Stemming heart failure with cardiac- or reprogrammed-stem cells

Kento Tateishi, Naofumi Takehara, Hiroaki Matsubara, Hidemasa Oh, Kento Tateishi, Naofumi Takehara, Hiroaki Matsubara, Hidemasa Oh

Abstract

Despite extensive efforts to control myocyte growth by genetic targeting of the cell cycle machinery and small molecules for cardiac repair, adult myocytes themselves appeared to divide a limited number of times in response to a variety of cardiac muscle stresses. Rare tissue-resident stem cells are thought to exist in many adult organs that are capable of self-renewal and differentiation and possess a range of actions that are potentially therapeutic. Recent studies suggest that a population of cardiac stem cells (CSCs) is maintained after cardiac development in the adult heart in mammals including human beings; however, homeostatic cardiomyocyte replacement might be stem cell-dependent, and functional myocardial regeneration after cardiac muscle damage is not yet considered as sufficient to fully maintain or reconstitute the cardiovascular system and function. Although it is clear that adult CSCs have limitations in their capabilities to proliferate extensively and differentiate in response to injury in vivo for replenishing mature car-diomyocytes and potentially function as resident stem cells. Transplantation of CSCs expanded ex vivo seems to require an integrated strategy of cell growth-enhancing factor(s) and tissue engineering technologies to support the donor cell survival and subsequent proliferation and differentiation in the host microenvironment. There has been substantial interest regarding the evidence that mammalian fibroblasts can be genetically reprogrammed to induced pluripotent stem (iPS) cells, which closely resemble embryonic stem (ES) cell properties capable of differentiating into functional cardiomyocytes, and these cells may provide an alternative cell source for generating patient-specific CSCs for therapeutic applications.

Figures

Figure 1
Figure 1
Isolation and characterization of clonal CSCs. Phase contrast and fluorescence micrographs of CSCs isolated from mouse (A) and human hearts (B). Human CSCs were stained with CD105 (C) and CD90 (D). Bars, 50 μm. (E) Single colony RT-PCR for genes characteristic of neural crest stem cells in mouse CSCs. The numbers on the right indicate the number of individual colonies that expressed the corresponding genes out of the colonies examined. ES, embryonic stem cells.
Figure 2
Figure 2
Cardiac stem cell niche in the adult mouse myocardium. (A—D) Immunohistochemistry of TERT promoter-driven GFP transgenic hearts using GFP antibody that was counter-stained with CD45 and eosin. TERT-positive cells in the left ventricle (A), left atria along vessel (B), outflow tract (C), right atria (D). Bars, 50 μm. CA: coronary artery; LV: left ventricle; LA: left atrium; RA: right atrium.
Figure 3
Figure 3
Sca-1 knockdown (KD) mice after acute myocardial infarction (MI) showed cardiac remodelling and reduced survival. (A) H&E staining of the hearts at baseline from wild-type (WT) and Sca-1 KD mice (top). Images of Masson's trichrome staining from hearts 4 weeks after Ml are shown (bottom). Scale bar, 1 mm. (B) Survival analysis of Sca-1 KD mice after MI. Each group started with the numbers indicated. Differences in survival rates between the Sca-1 KD and WT littermate mice after MI were significant by the Peto-Peto-Wilcoxon test. *, P < 0.01.

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