Muscular dystrophy therapy by nonautologous mesenchymal stem cells: muscle regeneration without immunosuppression and inflammation.
BACKGROUND
The use of nonautologous stem cells isolated from healthy donors for stem-cell therapy is an attractive approach, because the stem cells can be culture expanded in advance, thoroughly tested, and formulated into off-the-shelf medicine. However, human leukocyte antigen compatibility and related immunosuppressive protocols can compromise therapeutic efficacy and cause unwanted side effects.


METHODS
Mesenchymal stem cells (MSCs) have been postulated to possess unique immune regulatory function. We explored the immunomodulatory property of human and porcine MSCs for the treatment of delta-sarcoglycan-deficient dystrophic hamster muscle without immunosuppression. Circulating and tissue markers of inflammation were analyzed. Muscle regeneration and stem-cell fate were characterized.


RESULTS
Total white blood cell counts and leukocyte-distribution profiles were similar among the saline- and MSC-injected dystrophic hamsters 1 month posttreatment. Circulating levels of immunoglobulin A, vascular cell adhesion molecule-1, myeloperoxidase, and major cytokines involved in inflammatory response were not elevated by MSCs, nor were expression of the leukocyte common antigen CD45 and the cytokine transcriptional activator NF-kappaB in the injected muscle. Treated muscles exhibited increased cell-cycle activity and attenuated oxidative stress. Injected MSCs were found to be trapped in the musculature, contribute to both preexisting and new muscle fibers, and mediates capillary formation.


CONCLUSIONS
Intramuscular injection of nonautologous MSCs can be safely used for the treatment of dystrophic muscle in immunocompetent hosts without inflaming the host immune system.
Shabbir
Arsalan
A
Department of Biochemistry, University at Buffalo, Buffalo, NY 14214, USA.
Zisa
David
D
Leiker
Merced
M
Johnston
Curtis
C
Lin
Huey
H
Lee
Techung
T
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation; D006224:Cricetinae; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007273:Injections, Intramuscular; D015227:Lipid Peroxidation; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000276:immunology / Q000601:surgery*; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049031:Sarcoglycans / Q000172:deficiency; D014019:Tissue Donors; D014183:Transplantation, Heterologous / Q000379:methods*
D007166:Immunosuppressive Agents; D049031:Sarcoglycans