Engraftment of mesenchymal stem cells into dystrophin-deficient mice is not accompanied by functional recovery

Abstract

Mesenchymal stem cell preparations have been proposed for muscle regeneration in musculoskeletal disorders. Although MSCs have great in vitro expansion potential and possess the ability to differentiate into several mesenchymal lineages, myogenesis has proven to be much more difficult to induce. We have recently demonstrated that Pax3, the master regulator of the embryonic myogenic program, enables the in vitro differentiation of a murine mesenchymal stem cell line (MSCB9-Pax3) into myogenic progenitors. Here we show that injection of these cells into cardiotoxin-injured muscles of immunodeficient mice leads to the development of muscle tumors, resembling rhabdomyosarcomas. We then extended these studies to primary human mesenchymal stem cells (hMSCs) isolated from bone marrow. Upon genetic modification with a lentiviral vector encoding PAX3, hMSCs activated the myogenic program as demonstrated by expression of myogenic regulatory factors. Upon transplantation, the PAX3-modified MSCs did not generate rhabdomyosarcomas but rather, resulted in donor-derived myofibers. These were found at higher frequency in PAX3-transduced hMSCs than in mock-transduced MSCs. Nonetheless, neither engraftment of PAX3-modified or unmodified MSCs resulted in improved contractility.Thus these findings suggest that limitations remain to be overcome before MSC preparations result in effective treatment for muscular dystrophies.

Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells

“…MSCs have been shown to be capable of skeletal myogenesis (65). However, recently, Perlingeiro and colleagues demonstrated that although Pax3 activation enabled the in vitro differentiation of murine and human MSCs into MyoD + myogenic cells, these cells failed to cause functional muscle recovery in mdx mice, despite good engraftment (66). The reason for this failure remains unclear.…”

Distinct Embryonic and Adult Fates of Multipotent Myogenic Progenitors Isolated from Skeletal Muscle and Bone Marrow

“…More immature subpopulations of myogenic progenitors sorted by pre-defined cell surface markers from skeletal muscle are able to contribute to the satellite cell pool and give improved engraftments in dystrophin-deficient mdx mice [16][17][18]. Different populations of myogenic cells have also been derived from vascular progenitor cells [9], adipose-derived progenitors [10], genetically modified mesenchymal stem cells [19], and embryonic stem cells [20]. While the efficiency of engraftments is improving, muscle function has been limited, and variable [21,22], and tumorigenesis has been reported in studies [19,20].…”

Concise Review: Mesoangioblast and Mesenchymal Stem Cell Therapy for Muscular Dystrophy: Progress, Challenges, and Future Directions

“…Dystrophin was detected in 6%-11% of muscle fibers in the mdx mouse, a murine model for DMD [45][46][47] after transplantation of murine BM-MSCs transduced with a human microdystrophin gene [45,47] or human BM-MSCs [46]. However, only one of these studies demonstrated conclusively that the dystrophinpositive myofibers detected originated from the donor cells by examining the percentage of dystrophin-positive fibers that expressed human microdystrophin [46]. This distinction is relevant, because the low number of dystrophin-positive myofibers detected might have been naturally arising "revertant" fibers, which are detected at low levels in dystrophic muscle, rather than fibers generated by donor MSCs.…”

“…This finding is similar to that from a previous report in which human and rat green fluorescent protein (GFP)-positive BM-MSCs generated GFP-positive Pax7+ satellite cells in murine skeletal muscle that subsequently generated GFP-positive myofibers after cardiotoxin damage [49]. BMMSCs, therefore, could have the potential to generate new, dystrophin-expressing myofibers and contribute to the satellite cell niche in dystrophic muscle; however, they would do so at low rates, which is likely the reason for the lack of functional improvement [46,47].…”