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


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 × 10(5)) 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.
Dimomeletis
Ilias
I
Department of General and Vascular Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Deindl
Elisabeth
E
Zaruba
Marc
M
Groebner
Michael
M
Zahler
Stefan
S
Laslo
Saskia M
SM
David
Robert
R
Kostin
Sawa
S
Deutsch
Markus A
MA
Assmann
Gerd
G
Mueller-Hoecker
Josef
J
Feuring-Buske
Michaela
M
Franz
Wolfgang M
WM
D000199:Actins / Q000235:genetics; D000328:Adult; D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D006680:HLA Antigens / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D009130:Muscle, Smooth / Q000737:chemistry; D009203:Myocardial Infarction / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D012038:Regeneration / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation / Q000379:methods*; D019210:Troponin I / Q000235:genetics; D020107:Troponin T / Q000235:genetics
D000199:Actins; D006680:HLA Antigens; D050814:Octamer Transcription Factor-3; D019210:Troponin I; D020107:Troponin T