title: Hyperglycemia Promotes Schwann Cell De-differentiation and De-myelination via Sorbitol Accumulation and Igf1 Protein Down-regulation.
abstract: Diabetes mellitus (DM) is frequently accompanied by complications, such as peripheral nerve neuropathy. Schwann cells play a pivotal role in regulating peripheral nerve function and conduction velocity; however, changes in Schwann cell differentiation status in DM are not fully understood. Here, we report that Schwann cells de-differentiate into immature cells under hyperglycemic conditions as a result of sorbitol accumulation and decreased Igf1 expression in those cells. We found that de-differentiated Schwann cells could be re-differentiated in vitro into mature cells by treatment with an aldose reductase inhibitor, to reduce sorbitol levels, or with vitamin D3, to elevate Igf1 expression. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination, and all conditions were significantly rescued by aldose reductase inhibitor or vitamin D3 administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition.
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Wu
authors.initials: W
authors.lastname: Hao
authors.affiliation: Rehabilitation Medicine.
authors.forename: Syoichi
authors.initials: S
authors.lastname: Tashiro
authors.affiliation: the Department of Developmental Biology of Hard Tissue, Hokkaido University Graduate School of Dental Medicine, Kita 13 Nishi 7, Kita-ku, Sapporo, 060-8586, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: From the Departments of Orthopedic Surgery, Musculoskeletal Reconstruction and Regeneration Surgery.
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Sato
authors.affiliation: From the Departments of Orthopedic Surgery, Integrated Bone Metabolism and Immunology, and.
authors.forename: Tami
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Tando
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Eri
authors.initials: E
authors.lastname: Katsuyama
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Fujie
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 and.
authors.forename: Mayu
authors.initials: M
authors.lastname: Morita
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: the Department of Developmental Biology of Hard Tissue, Hokkaido University Graduate School of Dental Medicine, Kita 13 Nishi 7, Kita-ku, Sapporo, 060-8586, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Amizuka
authors.affiliation: From the Departments of Orthopedic Surgery.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: From the Departments of Orthopedic Surgery, Integrated Bone Metabolism and Immunology, and miyamoto@z5.keio.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D054337:Cell Dedifferentiation / Q000502:physiology; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology*; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D051381:Rats; D012236:Rhodanine / Q000031:analogs & derivatives / Q000494:pharmacology; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D013012:Sorbitol / Q000378:metabolism*; D053778:Thiazolidines / Q000494:pharmacology; D014807:Vitamin D / Q000031:analogs & derivatives
chemical_list: D004791:Enzyme Inhibitors; D053778:Thiazolidines; D014807:Vitamin D; C038131:epalrestat; D013012:Sorbitol; D007334:Insulin-Like Growth Factor I; D012236:Rhodanine; D000449:Aldehyde Reductase; D002117:Calcitriol; C547512:eldecalcitol; D005947:Glucose
keywords: Schwann cells; cell differentiation; cell metabolism; diabetes; differentiation; vitamin D