Dynamics of Myoblast Transplantation Reveal a Discrete Minority of Precursors with Stem Cell–like Properties as the Myogenic Source

Abstract

Myoblasts, the precursors of skeletal muscle fibers, can be induced to withdraw from the cell cycle and differentiate in vitro. Recent studies have also identified undifferentiated subpopulations that can self-renew and generate myogenic cells (Baroffio, A., M. Hamann, L. Bernheim, M.-L. Bochaton-Pillat, G. Gabbiani, and C.R. Bader. 1996. Differentiation. 60:47–57; Yoshida, N., S. Yoshida, K. Koishi, K. Masuda, and Y. Nabeshima. 1998. J. Cell Sci. 111:769–779). Cultured myoblasts can also differentiate and contribute to repair and new muscle formation in vivo, a capacity exploited in attempts to develop myoblast transplantation (MT) for genetic modification of adult muscle. Our studies of the dynamics of MT demonstrate that cultures of myoblasts contain distinct subpopulations defined by their behavior in vitro and divergent responses to grafting. By comparing a genomic and a semiconserved marker, we have followed the fate of myoblasts transplanted into muscles of dystrophic mice, finding that the majority of the grafted cells quickly die and only a minority are responsible for new muscle formation. This minority is behaviorally distinct, slowly dividing in tissue culture, but rapidly proliferative after grafting, suggesting a subpopulation with stem cell–like characteristics.

Systemic Delivery of Allogenic Muscle Stem Cells Induces Long-Term Muscle Repair and Clinical Efficacy in Duchenne Muscular Dystrophy Dogs

“…This revealed that MuStem cells were able to survive in the DMD context after in vitro expansion in contrast to cultured myoblasts known to have an extremely poor survival rate after injection in host muscle. 11,71,72 In parallel to fusion with host fibers and dystrophin recovery, MuStem cells generated satellite cells, an essential feature in the context of satellite cell pool exhaustion in muscular dystrophy. 73,74 This data suggested that MuStem cell injection could have a long-term impact on the regenerative potential of dystrophic fibers by their constant recruitment for the host fiber regeneration.…”

Muscle-derived cell-mediated ex vivo gene therapy for urological dysfunction

“…Furthermore, recent studies have reported that these cells may exist in skeletal muscle. 7,9,[23][24][25][26][27][28][29] The presence of stem cells in skeletal muscle makes this tissue an attractive source of cells that are capable of enhancing the healing of various tissues. 9 In fact, we have recently observed that the genetic engineering of MDC (mc13) to express rhBMP-2 can be used to enhance closure of a non-healing skull defect.…”

“…23 It is now well established that muscle satellite cells are heterogenous and that skeletal muscle tissue may be a source for pluripotent stem cells. 7,9,[24][25][26][27][28][29] In particular, stem cell populations from muscle were recently shown to reconstitute the hematopoietic compartment of lethally irradiated mice and to partially restore the expression of dystrophin in the mdx mouse, an animal model of Duchenne muscular dystrophy.…”

Muscle-derived stem cells

“…[30][31][32] It is now thought that only a few percent of donor cells survive the initial transplantation process, which includes a non-specific inflammatory reaction along with other necrotic, and yet undefined, events. [33][34][35][36][37][38] The survival of a portion of transplanted cells does not appear to be by default, rather, specific populations of muscle precursor cells may be more suited to survive this initial environment and contribute to the regeneration process. 31,33,35 Specific muscle precursor populations are now being investigated with regard to their ability to restore dystrophin expression both locally and systemically, and the results are suggestive of the existence of MDSCs.…”