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.

Keywords: advanced glycation end product (AGE); diabetes; mesenchymal stem cells; receptor of AGE (RAGE).