Xenotransplantation of Long Term Cultured Swine Bone Marrow-Derived Mesenchymal Stem Cells

¹ Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota
² Department of Internal Medicine and Cardiology, Osaka City University Medical School, Osaka, Japan

^* To whom correspondence should be addressed. E-mail: zhang047{at}umn.edu.

	Abstract

Swine-derived mesenchymal stem cells (MSCs) were efficiently isolated and extensively expanded using a low fetal serum content growth medium to which selected growth factors were added. After 96 cell doublings (PDs), MSCs were devoid of cytogenetic abnormalities. In vitro chondrogenic and osteogenic differentiation capacity was preserved after 80 PDs. To test therapeutic efficacy, 1X10⁶ 80 PDs MSCs were injected directly into the peri-infarct zone of hearts of immuno-deficient (NOD/SCID) mice at the time of acute myocardial infarction. Engrafted MSCs survived in the infarcted hearts for at least 4 weeks. Echocardiography at 2 and 4 weeks post-infarction revealed a significant preservation of the LV ejection fractions of infarct hearts receiving MSCs as compared to infarct hearts receiving saline. Peri-infarct zone capillarity was better preserved in MSCs treated hearts than other infarct groups of hearts, but infarct size was comparable in all groups. Only rare engrafted MSCs expressed cardiac specific or endothelial cell specific markers. Hence, 80 PDs MSCs retained the capacity to promote functional improvement in the infarcted heart despite minimal differentiation of MSCs into cardiomyocytes or endothelial cells. These data suggest that the beneficial effects of MSCs transplantation most likely result from the trophic effects of MSCs released substances on native cardiac and vascular cells. The capacity to massively expand MSCs cell lines without loss of therapeutic efficacy may prove to be useful in the clinical setting where "off the shelf" MSCs may be required for interventions in patients with acute coronary syndromes.

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