title: Preferential and comprehensive reconstitution of severely damaged sciatic nerve using murine skeletal muscle-derived multipotent stem cells.
abstract: Loss of vital functions in the somatic motor and sensory nervous systems can be induced by severe peripheral nerve transection with a long gap following trauma. In such cases, autologous nerve grafts have been used as the gold standard, with the expectation of activation and proliferation of graft-concomitant Schwann cells associated with their paracrine effects. However, there are a limited number of suitable sites available for harvesting of nerve autografts due to the unavoidable sacrifice of other healthy functions. To overcome this problem, the potential of skeletal muscle-derived multipotent stem cells (Sk-MSCs) was examined as a novel alternative cell source for peripheral nerve regeneration. Cultured/expanded Sk-MSCs were injected into severely crushed sciatic nerve corresponding to serious neurotmesis. After 4 weeks, engrafted Sk-MSCs preferentially differentiated into not only Schwann cells, but also perineurial/endoneurial cells, and formed myelin sheath and perineurium/endoneurium, encircling the regenerated axons. Increased vascular formation was also observed, leading to a favorable blood supply and waste product excretion. In addition, engrafted cells expressed key neurotrophic and nerve/vascular growth factor mRNAs; thus, endocrine/paracrine effects for the donor/recipient cells were also expected. Interestingly, skeletal myogenic capacity of expanded Sk-MSCs was clearly diminished in peripheral nerve niche. The same differentiation and tissue reconstitution capacity of Sk-MSCs was sufficiently exerted in the long nerve gap bridging the acellular conduit, which facilitated nerve regeneration/reconnection. These effects represent favorable functional recovery in Sk-MSC-treated mice, as demonstrated by good corduroy walking. We also demonstrated that these differentiation characteristics of the Sk-MSCs were comparable to native peripheral nerve-derived cells, whereas the therapeutic capacities were largely superior in Sk-MSCs. Therefore, Sk-MSCs can be a novel/suitable alternative cell source for healthy nerve autografts.
authors.affiliation: Muscle Physiology & Cell Biology Unit, Tokai University School of Medicine, Kanagawa, Japan; Department of Regenerative Medicine, Division of Basic Clinical Science, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Tamaki
authors.affiliation: Muscle Physiology & Cell Biology Unit, Tokai University School of Medicine, Kanagawa, Japan; Department of Regenerative Medicine, Division of Basic Clinical Science, Tokai University School of Medicine, Kanagawa, Japan; Teaching & Research Support Center, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Muscle Physiology & Cell Biology Unit, Tokai University School of Medicine, Kanagawa, Japan; Department of Urology, Division of Surgery, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Soeda
authors.affiliation: Muscle Physiology & Cell Biology Unit, Tokai University School of Medicine, Kanagawa, Japan; Department of Urology, Division of Surgery, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nakajima
authors.affiliation: Muscle Physiology & Cell Biology Unit, Tokai University School of Medicine, Kanagawa, Japan; Department of Otolaryngology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Saito
authors.affiliation: Muscle Physiology & Cell Biology Unit, Tokai University School of Medicine, Kanagawa, Japan; Department of Respiratory Surgery, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Kenei
authors.initials: K
authors.lastname: Nakazato
authors.affiliation: Muscle Physiology & Cell Biology Unit, Tokai University School of Medicine, Kanagawa, Japan; Teaching & Research Support Center, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Muscle Physiology & Cell Biology Unit, Tokai University School of Medicine, Kanagawa, Japan; Department of Orthopedics, Division of Surgery, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Muscle Physiology & Cell Biology Unit, Tokai University School of Medicine, Kanagawa, Japan; Department of Orthopedics, Division of Surgery, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Uchiyama
authors.affiliation: Department of Orthopedics, Division of Surgery, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Mochida
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D001808:Blood Vessels / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000648:ultrastructure; D032342:Muscle Cells / Q000166:cytology; D018482:Muscle, Skeletal / Q000166:cytology*; D009186:Myelin Sheath / Q000378:metabolism; D009409:Nerve Crush; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries* / Q000473:pathology / Q000648:ultrastructure; D033581:Stem Cell Transplantation
chemical_list: D012333:RNA, Messenger