the ability to reconstitute all types of cardiac cells, they represent a promising therapy to regenerate the heart. In that view, we have developed techniques to proliferate CPCs directly from a patient's own heart biopsy with a view towards transplanting these cells back into damaged myocardium. Despite the start of clinical trials using these cells, remarkably little is known about the molecular mechanisms that underlie their multipotency. We sectioned, enzymatically digested and plated myocardial tissue from 8-9 week old c-KitBAC-GFP transgenic mice. This mouse model genetically labels CPCs with green fluorescent protein (GFP) as transgene expression is controlled by the stem cell kit locus within a bacterial artificial chromosome (BAC). After several days in culture, a layer of stromal-like cells arose from the adherent plated tissue with clusters of small GFP+ CPCs (Figure panel A). As compared to non-transgenic mice, the overall GFP fluorescence of the c-KitBAC-GFP cultures progressively increased (Figure panel B and C; Day 14: 77 ± 45% vs. 12 ± 18%, P < 0.01). Given that CPCs represented 0.1 ± 0.1% of all cells in the native heart (aggregate data from 6 random fields, n = 6 mice), flow cytometry of collected cells confirmed the ability of explant culture to markedly increased the overall CPC yields (9.2 ± 2.3%, 1.3×106 ± 1.7×105 cells collected). To identify commonalities between the transcriptional profile of explant cultured CPCs and unrestricted pluripotent cells, we compared the expression profiles of mouse embryonic stem cells (C2 mESCs), CPCs and somatic cells (dermal fibroblasts; DF) using a gene expression micro-array (Affymetrix). The gene expression patterns of CPC lines showed many similarities with the mESCs cell line and more distantly with the somatic DF cell lines. We identified 587 genes that were expressed at greater levels in mouse CPCs than in somatic control cell lines. As shown in the Figure panel D, quantitative PCR of key pluripotent markers (Oct3, nanog and sox 2) were upregulated in both CPCs and C2 mESCs with a tendency to greater expression in the more pluripotent C2 mESCs. Explant culture of myocardial biopsies from c-KitBAC-GFP transgenic mice increased the proportion of CPCs above that found in the native heart. These CPCs express genetic markers similar to mESCs and not somatic cells; hinting these genes are involved in the multipotent phenotype of CPCs.

Cardioprotection of Insulin-Like Growth Factor-1 During Reperfusion Therapy

In the setting of acute myocardial infarction, reperfusion of ischemic myocardium carried out early after coronary occlusion can salvage reversibly injured, viable myocardium. Although still controversial, however, reperfusion itself may cause a population of reversibly injured cells to die, a phenomenon termed lethal reperfusion injury .1 A variety of pharmacological agents have been studied to limit ischemia/reperfusion injury as an adjunct to current reperfusion, and some beneficial effects have been demonstrated in experimental animal research, but their clinical applications have not been achieved.2–4 Article see p 327 Among the various agents claimed to have cardioprotective effects is insulin-like growth factor-1 (IGF-1), which is a hormone produced primarily by the liver. Its molecular structure is similar to that of insulin. IGF-1 plays an important role in cellular survival and growth by binding to its specific receptor (IGF1R), which is present on many cell types, including cardiac cells. Activation of IGF1R, a receptor tyrosine kinase, has been demonstrated to attenuate both apoptotic and necrotic cell death induced by ischemia/reperfusion injury through stimulating both the intracellular phosphoinositide 3-kinase/protein kinase B signaling pathway and extracellular signal-regulated kinase 1/2 signaling cascades.5 Buerke at al6 administered IGF-I 1 hour before ischemia in a murine model of 20 minutes of myocardial ischemia followed by 24 hours of reperfusion. IGF-I preserved ischemic/reperfused myocardium through inhibition of polymorphonuclear leukocyte-induced cardiac necrosis and inhibition of reperfusion-induced apoptosis of cardiac myocytes. Davani et al7 subjected isolated murine hearts to 20 minutes of global ischemia followed by 2 hours of reperfusion with either modified Kreb's solution alone or …

Stem Cell Therapy for Ischemic Heart Disease

Stem cell transplantation has emerged as a novel treatment option for ischemic heart disease. Different cell types have been utilized and the recent development of induced pluripotent stem cells has generated tremendous excitement in the regenerative field. Bone marrow-derived multipotent progenitor cell transplantation in preclinical large animal models of postinfarction left ventricular remodeling has demonstrated long-term functional and bioenergetic improvement. These beneficial effects are observed despite no significant engraftment of bone marrow cells in the myocardium and even lower differentiation of these cells into cardiomyocytes. It is thought to be related to the paracrine effect of these stem cells, which secrete factors that lead to long-term gene expression changes in the host myocardium, thereby promoting neovascularization, inhibiting apoptosis, and stimulating resident cardiac progenitor cells. Future studies are warranted to examine the changes in the recipient myocardium after stem cell transplantation and to investigate the signaling pathways involved in these effects.

Cardiac Cell Therapies: The Next Generation

Although significant advances have been made in terms of pharmacological, catheter-based, and surgical palliation, heart failure remains a fatal disease. As a curative concept, regenerative medicine aims at the restoration of the physiologic cellular composition of diseased organs. So far, clinical cardiac regeneration attempts have only been moderately successful, but a better understanding of myocardial cell homeostasis and somatic as well as embryonic stem cell biology has opened the door for the development of more potent therapeutic cardiac regeneration strategies. Accumulating evidence indicates that the postnatal mammalian heart retains a pool of tissue-specific progenitor cells and is also repopulated by cells from extracardiac sources. However, this intrinsic myocardial regeneration potential clearly needs to be augmented by either manipulation of the cell cycle of differentiated cells, activation of resident cardiac progenitor cells, and/or the transplantation of exogenous cells. This review summarizes the recent developments in cardiac regenerative medicine, many of which may find their way into the clinical setting in the foreseeable future.

REVIEW: Stem Cell Therapy in Cardiovascular Disorders

SUMMARYHeart insufficiency remains the leading cause of death despite pharmacological and interventional therapy as well as primary and secondary prevention. Laboratory research on cardiac repair implementing stem cells and progenitor cells has raised great expectations as well as controversies. The potential of diverse progenitor cells to repair damaged heart tissue includes replacement (tissue transplant), restoration (activation of resident cardiac progenitor cells, paracrine effects), and regeneration (stem cell engraftment forming new myocytes). Based on promising experimental results clinical trials including several hundreds of patients with ischemic heart disease have been initiated using mostly bone marrow‐derived cells. Probably, due to a lack of standardization of cell isolation and delivery methods these trials showed controverse results regarding effectiveness. However, significant therapeutic regeneration of human myocardium could not be proven until now. Several issues are at debate concerning the translation of the experimental data into the clinic discussing the adequate cell type, dosing, timing, and delivery mode of myocardial stem cell therapy. This review focusses on the potential and clinical translation of cell based therapies in cardiovascular disease.

The Multiple Phases and Faces of Wnt Signaling During Cardiac Differentiation and Development

Understanding heart development on a molecular level is a prerequisite for uncovering the causes of congenital heart diseases. Therapeutic approaches that try to enhance cardiac regeneration or that involve the differentiation of resident cardiac progenitor cells or patient-specific induced pluripotent stem cells will also benefit tremendously from this knowledge. Wnt proteins have been shown to play multiple roles during cardiac differentiation and development. They are extracellular growth factors that activate different intracellular signaling branches. Here, we summarize our current understanding of how these factors affect different aspects of cardiogenesis, starting from early specification of cardiac progenitors and continuing on to later developmental steps, such as morphogenetic processes, valve formation, and establishment of the conduction system.

Cardiac progenitor cells: Potency and control

Stem cell-based regeneration of the heart has focused much scientific and public attention being cardiac diseases the major cause of disability and death in industrialized countries. Innumerable efforts have been taken to unveil the mechanisms undergoing stem cell proliferation and fate, but much remains to be endeavoured for their application in clinical practice. Nevertheless, the discovery of progenitor cells resident within the cardiac tissue has sparked off enthusiasm about the possibility of efficiently and safely engineering them to repair the injured myocardium. Indeed, the early applications of the cardiac progenitor cells, mostly based on simplistic concepts and techniques, have failed highlighting the prerequisite of expanding the knowledge about progenitor cell features and microenvironmental conditioning. In this review, recent information on resident cardiac progenitor cells has been systematically gathered in order to create a valuable instrument to support investigators in their efforts to establish an efficient cardiac cell therapy.

Hepatocyte growth factor/Met gene transfer in cardiac stem cells—potential for cardiac repair

The adult heart has been recently recognized as a self-renewing organ that contains a pool of committed resident cardiac stem cells (CSCs) and cardiac progenitor cells (CPCs). These adult CSCs and CPCs can be induced by cytokines and growth factors to migrate, differentiate, and proliferate in situ and potentially replace lost cardiomyocytes. Ligand-receptor systems, such as the tyrosine kinase receptor mesenchymal-epithelial transition factor (Met) and its ligand hepatocyte growth factor (HGF), are potential candidates for boosting migration, engraftment and commitment of CSCs. Here, we discuss the possible application of HGF/Met gene therapy to enhance the ability of CSCs to promote myocardial regeneration.