Human Skeletal Muscle–derived CD133+ Cells Form Functional Satellite Cells After Intramuscular Transplantation in Immunodeficient Host Mice

Abstract

Stem cell therapy is a promising strategy for treatment of muscular dystrophies. In addition to muscle fiber formation, reconstitution of functional stem cell pool by donor cells is vital for long-term treatment. We show here that some CD133(+) cells within human muscle are located underneath the basal lamina of muscle fibers, in the position of the muscle satellite cell. Cultured hCD133(+) cells are heterogeneous and multipotent, capable of forming myotubes and reserve satellite cells in vitro. They contribute to extensive muscle regeneration and satellite cell formation following intramuscular transplantation into irradiated and cryodamaged tibialis anterior muscles of immunodeficient Rag2-/γ chain-/C5-mice. Some donor-derived satellite cells expressed the myogenic regulatory factor MyoD, indicating that they were activated. In addition, when transplanted host muscles were reinjured, there was significantly more newly-regenerated muscle fibers of donor origin in treated than in control, nonreinjured muscles, indicating that hCD133(+) cells had given rise to functional muscle stem cells, which were able to activate in response to injury and contribute to a further round of muscle regeneration. Our findings provide new evidence for the location and characterization of hCD133(+) cells, and highlight that these cells are highly suitable for future clinical application.

Cell therapy to improve regeneration of skeletal muscle injuries

“…However, their kinetics of myogenic differentiation vary significantly than that of SCs, only expressing myogenic markers at the onset of terminal differentiation . In a mouse cryoinjury model, intramuscular transplantation of muscle‐derived CD133+ cells re‐populated the SC niche, and these donor cells were observed to mount a potent regenerative response after subsequent re‐injury …”

Biomaterial and stem cell‐based strategies for skeletal muscle regeneration

“…The results showed that the CD133 + stem cells outperformed myoblasts in terms of migration, repopulation of the satellite cell niche, and overall regenerative capacity. A recent study demonstrated that human CD133 + cells transplanted into mouse muscles are functional and can give rise to satellite cells in vitro and in vivo . However, similar to myoblasts, the prolonged culture of donor CD133 + cells was shown to reduce their effectiveness in vivo.…”

“…A recent study demonstrated that human CD133 þ cells transplanted into mouse muscles are functional and can give rise to satellite cells in vitro and in vivo. 121 However, similar to myoblasts, the prolonged culture of donor CD133 þ cells was shown to reduce their effectiveness in vivo. In another study, human adult CD133 þ stem cells were mobilized from the peripheral blood by granulocyte colony-stimulating factor (G-CSF) and intramuscularly injected into lacerated muscles in athymic rats.…”

Coaxing stem cells for skeletal muscle repair

“…These authors have isolated muscle-derived CD133+ stem cells from DMD patients and genetically corrected these to express a functional form of dystrophin. The genetically corrected human CD133+ cells were transplanted into immunodeficient dystrophic mice and showed recovery of dystrophin expression, regeneration of muscle fibers and notably, greater in vitro and in vivo measured muscular force output [78–80]. …”