title: Implication of anti-inflammatory macrophages in regenerative moto-neuritogenesis: promotion of myoblast migration and neural chemorepellent semaphorin 3A expression in injured muscle.
abstract: Regenerative mechanisms that regulate intramuscular motor innervation are thought to reside in the spatiotemporal expression of axon-guidance molecules. Our previous studies proposed a heretofore unexplored role of resident myogenic stem cell (satellite cell)-derived myoblasts as a key presenter of a secreted neural chemorepellent semaphorin 3A (Sema3A); hepatocyte growth factor (HGF) triggered its expression exclusively at the early-differentiation phase. In order to verify this concept, the present study was designed to clarify a paracrine source of HGF release. In vitro experiments demonstrated that activated anti-inflammatory macrophages (CD206-positive M2) produce HGF and thereby promote myoblast chemoattraction and Sema3A expression. Media from pro-inflammatory macrophage cultures (M1) did not show any significant effect. M2 also enhanced the expression of myoblast-differentiation markers in culture, and infiltrated predominantly at the early-differentiation phase (3-5 days post-injury); M2 were confirmed to produce HGF as monitored by in vivo/ex vivo immunocytochemistry of CD11b/CD206/HGF-positive cells and by HGF in situ hybridization of cardiotoxin- or crush-injured tibialis anterior muscle, respectively. These studies advance our understanding of the stage-specific activation of Sema3A expression signaling. Findings, therefore, encourage the idea that M2 contribute to spatiotemporal up-regulation of extracellular Sema3A concentrations by producing HGF that, in turn, stimulates a burst of Sema3A secretion by myoblasts that are recruited to site of injury. This model may ensure a coordinated delay in re-attachment of motoneuron terminals onto damaged fibers early in muscle regeneration, and thus synchronize the recovery of muscle-fiber integrity and the early resolution of inflammation after injury.
authors.affiliation: Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Sakaguchi
authors.affiliation: Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Shono
authors.affiliation: Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Sawano
authors.affiliation: Department of Biological Sciences, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada.
authors.forename: Judy E
authors.initials: JE
authors.lastname: Anderson
authors.affiliation: Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Mai-Khoi Q
authors.initials: MK
authors.lastname: Do
authors.affiliation: Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ohtsubo
authors.affiliation: Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Mizunoya
authors.affiliation: Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Faculty of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Mako
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Furuse
authors.affiliation: Department of Food Science and Biotechnology, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Ikeuchi
authors.affiliation: Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 8128581, Japan. Electronic address: rtatsumi@agr.kyushu-u.ac.jp.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tatsumi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D017403:In Situ Hybridization; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000293:injuries / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000893:Anti-Inflammatory Agents; D012333:RNA, Messenger; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D017228:Hepatocyte Growth Factor
keywords: Activated macrophage; Hepatocyte growth factor; Migration; Regenerative moto-neuritogenesis; Semaphorin 3A