Abstract
Muscle satellite cells are essential for muscle regeneration. However, efficient regeneration does not occur without muscle-resident mesenchymal progenitor cells. We show here that bone marrow-derived mesenchymal stromal cells (Bm-MSCs) also facilitate muscle regeneration in Duchenne muscular dystrophy (DMD) model mice. Bm-MSCs transplanted into peritoneal cavities of DMD model mice with severe muscle degeneration strongly suppressed dystrophic pathology and improved death-related symptoms, which resulted in dramatic lifespan extension. Isolated single myofibers from Bm-MSC-transplanted mice manifested considerably less myofiber splitting compared with myofibers from non-transplanted mice, which indicated that transplantation significantly ameliorated abnormal regeneration. With regard to the number of satellite cells, several cells remained on myofibers from Bm-MSC-transplanted model mice, but satellite cells rarely occurred on myofibers from non-transplanted mice. Also, CXCL12 was crucial for muscle regeneration. CXCL12 facilitated muscle regeneration and paired box protein–7 (PAX7) expression after cardiotoxin-related muscle injury in vivo. The majority of primary muscle satellite cells sorted by integrin-α7 and CD34 expressed CXCR4, a receptor specific for CXCL12. CXCL12 strongly suppressed p-STAT3 expression in these sorted cells in vitro. CXCL12 may therefore influence muscle regeneration through STAT3 signaling in satellite cells. Targeting these proteins in or on muscle satellite cells may improve many degenerative muscle diseases.
Highlights
Published studies revealed that many adult organs maintain regenerative competence because of various populations of resident stem/progenitor cells
bone marrow-derived mesenchymal stromal cells (Bm-MSCs) used in this experiment had only an mdx mutation in the dystrophin gene and a null mutation in the utrophin gene (Supplementary Fig. S1)
We used a fluorescence-activated cell sorter (FACS) to identify cell surface markers in cultured cells. These cells were positive for stem cell antigen-1 (Sca-1), CD44, CD105, and CD106 and negative for CD45 and CD11b15 (Supplementary Fig. S2b)
Summary
Published studies revealed that many adult organs maintain regenerative competence because of various populations of resident stem/progenitor cells. Another type of regeneration-facilitating cell has been found—mesenchymal progenitor cells (MPCs)—which secrete various soluble factors in damaged organs to provide an optimal regenerative milieu. With regard to MSCs in bone marrow, nestin-expressing mesenchymal stem cells (nestin+ MSCs)[4] and CXCL12-abundant reticular (CAR) cells[5, 6] contribute to HSC niches. Nestin+ MSCs express higher levels of HSC maintenance factors, including CXCL12 ( named stromal cell-derived factor-1), osteopontin (OPN; called secreted phosphoprotein-1, SPP-1), stem cell factor, and others. STAT3 may be thought of as a critical factor for satellite cells, whether immature or senile
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