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Updated: Aug 17, 2026
Identification, Isolation, and Characterization of Fibro-Adipogenic Progenitors (FAPs) and Myogenic Progenitors (MPs) in Skeletal Muscle in the Rat
Published on: June 9, 2021
Participation of bone marrow-derived cells in fibrotic changes in denervated skeletal muscle
Yasushi Mochizuki1, Koichi Ojima, Akiyoshi Uezumi
1Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi-cho, Kodaira, Tokyo 187-8502, Japan.
Abstract:
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.
Insights
Bone marrow-derived cells infiltrate denervated muscle, acting as macrophages that regulate fibrosis. Muscle-derived fibroblasts, however, are the primary drivers of fibrotic changes in skeletal muscle.
Area of Science:
- Muscle biology
- Cellular and Molecular Medicine
- Immunology
Background:
- Mononuclear interstitial cells accumulate in denervated skeletal muscle, preceding fibrosis.
- These cells were previously thought to be solely muscle tissue-derived fibroblasts.
Purpose of the Study:
- To investigate the origin and role of mononuclear interstitial cells in denervated skeletal muscle fibrosis.
- To differentiate the functions of bone marrow-derived cells (BM-DCs) and muscle tissue-derived cells in this process.
Main Methods:
- Sciatic nerve denervation in GFP-bone marrow chimeric mice.
- Immunohistochemistry and Flow Cytometry (FACS) for cell lineage identification (CD45, CD11b).
- BrdU incorporation for proliferation assessment.
- RT-PCR for gene expression analysis (collagen, tenascin-C, TGF-β1).
Main Results:
- BM-DCs infiltrated denervated muscle, accumulating in perisynaptic regions and comprising nearly half of the increased mononuclear cells.
- BM-DCs were identified as CD45+/CD11b+ macrophages/monocytes with low proliferation rates.
- BM-DCs expressed TGF-β1 but not collagen or tenascin-C.
- Muscle tissue-derived interstitial cells expressed collagen and tenascin-C, indicating their role as fibrosis effectors.
Conclusions:
- Bone marrow-derived cells (macrophages/monocytes) play a regulatory role in denervated skeletal muscle fibrosis by expressing TGF-β1.
- Muscle tissue-derived interstitial cells are the primary effectors of fibrosis, producing collagen and tenascin-C.
- Targeting BM-DC migration, homing, differentiation, and function may offer a strategy to ameliorate skeletal muscle fibrosis.
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