We recently demonstrated that primitive neural crest-derived (NC) cells migrate from the cardiac neural crest during embryonic development and remain in the heart as dormant stem cells, with the capacity to differentiate into various cell types, including cardiomyocytes. Here, we examined the migration and differentiation potential of these cells on myocardial infarction (MI).
We obtained double-transgenic mice by crossing protein-0 promoter-Cre mice with Floxed-enhanced green fluorescent protein mice, in which the NC cells express enhanced green fluorescent protein. In the neonatal heart, NC stem cells (NCSCs) were localized predominantly in the outflow tract, but they were also distributed in a gradient from base to apex throughout the ventricular myocardium. Time-lapse video analysis revealed that the NCSCs were migratory. Some NCSCs persisted in the adult heart. On MI, NCSCs accumulated at the ischemic border zone area (BZA), which expresses monocyte chemoattractant protein-1 (MCP-1). Ex vivo cell migration assays demonstrated that MCP-1 induced NCSC migration and that this chemotactic effect was significantly depressed by an anti-MCP-1 antibody. Small NC cardiomyocytes first appeared in the BZA 2 weeks post-MI and gradually increased in number thereafter.
These results suggested that NCSCs migrate into the BZA via MCP-1/CCR2 signaling and contribute to the provision of cardiomyocytes for cardiac regeneration after MI.
"In the healthy heart, neural-crest derived (GFP+) cardiomyocytes were undetectable during the first week after birth but appeared at 2 weeks postnatally and increased in number thereafter; however, their absolute contributions to the myocyte pool were minimal (∼0.3% GFP+ cardiomyocytes in the septum, < 0.1% GFP+ cardiomyocytes in the rest of the left ventricle). After myocardial infarction, small GFP+ cardiomyocytes (presumably arising from differentiation of neural-crest-derived cells) first appeared in the border zone 2 weeks post-injury and gradually increased in number thereafter (comprising 3% of total cardiomyocytes in the border zone at 12 weeks post-injury).33 While this study is limited by the fact that the activity of Cre-recombinase was not temporally controlled in an inducible manner (and thus spontaneous activation of the protein-0 promoter in resident cardiomyocytes would result in GFP labeling) it suggests that progenitor cells may contribute to generation of new myocytes (especially post-injury). "
[Show abstract][Hide abstract] ABSTRACT: In recent years, several landmark studies have provided compelling evidence that cardiomyogenesis occurs in the adult mammalian heart. However, the rate of new cardiomyocyte formation is inadequate for complete restoration of the normal mass of myocardial tissue, should a significant myocardial injury occur, such as myocardial infarction. The cellular origin of postnatal cardiomyogenesis in mammals remains a controversial issue and two mechanisms seem to be participating, proliferation of pre-existing cardiomyocytes and myogenic differentiation of progenitor cells. We will discuss the relative importance of these two processes in different settings, such as normal ageing and post-myocardial injury, as well as the strengths and limitations of the existing experimental methodologies used in the relevant studies. Further clarification of the mechanisms underlying cardiomyogenesis in mammals will open the way for their therapeutic exploitation in the clinical field, with the scope of myocardial regeneration.
"Recently, lineage mapping has been utilized to locate niches in animal models by genetically labeling SC markers and identifying their location in adult tissue.78,79 An example of lineage mapping is the recent study of Tamura et al78 of neural crest-derived SCs found in the heart that migrate and differentiate into cardiomyocytes after MI. The lineage mapping has been utilized for locating SC niches in a variety of developing organisms.79 "
[Show abstract][Hide abstract] ABSTRACT: Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The use of stem cells to improve recovery of the injured heart after myocardial infarction (MI) is an important emerging therapeutic strategy. However, recent reviews of clinical trials of stem cell therapy for MI and ischemic heart disease recovery report that less than half of the trials found only small improvements in cardiac function. In clinical trials, bone marrow, peripheral blood, or umbilical cord blood cells were used as the source of stem cells delivered by intracoronary infusion. Some trials administered only a stem cell mobilizing agent that recruits endogenous sources of stem cells. Important challenges to improve the effectiveness of stem cell therapy for CVD include: (1) improved identification, recruitment, and expansion of autologous stem cells; (2) identification of mobilizing and homing agents that increase recruitment; and (3) development of strategies to improve stem cell survival and engraftment of both endogenous and exogenous sources of stem cells. This review is an overview of stem cell therapy for CVD and discusses the challenges these three areas present for maximum optimization of the efficacy of stem cell therapy for heart disease, and new strategies in progress.
Vascular Health and Risk Management 02/2012; 8(1):99-113. DOI:10.2147/VHRM.S25665
"Previous studies have shown that non-hematocrit-inducing EPO derivatives can also directly protect cardiomyocytes from apoptosis (Ueba et al., 2010). EPO treatment also induced CCL2 promoter activity in cardiomyocytes and, because CCL2 can protect cardiomyocytes from apoptosis (Tarzami et al., 2005) and promote regeneration of cardiomyocytes by inducing migration of neuronal crest cells into the injured heart (Tamura et al., 2011), the link between EPO and CCL2 signaling may be beneficial not only for the cardiac vasculature but also for other cardiac cells. The cardioprotective effect seen with CERA treatment in the two mouse models that we studied could therefore be multifaceted. "
[Show abstract][Hide abstract] ABSTRACT: Anticancer therapies, such as targeting of STAT3 or the use of anthracyclins (doxorubicin), can induce cardiomyopathy. In mice prone to developing heart failure as a result of reduced cardiac STAT3 expression (cardiomyocyte-restricted deficiency of STAT3) or treatment with doxorubicin, we observed impaired endothelial differentiation capacity of Sca-1(+) cardiac progenitor cells (CPCs) in conjunction with attenuated CCL2/CCR2 activation. Mice in both models also displayed reduced erythropoietin (EPO) levels in the cardiac microenvironment. EPO binds to CPCs and seems to be responsible for maintaining an active CCL2/CCR2 system. Supplementation with the EPO derivative CERA in a hematocrit-inactive low dose was sufficient to upregulate CCL2, restore endothelial differentiation of CPCs, and preserve the cardiac microvasculature and cardiac function in both mouse models. Thus, low-dose EPO treatment could potentially be exploited as a therapeutic strategy to reduce the risk of heart failure in certain treatment regimens.
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