Discussion: Regeneration of Vascularized Corticocancellous Bone and Diploic Space Using Muscle-Derived Stem Cells

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Autologous bone grafts remain the standard of care for reconstruction of large defects, given their osteoconductive and osteoinductive capacity. They are, however, limited in availability, and can be associated with significant donor-site morbidity.1 Tissue regenerative strategies that exploit both the mechanical properties of bioengineered materials and the bone-forming capacity of biological cellular building blocks represent a promising strategy with which to address some of the limitations of currently available techniques.
In the present study by Lough et al., use of muscle-derived stem cells as a cellular-based therapy for large craniofacial skeletal defects was explored. Although the osteogenic potential of muscle-derived stem cells has already been well documented in the literature,2–4 this study further elaborated on their osteogenic capacity with the demonstration that muscle-derived stem cells are capable of forming organized, corticocancellous bone when in the presence of bone morphogenetic protein-2 and a collagen scaffold. In addition, the increased angiogenesis and diploic space formation seen with muscle-derived stem cells was not observed with adipose-derived stem cells and bone marrow–derived stem cells when implanted into cranial defects. Although adipose-derived stem cells and bone marrow–derived stem cells generated more random bone, no self-organizing structure that duplicated the appearance of native bone was observed.
The finding of organized corticocancellous bone formation by muscle-derived stem cells alone is particularly interesting, given recent studies by Chan and colleagues characterizing the mouse skeletal stem cell.5,6 Rainbow clonal analysis of femoral growth plates in mice has led to the identification of a skeletal stem cell capable of hierarchical differentiation into lineage-restricted progenitors including chondrogenic and osteogenic cells, and hematopoietic supportive stroma. The in vivo activity of the mouse skeletal stem cell, however, is dependent on a proper niche, as engraftment and subsequent formation of progeny were not observed without co-implantation with supportive fetal long bone cells and, similar to what Lough et al. described, bone morphogenetic protein-2 delivered with a collagen sponge was capable of stimulating skeletal stem cells to form abundant osseous osteoids replete with marrow at extraskeletal sites.5 Importantly, the mouse skeletal stem cell is not normally detectable and is exceedingly rare in subcutaneous adipose tissue, and this parallels what Lough and colleagues described, with adipose-derived stem cells derived from the inguinal fat pad incapable of regenerating corticocancellous bone. However, the description of native bone with diploic space formed by muscle-derived stem cells hints at the possibility that mouse skeletal stem cells may be more prevalent in muscle.
The findings in this present study are compelling with regard to efforts aimed at regenerating sufficient functional bone for complex skeletal defects. However, the availability of sufficient cells remains one obstacle to the clinical translation of muscle-derived stem cells for bone regeneration. Although adipose-derived stem cells can be readily obtained in high numbers through liposuction, muscle-derived stem cells may prove more challenging to harvest. Furthermore, obtaining an adequate number of cells to reconstruct a large defect may require a period of ex vivo expansion for muscle-derived stem cells. That said, muscle-derived stem cells remain an underappreciated and underresearched cellular building block for bone tissue regenerative strategies. The authors’ findings show promise for muscle-derived stem cells in the reconstruction of complex skeletal defects, and they highlight an important addition to the efforts to regenerate sufficient functional bone.
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