Abstract
Laboratory large animal models are important for establishing the efficacy of stem cell therapies that may be translated into clinical use. The similarity of ovine and human cardiovascular systems provides an opportunity to use the sheep as a large animal model in which to optimize cell-based treatments for the heart. Recent clinical trials in humans using endogenous cardiovascular progenitor cells report significant improvement in cardiac function following stem cell-based therapy. To date, however, endogenous cardiovascular progenitor cells have not been isolated from the sheep heart. Cardiovascular cells expressing SSEA-4, CD105 and c-kit were isolated by flow cytometry and cloned from the right atrium of neonatal sheep. The expression of GATA-4, c-kit, and Isl1 was identified by PCR in the cloned cells. Immunohistochemical staining was used to compare the number of SSEA-4 positive cells in the right auricle, right atrium, left ventricle and the apex of the heart of fetal, neonatal and adult sheep. The number of SSEA4+cells was also compared in fetal, pregnant and non-pregnant adult sheep. Four distinct cardiac progenitor cell sub-populations were identified in sheep, including CD105+SSEA-4+c-kit+Isl1+GATA-4+cells, CD105+SSEA-4+c-kit+Isl1+GATA-4-cells, CD105+SSEA-4-c-kit-Isl1+GATA-4-cells, and CD105+SSEA-4-c-kit+Isl1+GATA-4-cells. Immunohistochemical staining for SSEA-4 showed that labeled cells were most abundant in the right atrium of fetal hearts where niches of progenitor cells could be identified. We determined the phenotype and distribution of cardiac progenitor cells in the sheep heart. The availability of cloned endogenous cardiac progenitor cells from sheep will provide a valuable resource for optimizing the conditions for cardiac repair in the ovine model.
Highlights
Small animal models have been used widely to explore the impact of stem cell transplantation on cardiac function [1,2,3,4]
Cell surface markers expressed on neonatal sheep cardiovascular cell clones
A total of 36 clones were derived from neonatal sheep hearts and were tested for stage-specific embryonic antigen 4 (SSEA-4), CD105 and c-kit expression levels by flow cytometry (Figure 1)
Summary
Small animal models have been used widely to explore the impact of stem cell transplantation on cardiac function [1,2,3,4]. Stem cell-derived cardiovascular progenitors are capable of both neovascularization and cardiomyogenesis [5,6] Administration of these cells for cardiovascular repair frequently provides a functional benefit in both mice and rats [7,8]. Data from several laboratories document the ability to expand these cells readily, and the ability of these progenitors to be differentiated in vitro into cardiovascular cells [13,14,15] In clinical trials, these cells have been introduced into patients with ischemic cardiomyopathy (SCIPIO study) with promising results [16]. Recent clinical trials in humans using endogenous cardiovascular progenitor cells report significant improvement in cardiac function following stem cell-based therapy. Endogenous cardiovascular progenitor cells have not been isolated from the sheep heart
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