title: Acute and temporal expression of tumor necrosis factor (TNF)-α-stimulated gene 6 product, TSG6, in mesenchymal stem cells creates microenvironments required for their successful transplantation into muscle tissue.
abstract: Previously, we demonstrated that when mesenchymal stem cells (MSCs) from mouse ES cells were transplanted into skeletal muscle, more than 60% of them differentiated into muscles in the crush-injured tibialis anterior muscle in vivo, although MSCs neither differentiated nor settled in the intact muscle. Microenvironments, including the extracellular matrix between the injured and intact muscle, were quite different. In the injured muscle, hyaluronan (HA), heavy chains of inter-α-inhibitor (IαI), CD44, and TNF-α-stimulated gene 6 product (TSG-6) increased 24-48 h after injury, although basement membrane components of differentiated muscle such as perlecan, laminin, and type IV collagen increased gradually 4 days after the crush. We then investigated the microenvironments crucial for cell transplantation, using the lysate of C2C12 myotubules for mimicking injured circumstances in vivo. MSCs settled in the intact muscle when they were transplanted together with the C2C12 lysate or TSG6. MSCs produced and released TSG6 when they were cultured with C2C12 lysates in vitro. MSCs pretreated with the lysate also settled in the intact muscle. Furthermore, MSCs whose TSG6 was knocked down by shRNA, even if transplanted or pretreated with the lysate, could not settle in the muscle. Immunofluorescent staining showed that HA and IαI always co-localized or were distributed closely, suggesting formation of covalent complexes, i.e. the SHAP-HA complex in the presence of TSG6. Thus, TSG6, HA, and IαI were crucial factors for the settlement and probably the subsequent differentiation of MSCs.
authors.affiliation: From the Department of Rehabilitation Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-9673, Japan.
authors.forename: Shigeko
authors.initials: S
authors.lastname: Torihashi
authors.affiliation: the Department of Physical Therapy, Nagoya University School of Health Sciences, Nagoya 461-8673, Japan.
authors.forename: Mioko
authors.initials: M
authors.lastname: Ho
authors.affiliation: the Department of Physical Therapy, Nagoya University School of Health Sciences, Nagoya 461-8673, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kawakubo
authors.affiliation: the Department of Physical Therapy, Nagoya University School of Health Sciences, Nagoya 461-8673, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Komatsu
authors.affiliation: the Department of Physical Therapy, Nagoya University School of Health Sciences, Nagoya 461-8673, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Nagai
authors.affiliation: the Department of Physical Therapy, Nagoya University School of Health Sciences, Nagoya 461-8673, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Hirayama
authors.affiliation: From the Department of Rehabilitation Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-9673, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kawabata
authors.affiliation: From the Department of Rehabilitation Sciences, Nagoya University Graduate School of Medicine, Nagoya 461-9673, Japan, the Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan, and.
authors.forename: Nana
authors.initials: N
authors.lastname: Takenaka-Ninagawa
authors.affiliation: the Advanced Medical Research Center and Multidisciplinary Pain Center, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan, the Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Orawan
authors.initials: O
authors.lastname: Wanachewin
authors.affiliation: the Advanced Medical Research Center and Multidisciplinary Pain Center, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhuo
authors.affiliation: the Advanced Medical Research Center and Multidisciplinary Pain Center, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan, kimata@aichi-med-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Kimata
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D018920:Coculture Techniques; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D055153:Stem Cell Niche
chemical_list: D015815:Cell Adhesion Molecules; C513057:Tnfaip6 protein, mouse
keywords: IαI, foothold; SHAP-hyaluronan complex; extracellular matrix; fibrosis; mesenchymal stem cells (MSCs); regenerative medicine; skeletal muscle; tumor necrosis factor (TNF)