Transplanted human cord blood derived unrestricted somatic stem cells improve left-ventricular function and prevent left-ventricular dilation and scar formation after acute myocardial infarction

Alireza Ghodsizad ¹, Michael Niehaus ², Gesine Koegler ¹, Ulrich Martin ², Peter Wernet ¹, Christoph Bara ², Nawid Khaladj ², Anneke Loos ², Mike Makoui ², Juergen Thiele ³, Michael Mengel ², Matthias Karck ⁴, Hans Michael Klein ¹, Axel Haverich ² and Arjang Ruhparwar ^4*

¹ Heinrich-Heine-University Duesseldorf, Germany
² Hannover Medical School, Germany
³ University of Cologne, Germany
⁴ University of Heidelberg, Germany

^* To whom correspondence should be addressed. E-mail: arjang.ruhparwar{at}med.uni-heidelberg.de.

Accepted 13 May 2008

Abstract

Objective Functional improvement after acute myocardial ischemia (MI) has been achieved by transplantation of different adult stem and progenitor cell types. It is controversial, whether these cell types are able to form novel functional myocardium. Alternatively, graft- or immune-related paracrine mechanisms may preserve existing myocardium, improve neovascularization, affect tissue remodeling or induce endogenous de novo formation of functional myocardium. We have applied an alternative somatic cell type, human cord-blood derived unrestricted somatic stem cells (USSCs), in a porcine model of acute MI.

Methods USSCs were transplanted into the acutely ischemic lateral wall of the left ventricle. LV dimension and function were assessed by transesophageal echocardiography (TEE) pre-MI, immediately post-MI, 48 hours and 8 weeks after USSC injection. Additionally, apoptosis, mitosis and recruitment of macrophages were examimined 48 hours post-engraftment.

Results Gender- and species-specific FISH / immunostaining failed to detect engrafted donor cells 8 weeks post-MI. Nevertheless, cell treatment effectively preserved natural myocardial architecture. Global left ventricular ejection fraction (LVEF) prior to MI was 60 ± 7 %. Post-MI, LVEF decreased to 34 ± 8 %. After 8 weeks, LVEF had further decreased to 27 ± 6 % in the control group and recovered to 52 ± 2 % in the USSC group (p < 0.01). Left-ventricular end-diastolic volume (LVEDV) prior to MI was 28 ± 2 ml. 8 weeks post-MI, LVEDV had increased to 77 ± 4 ml in the control group. No LV dilation was detected in the USSC group (LVEDV: 26 ± 2 ml, p < 0.01). Neither apoptosis nor recruitment of macrophages and mitosis were different in both groups.

Conclusions Transplantation of USSCs significantly improved LV function and prevented scar formation as well as LV dilation. Since differentiation, apoptosis and macrophage mobilization at infarct site were excluded as underlying mechanisms, paracrine effects are most likely to account for the observed effects of USSC treatment.