CD117-Positive Cells in Adult Human Heart Are Localized in the Subepicardium, and Their Activation Is Associated with Laminin-1 and α6 Integrin Expression

Castaldo, Clotilde; Meglio, Franca Di; Nurzynska, Daria; Romano, Gianpaolo; Maiello, Ciro; Bancone, Ciro; Müller, Patrick; Böhm, Michael; Cotrufo, Maurizio; Montagnani, Stefania

doi:10.1634/stemcells.2007-0732

Cited by 80 publications

(67 citation statements)

References 33 publications

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“…The recognition that the adult heart harbors a compartment of multipotent c-kit-positive cardiac stem cells (CSCs) (15)(16)(17)(18)(19)(20)(21)(22)(23) and other progenitor cell classes (24)(25)(26)(27)(28)(29) capable of differentiating into cardiomyocytes and coronary vessels has raised the challenging question concerning their embryologic origin and role in cardiac cell turnover and regeneration. CSCs are stored in interstitial structures with the characteristics of stem cell niches and can divide symmetrically and asymmetrically, with the ability to self-renew and form a committed progeny (17,21,30).…”

Section: Introductionmentioning

confidence: 99%

Regenerating new heart with stem cells

Anversa

Kajstura²,

Rota³

et al. 2013

J. Clin. Invest.

142

126

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This article discusses current understanding of myocardial biology, emphasizing the regeneration potential of the adult human heart and the mechanisms involved. In the last decade, a novel conceptual view has emerged. The heart is no longer considered a postmitotic organ, but is viewed as a self-renewing organ characterized by a resident stem cell compartment responsible for tissue homeostasis and cardiac repair following injury. Additionally, HSCs possess the ability to transdifferentiate and acquire the cardiomyocyte, vascular endothelial, and smooth muscle cell lineages. Both cardiac and hematopoietic stem cells may be used therapeutically in an attempt to reverse the devastating consequences of chronic heart failure of ischemic and nonischemic origin. IntroductionOur understanding of the process of myocardial regeneration is currently under debate. Although the adult human heart is no longer considered a static organ unable to replace its parenchymal cells during the course of life, the rate of myocyte regeneration reported thus far varies dramatically. Minimal levels of myocyte turnover, which decrease with age, have been claimed (1-5), but results have also been obtained supporting continuous myocyte renewal at a remarkable degree (6-12). Independent from the extent of the process, the debate is further intensified by contrasting views regarding the origin of newly formed cardiomyocytes (13,14). These issues have important implications because knowledge of the magnitude of cell regeneration and the mechanisms involved may offer a novel dynamic perspective of cardiac homeostasis and myocardial biology. This information is critical for the identification of strategies aiming at the restoration of the functional and structural integrity of the failing human heart.The recognition that the adult heart harbors a compartment of multipotent c-kit-positive cardiac stem cells (CSCs) (15-23) and other progenitor cell classes (24-29) capable of differentiating into cardiomyocytes and coronary vessels has raised the challenging question concerning their embryologic origin and role in cardiac cell turnover and regeneration. CSCs are stored in interstitial structures with the characteristics of stem cell niches and can divide symmetrically and asymmetrically, with the ability to self-renew and form a committed progeny (17,21,30). But whether this stem cell pool is actually self-autonomous and fully distinct from HSCs in the bone marrow remains to be determined. c-kit-positive HSCs transdifferentiate and acquire the myocyte, endothelial cell, and smooth muscle cell lineage (31), suggesting that the bone marrow participates in the homeostatic control of the myocardium and the restoration of myocytes and coronary vessels following injury. Additionally, the possibility has been advanced that postmitotic myocytes dedifferentiate, acquire an immature cell phenotype, and then reenter the cell cycle and divide (32-35), representing an alternative or complementary modality of myocyte formation. In this Review, we discuss CSCs, HS...

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Section: Introductionmentioning

confidence: 99%

Regenerating new heart with stem cells

Anversa

Kajstura²,

Rota³

et al. 2013

J. Clin. Invest.

142

126

View full text Add to dashboard Cite

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“…However, KIT is not a unique marker of this proposed cardiac stem cell population. KIT expression has been reported in postnatal cardiomyocytes , in adult cardiomyocytes induced to dedifferentiate (Jesty et al, 2012;Kubin et al, 2011;Zhang et al, 2010), as well as in coronary endothelial cells and epicardial cells (Castaldo et al, 2008;Limana et al, 2007;Tallini et al, 2009). KIT expression can also be induced from KIT − cells in vitro (Keith and Bolli, 2015).…”

Section: Endogenous Adult Cardiac Stem Cellsmentioning

confidence: 99%

Developmental origin and lineage plasticity of endogenous cardiac stem cells

et al. 2016

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Over the past two decades, several populations of cardiac stem cells have been described in the adult mammalian heart. For the most part, however, their lineage origins and in vivo functions remain largely unexplored. This Review summarizes what is known about different populations of embryonic and adult cardiac stem cells, including KIT + , PDGFRα + , ISL1 + and SCA1 + cells, side population cells, cardiospheres and epicardial cells. We discuss their developmental origins and defining characteristics, and consider their possible contribution to heart organogenesis and regeneration. We also summarize the origin and plasticity of cardiac fibroblasts and circulating endothelial progenitor cells, and consider what role these cells have in contributing to cardiac repair.

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“…6 Regarding immature cells, activation of CD117-positive cells localized in the subepicardium of adult human heart is associated with ␣6 expression. 7 Cell transplantation experiments on irradiated mice have shown that ␣6 plays a role in hematopoietic stem cell homing to bone marrow. 8 Because hematopoietic cells and endothelial cells might arise from a common precursor (the hemangioblast), we investigated the possible role of ␣6 in the homing of endothelial progenitor cells (EPCs).…”

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confidence: 99%

α6-Integrin Subunit Plays a Major Role in the Proangiogenic Properties of Endothelial Progenitor Cells

Bouvard

Gafsou

Dizier

et al. 2010

ATVB

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Objective-Alpha6 integrin subunit (␣6) expression is increased by proangiogenic growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor. This increase correlates with enhanced in vitro tube formation by endothelial cells and their progenitors called Endothelial Colony-Forming Cells (ECFCs). We thus studied the role of ␣6 in vasculogenesis induced by human ECFCs, in a mouse model of hindlimb ischemia. Methods and Results-We used small interfering RNA (siRNA) to inhibit ␣6 expression on the surface of ECFCs. For in vivo studies, human ECFCs were injected intravenously into a nude mouse model of unilateral hind limb ischemia. Transfection with siRNA ␣6 abrogated neovessel formation and reperfusion of the ischemic hind limb induced by ECFCs (PϽ0.01 and PϽ0.001, respectively). It also inhibited ECFC incorporation into the vasculature of the ischemic muscle (PϽ0.001). In vitro, siRNA ␣6 inhibited ECFC adhesion (PϽ0.01), pseudotube formation on Matrigel, migration, and AKT phosphorylation (PϽ0.0001), with no effect on cell proliferation or apoptosis. Key Words: adhesion molecules Ⅲ angiogenesis Ⅲ ischemia Ⅲ peripheral arterial disease Ⅲ vascular biology T he ␣6-integrin subunit (␣6) is a 140-kDa protein that can associate with ␤1-or ␤4-integrin subunits. Integrin ␣6␤1 is a receptor for laminin, the main component of the basement membrane, but can also bind other extracellular matrix (ECM) proteins, such as the angiogenic inducer CYR61. 1 It is expressed on platelets, monocytes/macrophages, neutrophils, and endothelial cells. Integrin ␣6␤4 primarily binds laminin; its expression is restricted to epithelial tissues, endothelia, and peripheral nerves; and it is responsible for adhesion junctions called hemidesmosomes. Conclusion-␣6In mice, deletion of the gene coding for ␣6 leads to an absence of hemidesmosomes and, consequently, to severe skin blistering and neonatal death. 2 In humans, defects in ␣6 result in hemidesmosome deficiency, causing epidermolysis bullosa or pyloric atresia and, in most cases, early postnatal death. 3,4 No obvious vascular abnormalities have been reported in such patients or in ␣6 knockout mice, suggesting that ␣6 does not have a major role in vasculogenesis during embryogenesis. In contrast, ␣6 is involved in the angiogenic properties of mature cells. For example, ␣6 is required for the formation of vascular networks in vitro by human brain microvascular endothelial cells 5 and human umbilical vein endothelial cells. 6 Regarding immature cells, activation of CD117-positive cells localized in the subepicardium of adult human heart is associated with ␣6 expression. 7 Cell transplantation experiments on irradiated mice have shown that ␣6 plays a role in hematopoietic stem cell homing to bone marrow. 8 Because hematopoietic cells and endothelial cells might arise from a common precursor (the hemangioblast), we investigated the possible role of ␣6 in the homing of endothelial progenitor cells (EPCs).EPCs are marrow-derived circulating cells involved in postnata...

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CD117-Positive Cells in Adult Human Heart Are Localized in the Subepicardium, and Their Activation Is Associated with Laminin-1 and α6 Integrin Expression

Cited by 80 publications

References 33 publications

Regenerating new heart with stem cells

Regenerating new heart with stem cells

Developmental origin and lineage plasticity of endogenous cardiac stem cells

α6-Integrin Subunit Plays a Major Role in the Proangiogenic Properties of Endothelial Progenitor Cells

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