Assessment of human MAPCs for stem cell transplantation and cardiac regeneration after myocardial infarction in SCID mice

Dimomeletis, Ilias; Deindl, Elisabeth; Zaruba, Marc; Groebner, Michael; Zahler, Stefan; Laslo, Saskia M.; David, Robert; Kostin, Sawa; Deutsch, Markus A.; Assmann, Gerd; Mueller-Hoecker, Josef; Feuring-Buske, Michaela; Franz, Wolfgang M.

doi:10.1016/j.exphem.2010.06.013

« Previous Next »Experimental Hematology
Volume 38, Issue 11 , Pages 1105-1114, November 2010

Assessment of human MAPCs for stem cell transplantation and cardiac regeneration after myocardial infarction in SCID mice

Ilias Dimomeletis
- Department of General and Vascular Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany
- Drs. Dimomeletis and Deindl contributed equally to this work.
Elisabeth Deindl
- Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany
- Drs. Dimomeletis and Deindl contributed equally to this work.
Marc Zaruba
- Medical Clinic I, Department of Cardiology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany
Michael Groebner
- Medical Clinic I, Department of Cardiology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany
Stefan Zahler
- Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, Munich, Germany
Saskia M. Laslo
- Medical Clinic I, Department of Cardiology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany
Robert David
- Medical Clinic I, Department of Cardiology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany
Sawa Kostin
- Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
Markus A. Deutsch
- Medical Clinic I, Department of Cardiology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany
Gerd Assmann
- Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany
Josef Mueller-Hoecker
- Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany
Michaela Feuring-Buske
- Medical Clinic IIII, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany
Wolfgang M. Franz
- Medical Clinic I, Department of Cardiology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany
- Offprint requests to: Wolfgang M. Franz, Ph.D., Medizinische Klinik und Poliklinik I der LMU, Klinikum der Universität München-Großhadern, Marchioninistr. 15, D-81377 München

Received 4 February 2010; received in revised form 30 June 2010; accepted 30 June 2010. published online 12 July 2010.

Objective

Clinical studies suggest that transplantation of total bone marrow (BM) after myocardial infarction (MI) is feasible and potentially effective. However, focusing on a defined BM-derived stem cell type may enable a more specific and optimized treatment. Multilineage differentiation potential makes BM-derived multipotent adult progenitor cells (MAPCs) a promising stem cell pool for regenerative purposes. We analyzed the cardioregenerative potential of human MAPCs in a murine model of myocardial infarction.

Materials and Methods

Human MAPCs were selected by negative depletion of CD45⁺/glycophorin⁺ BM cells and plated on fibronectin-coated dishes. In vitro, stem cells were analyzed by reverse transcription polymerase chain reaction. In vivo, we transplanted human MAPCs (5 × 10⁵) by intramyocardial injection after MI in severe combined immunodeficient (SCID) beige mice. Six and 30 days after the surgical procedure, pressure-volume relationships were investigated in vivo. Heart tissues were analyzed immunohistochemically.

Results

Reverse transcription polymerase chain reaction experiments on early human MAPC passages evidenced an expression of Oct-4, a stem cell marker indicating pluripotency. In later passages, cardiac markers (Nkx2.5, GATA4, MLC-2v, MLC-2a, ANP, cTnT, cTnI,) and smooth muscle cell markers (SMA, SM22α) were expressed. Transplantation of human MAPCs into the ischemic border zone after MI resulted in an improved cardiac function at day 6 (ejection fraction, 26% vs 20%) and day 30 (ejection fraction, 30% vs 23%). Confirmation of human MAPC marker vimentin in immunohistochemistry demonstrated that human MAPC integrated in the peri-infarct region. The proliferation marker Ki67 was absent in immunohistochemistry and teratoma formation was not found, indicating no tumorous potential of transplanted human MAPCs in the tumor-sensitive SCID model.

Conclusions

Transplantation of human MAPCs after MI ameliorates myocardial function, which may be explained by trophic effects of human MAPCs. Lack of evidence of tumorous potential in the tumor-sensitive SCID model indicates that human MAPCs may deliver an effective and safe stem cell pool for potential treatment of ischemic heart disease.