title: Receptor for Advanced Glycation End Products-Mediated Signaling Impairs the Maintenance of Bone Marrow Mesenchymal Stromal Cells in Diabetic Model Mice.
abstract: Bone marrow mesenchymal stromal cells (BM-MSCs) have been demonstrated to contribute to tissue regeneration. However, chronic pathological conditions, such as diabetes and aging, can result in a decreased number and/or quality of BM-MSCs. We therefore investigated the maintenance mechanism of BM-MSCs by studying signaling through the receptor for advanced glycation end products (RAGE), which is thought to be activated under various pathological conditions. The abundance of endogenous BM-MSCs decreased in a type 2 diabetes mellitus (DM2) model, as determined by performing colony-forming unit (CFU) assays. Flow cytometric analysis revealed that the prevalence of the Lin-/ckit-/CD106+/CD44-BM population, which was previously identified as a slow-cycling BM-MSC population, also decreased. Furthermore, in a streptozotocin-induced type 1 DM model (DM1), the CFUs of fibroblasts and the prevalence of the Lin-/ckit-/CD106+/CD44-BM population also significantly decreased. BM-MSCs in RAGE knockout (KO) mice were resistant to such reduction induced by streptozotocin treatment, suggesting that chronic RAGE signaling worsened the maintenance mechanism of BM-MSCs. Using an in vitro culture condition, BM-MSCs from RAGE-KO mice showed less proliferation and expressed significantly more Nanog and Oct-4, which are key factors in multipotency, than did wild-type BM-MSCs. Furthermore, RAGE-KO BM-MSCs showed a greater capacity for differentiation into mesenchymal lineages, such as adipocytes and osteocytes. These data suggested that RAGE signaling inhibition is useful for maintaining BM-MSCs in vitro. Together, our findings indicated that perturbation of BM-MSCs in DM could be partially explained by chronic RAGE signaling and that targeting the RAGE signaling pathway is a viable approach for maintaining BM-MSCs under chronic pathological conditions.
authors.affiliation: 1 Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University , Suita, Japan .
authors.forename: Eriko
authors.initials: E
authors.lastname: Aikawa
authors.affiliation: 1 Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University , Suita, Japan .|2 Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan .|3 Division of Gene Therapy Science, Graduate School of Medicine, Osaka University , Suita, Japan .
authors.forename: Ryo
authors.initials: R
authors.lastname: Fujita
authors.affiliation: 4 Faculty of Medicine, Hiroshima University , Higashihiroshima, Japan .
authors.forename: Maiko
authors.initials: M
authors.lastname: Asai
authors.affiliation: 3 Division of Gene Therapy Science, Graduate School of Medicine, Osaka University , Suita, Japan .
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
authors.affiliation: 1 Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University , Suita, Japan .
authors.forename: Katsuto
authors.initials: K
authors.lastname: Tamai
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C000593873:Ager protein, mouse; D000067759:Receptor for Advanced Glycation End Products
keywords: advanced glycation end product (AGE); diabetes; mesenchymal stem cells; receptor of AGE (RAGE)