Bone Marrow Stromal Cells Generate Muscle Cells and Repair Muscle Degeneration

Abstract

Bone marrow stromal cells (MSCs) have great potential as therapeutic agents. We report a method for inducing skeletal muscle lineage cells from human and rat general adherent MSCs with an efficiency of 89%. Induced cells differentiated into muscle fibers upon transplantation into degenerated muscles of rats and mdx-nude mice. The induced population contained Pax7-positive cells that contributed to subsequent regeneration of muscle upon repetitive damage without additional transplantation of cells. These MSCs represent a more ready supply of myogenic cells than do the rare myogenic stem cells normally found in muscle and bone marrow.

Pax3 activation promotes the differentiation of mesenchymal stem cells toward the myogenic lineage

“…3A-E). Previous work has demonstrated improved muscle differentiation of MSCs in the presence of Notch signaling [21]. Here the effect of Pax3 on muscle differentiation seems independent of the Notch pathway, as no up-regulation of Hes1 and Hes5, downstream targets of Notch, was observed (Fig.…”

“…This conversion seems to occur via activation of the myogenic regulatory factors (MRFs), including Myf-5, MyoD, and myogenin [15], as observed during embryonic myogenesis [18][19][20]. Another reported approach [21] made use of activated Notch to generate skeletal muscle cells from human MSCs. Although the results were somewhat encouraging, the rationale for using Notch1 was not made clear.…”

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

“…Encouraging results have been obtained following the transplantation of several stem cell preparations [29,[41][42][43][44][45][46][47][48] into mouse models of muscular dystrophy. Although most of these studies comprise cell populations isolated directly from muscle tissues, such as satellite cells and mesoangioblasts, stromal cells from bone marrow [29] and adipose tissues [46,47] have also been attributed with in vivo muscle regenerative potential.…”

“…To test their muscle differentiation potential in vitro, we cultured hMSC-PAX3 and hMSC-Vector cells under several muscle inductive conditions (#2, 10% FBS, bFGF, neuregulin, PDGF-AA and forskolin) [29]; #3, 2% HS [40], and #4, 10% FBS and 5-azacitidine for up to 4 weeks [26] (Fig. 4), along with control conditions, including basic MSC medium (#1, 16.5% FBS) [39], complete expansion medium (#5, 10% FBS and PDGF-BB/EGF) [39], and expansion medium without growth factors (#6).…”

“…Experimental approaches involving induction of MSCs with 5-azacytidine [26], co-culture of MSCs with myoblasts [27] or myoblast-conditioned medium [28], and more recently activated Notch [29], suggest that skeletal muscle progenitors can also be obtained from MSCs. Although MSCs represent less than 0.01% of the BM mononuclear cell fraction, they are easily expanded in vitro and thus, amenable to genetic manipulation.…”