In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes

Abstract

SUMMARYThe reprogramming of adult cells into pluripotent cells or directly into alternative adult cell types holds great promise for regenerative medicine. We reported that cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be directly reprogrammed to adult cardiomyocyte-like cells in vitro by the addition of Gata4, Mef2c and Tbx5 (GMT). Here, we use genetic lineage-tracing to show that resident non-myocytes in the murine heart can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of GMT after coronary ligation. Induced cardiomyocytes became bi-nucleate, assembled sarcomeres and had cardiomyocyte-like gene expression. Analysis of single cells revealed ventricular cardiomyocyte-like action potentials, beating upon electrical stimulation, and evidence of electrical coupling. In vivo delivery of GMT decreased infarct size and modestly attenuated cardiac dysfunction up to 3 months after coronary ligation. Delivery of the pro-angiogenic and fibroblast activating peptide, Thymosin β4, along with GMT, resulted in further improvements in scar area and cardiac function. These findings demonstrate that cardiac fibroblasts can be reprogrammed into cardiomyocyte-like cells in their native environment for potential regenerative purposes.

How stem cells speak with host immune cells in inflammatory brain diseases

“…MSCs lack the expression of CD44, a cell-surface glycoprotein that binds to hyaluronic acid (HA) and is expressed in activated T cells (DeGrendele et al, 1997); yet, they acquire CD44 expression after extensive in vitro expansion (Qian et al, 2012). CD44-expressing NPCs ( Fig.…”

Hydrogen peroxide primes heart regeneration with a derepression mechanism

“…The dedifferentiation model for the cellular sources of cardiac repair/regeneration was supported by the fact that cardiac muscles mainly regenerate from pre-existing cardiomyocytes after injury in zebrafish [8,9] and mammals [10][11][12]. The stem cell/progenitor cell model for cardiac regeneration in mammals was also recognized by the existence of Sca1 + and c-Kit + cardiac stem cells in mice [13,14], while the transdifferentiation or lineage reprogramming model was proposed partly based on the ability of cardiac fibroblast transdifferentiation into myocytes upon induction by reprogramming factors or microRNA in mice [15][16][17] and reprogramming of embryonic atrial into ventricular myocytes after injury in zebrafish [18]. In spite of great efforts, the molecular mechanisms underlying heart regeneration remain incompletely understood.…”

Vers une régénération induite du système nerveux

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