Suppression of macrophage functions impairs skeletal muscle regeneration with severe fibrosis.
When damaged, skeletal muscle regenerates. In the early phases of regeneration, inflammatory cells such as neutrophils/granulocytes and macrophages infiltrate damaged muscle tissue. To reveal the roles of macrophages during skeletal muscle regeneration, we injected an antibody, AFS98 that blocks the binding of M-CSF to its receptor into normal mice that received muscle damages. Anti-M-CSF receptor administration suppressed macrophage but not neutrophil infiltration. Histological study indicated that suppression of macrophages function leads to the incomplete muscle regeneration. In addition FACS and immunohistochemical study showed that the acute lack of macrophages delayed proliferation and differentiation of muscle satellite cells in vivo. Furthermore, mice injected with the anti-M-CSF receptor antibody exhibited not only adipogenesis, but also significant collagen deposition, i.e., fibrosis and continuous high expression of connective tissue growth factor. Finally we indicate that these fibrosis markers were strongly enriched in CD90(+) cells that do not include myogenic cells. These results indicate that macrophages directly affect satellite cell proliferation and that a macrophage deficiency severely impairs skeletal muscle regeneration and causes fibrosis.
Segawa
Masashi
M
Department of Immunology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, 1-6 Yamada-oka, Osaka 565-0871, Japan.
Fukada
So-ichiro
S
Yamamoto
Yukiko
Y
Yahagi
Hiroshi
H
Kanematsu
Masanori
M
Sato
Masaki
M
Ito
Takahito
T
Uezumi
Akiyoshi
A
Hayashi
Shin'ichi
S
Miyagoe-Suzuki
Yuko
Y
Takeda
Shin'ichi
S
Tsujikawa
Kazutake
K
Yamamoto
Hiroshi
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005355:Fibrosis / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D018482:Muscle, Skeletal / Q000166:cytology / Q000473:pathology* / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction / Q000502:physiology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015415:Biomarkers; D015820:Cadherins; C070896:M-cadherin; D016186:Receptor, Macrophage Colony-Stimulating Factor