Long-term contribution of human bone marrow mesenchymal stromal cells to skeletal muscle regeneration in mice.
Mesenchymal stromal cells (MSCs) are attractive for cellular therapy of muscular dystrophies as they are easy to procure, can be greatly expanded ex vivo, and contribute to skeletal muscle repair in vivo. However, detailed information about the contribution of bone marrow (BM)-derived human MSCs (BM-hMSCs) to skeletal muscle regeneration in vivo is very limited. Here, we present the results of a comprehensive study of the fate of LacZ-tagged BM-hMSCs following implantation in cardiotoxin (CTX)-injured tibialis anterior muscles (TAMs) of immunodeficient mice. β-Galactosidase-positive (β-gal(+)) human-mouse hybrid myofibers (HMs) were counted in serial cross sections over the full length of the treated TAMs of groups of mice at monthly intervals. The number of human cells was estimated using chemiluminescence assays. While the number of human cells declined gradually to about 10% of the injected cells at 60 days after transplantation, the number of HMs increased from day 10 onwards, reaching 104 ± 39.1 per TAM at 4 months postinjection. β-gal(+) cells and HMs were distributed over the entire muscle, indicating migration of the former from the central injection site to the ends of the TAMs. The identification of HMs that stained positive for human spectrin suggests myogenic reprogramming of hMSC nuclei. In summary, our findings reveal that BM-hMSCs continue to participate in the regeneration/remodeling of CTX-injured TAMs, resulting in ±5% HMs at 4 months after damage induction. Moreover, donor-derived cells were shown to express genetic information, both endogenous and transgenic, in recipient myofibers.
de la Garza-Rodea
Anabel S
AS
Virus and Stem Cell Biology Laboratory, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
van der Velde
Ietje
I
Boersma
Hester
H
Gonçalves
Manuel A F V
MA
van Bekkum
Dirk W
DW
de Vries
Antoine A F
AA
Knaän-Shanzer
Shoshan
S
D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004058:Diffusion; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D001616:beta-Galactosidase / Q000378:metabolism
D016222:Fibroblast Growth Factor 2; D001616:beta-Galactosidase