Improved cardiac function in infarcted mice after treatment with pluripotent embryonic stem cells

Department of Cell Biology, Neurobiology, and Anatomy and the Cardiovascular Center Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
The Anatomical Record Part A Discoveries in Molecular Cellular and Evolutionary Biology 11/2006; 288(11):1216-24. DOI: 10.1002/ar.a.20388
Source: PubMed


Because pluripotent embryonic stem cells (ESCs) are able to differentiate into any tissue, they are attractive agents for tissue regeneration. Although improvement of cardiac function has been observed after transplantation of pluripotent ESCs, the extent to which these effects reflect ESC-mediated remuscularization, revascularization, or paracrine mechanisms is unknown. Moreover, because ESCs may generate teratomas, the ability to predict the outcome of cellular differentiation, especially when transplanting pluripotent ESCs, is essential; conversely, a requirement to use predifferentiated ESCs would limit their application to highly characterized subsets that are available in limited numbers. In the experiments reported here, we transplanted low numbers of two murine ESC lines, respectively engineered to express a beta-galactosidase gene from either a constitutive (elongation factor) or a cardiac-specific (alpha-myosin heavy chain) promoter, into infarcted mouse myocardium. Although ESC-derived tumors formed within the pericardial space in 21% of injected hearts, lacZ histochemistry revealed that engraftment of ESC was restricted to the ischemic myocardium. Echocardiographic monitoring of ESC-injected hearts that did not form tumors revealed functional improvements by 4 weeks postinfarction, including significant increases in ejection fraction, circumferential fiber shortening velocity, and peak mitral blood flow velocity. These experiments indicate that the infarcted myocardial environment can support engraftment and cardiomyogenic differentiation of pluripotent ESCs, concomitant with partial functional recovery.

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Available from: Zhi-Dong Ge
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    • "This plasticity is a challenge because we do not understand the myriad of cues capable of directing differentiation. This is particularly problematic with pluripotent stem cells whose ability to generate cells of all embryonic germ layers presents the very real problem of teratoma formation when these cells are used for tissue repair [1], [2]. To circumvent this problem, one method would be to separate the differentiating cells from those that retain pluripotency. "
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    • "Moreover, their unique characteristics related to the differentiation, regeneration, development, remodeling, and replenishment of aged and diseased tissues make them perfect candidates in this area. In a very easy and simple way, stem cells can be conceptually divided into two types: embryonic stem cells (ESCs) – derived from a very early embryo and adult stem cells – found in postnatal tissues, of both the body (bone marrow [BM], adipose tissue, etc) and the umbilical cord (UC).1 "
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    • "Neoplastic progression of differentiated somatic cells used for cell based therapy is a critical problem [4]. However, failure to execute differentiation in a small fraction of cells that could contaminate the donor cells used for transplantation is also critical to PSC tumorigenicity, as the most common tumor type documented after transplantation of differentiated donor cells derived from PSCs are teratomas [3], [12], [13], [14], [15], [16]. In one study using murine induced pluripotent stem (iPS) cells, it was shown that the number of Nanog-positive ECCs that persisted during neurosphere differentiation in vitro correlated with teratoma formation of the transplanted neurospheres in vivo [3]. "
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