Participation of bone marrow-derived cells in fibrotic changes in denervated skeletal muscle.

In denervated skeletal muscle, mononuclear interstitial cells accumulate in the perisynaptic regions before fibrotic change occurs. These cells are currently considered to be fibroblasts that originate from muscle tissue. However, when we denervated hind limbs of GFP-bone marrow chimeric mice by excising the sciatic nerve unilaterally, many bone marrow-derived cells (BM-DCs) infiltrated the interstitial spaces and accumulated in the perisynaptic regions, peaking 14 days after denervation. They accounted for nearly one-half of the increase in mononuclear interstitial cells. Although BM-DCs did not incorporate into satellite cells, immunohistochemical and FACS analyses revealed that BM-DCs were both CD45 and CD11b positive, indicating that they were of macrophage/monocyte lineage. BrdU staining showed inactive proliferation of BM-DCs. Reverse transcriptase-polymerase chain reaction of mononuclear cells isolated by FACS revealed that BM-DCs did not express type I collagen or tenascin-C; however, they did express transforming growth factor-beta1, suggesting that they regulate the fibrotic process. In contrast, muscle tissue-derived interstitial cells expressed type I collagen and tenascin-C, suggesting that these populations were the final effectors of fibrosis. These findings identify elementary targets that may regulate the migration, homing, differentiation, and function of BM-DCs, leading to amelioration of the excessive fibrosis of denervated skeletal muscle.