Epithelial–mesenchymal transition of epicardial mesothelium is a source of cardiac CD117-positive stem cells in adult human heart

Meglio, Franca Di; Castaldo, Clotilde; Nurzynska, Daria; Romano, Veronica; Miraglia, Rita; Bancone, Ciro; Langella, Giuseppina; Vosa, Carlo; Montagnani, Stefania

doi:10.1016/j.yjmcc.2010.05.013

Cited by 65 publications

(52 citation statements)

References 43 publications

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“…WT-1 binds to promoters of SNAI1 and CDH1 to induce or inhibit their activity, respectively, and promotes EMT [54]. Together with the EMT gene profile, the significant up-regulation of WT1 on CSps formation suggests a re-activation of the developmental and injury-induced epicardial program that might constitute an in vitro recapitulation of the formation of cardiogenic progenitors during development and in the adult [53,[55][56][57].…”

Section: Discussionmentioning

confidence: 93%

TGFβ-Dependent Epithelial-to-Mesenchymal Transition Is Required to Generate Cardiospheres from Human Adult Heart Biopsies

Forte

Miraldi

Chimenti³

et al. 2012

Stem Cells and Development

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Autologous cardiac progenitor cells (CPCs) isolated as cardiospheres (CSps) represent a promising candidate for cardiac regenerative therapy. A better understanding of the origin and mechanisms underlying human CSps formation and maturation is undoubtedly required to enhance their cardiomyogenic potential. Epithelial-to-mesenchymal transition (EMT) is a key morphogenetic process that is implicated in the acquisition of stem cell-like properties in different adult tissues, and it is activated in the epicardium after ischemic injury to the heart. We investigated whether EMT is involved in the formation and differentiation of human CSps, revealing that an up-regulation of the expression of EMT-related genes accompanies CSps formation that is relative to primary explant-derived cells and CSp-derived cells grown in a monolayer. EMT and CSps formation is enhanced in the presence of transforming growth factor b1 (TGFb1) and drastically blocked by the type I TGFb-receptor inhibitor SB431452, indicating that TGFb-dependent EMT is essential for the formation of these niche-like 3D-multicellular clusters. Since TGFb is activated in the myocardium in response to injury, our data suggest that CSps formation mimics an adaptive mechanism that could potentially be enhanced to increase in vivo or ex vivo regenerative potential of adult CPCs.

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Section: Discussionmentioning

confidence: 93%

TGFβ-Dependent Epithelial-to-Mesenchymal Transition Is Required to Generate Cardiospheres from Human Adult Heart Biopsies

Forte

Miraldi

Chimenti³

et al. 2012

Stem Cells and Development

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“…The epicardial lining has been employed to define anatomically several classes of niches in the adult heart (59,93,94,166,204,205,285,305). However, cardiac niches are not limited to the subepicardium and are dispersed throughout the myocardium (328).…”

Section: Cpc Nichesmentioning

confidence: 99%

Aging Effects on Cardiac Progenitor Cell Physiology

Rota

Goichberg

Anversa

et al. 2015

Comprehensive Physiology

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Cardiac aging has been confounded by the concept that the heart is a postmitotic organ characterized by a predetermined number of myocytes, which is established at birth and largely preserved throughout life until death of the organ and organism. Based on this premise, the age of cardiac cells should coincide with that of the organism; at any given time, the heart would be composed of a homogeneous population of myocytes of identical age. The discovery that stem cells reside in the heart and generate cardiac cell lineages has imposed a reconsideration of the mechanisms implicated in the manifestations of the aging myopathy. The progressive alterations of terminally differentiated myocytes, and vascular smooth muscle cells and endothelial cells may represent an epiphenomenon dictated by aging effects on cardiac progenitor cells (CPCs). Changes in the properties of CPCs with time may involve loss of self-renewing capacity, increased symmetric division with formation of daughter committed cells, partial depletion of the primitive pool, biased differentiation to the fibroblast fate, impaired ability to migrate, and forced entry into an irreversible quiescent state. Telomere shortening is a major variable of cellular senescence and organ aging, and support the notion that CPCs with critically shortened or dysfunctional telomeres contribute to myocardial aging and chronic heart failure. These defects constitute the critical variables that define the aging myopathy in humans. Importantly, a compartment of functionally competent human CPCs persists in the decompensated heart pointing to stem cell therapy as a novel form of treatment for the aging myopathy.

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“…Evidence of epicardial EMT-mediated formation of c-kit + cells has been further provided by the identification, in the subepicardial space of adult human hearts, of mesothelial cells expressing both epithelial and mesenchymal markers with an increase in mesenchymal markers in hearts with ischemic cardiomyopathy compared to normal hearts [62] (Fig. 3).…”

Section: Emt In Heart Developmentmentioning

confidence: 96%

“…When mice were treated with thymosin β4 after MI, epicardial activation led to angiogenesis but not to cardiogenesis [58]. Notably, a subset of c-kit + epicardial cells has been identified in the subepicardial space of human hearts with ischemic cardiomyopathy [61,62]. In a mouse model of MI, we have recently demonstrated that soluble factors present in the pericardial fluid (PF) stimulate epicardial cells giving origin to c-kit + cells that migrate from the epicardium to the infarct, where they proliferate and differentiate into myocyte precursors and vascular cells through the reactivation of the embryonic program [63,64].…”

Section: Cardiac Progenitor Cells and Heart Repairmentioning

confidence: 99%

Generation of cardiac progenitor cells through epicardial to mesenchymal transition

et al. 2015

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The epithelial to mesenchymal transition (EMT) is a biological process that drives the formation of cells involved both in tissue repair and in pathological conditions, including tissue fibrosis and tumor metastasis by providing cancer cells with stem cell properties. Recent findings suggest that EMT is reactivated in the heart following ischemic injury. Specifically, epicardial EMT might be involved in the formation of cardiac progenitor cells (CPCs) that can differentiate into endothelial cells, smooth muscle cells, and, possibly, cardiomyocytes. The identification of mechanisms and signaling pathways governing EMT-derived CPC generation and differentiation may contribute to the development of a more efficient regenerative approach for adult heart repair. Here, we summarize key literature in the field.

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Epithelial–mesenchymal transition of epicardial mesothelium is a source of cardiac CD117-positive stem cells in adult human heart

Cited by 65 publications

References 43 publications

TGFβ-Dependent Epithelial-to-Mesenchymal Transition Is Required to Generate Cardiospheres from Human Adult Heart Biopsies

TGFβ-Dependent Epithelial-to-Mesenchymal Transition Is Required to Generate Cardiospheres from Human Adult Heart Biopsies

Aging Effects on Cardiac Progenitor Cell Physiology

Generation of cardiac progenitor cells through epicardial to mesenchymal transition

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