Receptor for Advanced Glycation End Products-Mediated Signaling Impairs the Maintenance of Bone Marrow Mesenchymal Stromal Cells in Diabetic Model Mice
Receptor for Advanced Glycation End Products-Mediated Signaling Impairs the Maintenance of Bone Marrow Mesenchymal Stromal Cells in Diabetic Model Mice
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DOI：
10.1089/scd.2016.0067
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发表时间：
2016-11-15
影响因子：
4
通讯作者：
Tamai, Katsuto
中科院分区：
文献类型：
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作者：
Aikawa, Eriko;Fujita, Ryo;Tamai, Katsuto
骨髓间充质基质细胞（BM-MSC）已被证明有助于组织再生。然而，慢性病理状况，例如糖尿病和衰老，可能导致 BM-MSC 数量和/或质量下降。因此，我们通过研究晚期糖基化终末产物 (RAGE) 受体的信号传导来研究 BM-MSC 的维持机制，该受体被认为在各种病理条件下会被激活。通过进行集落形成单位 (CFU) 测定确定，2 型糖尿病 (DM2) 模型中内源 BM-MSC 的丰度下降。流式细胞术分析显示，先前被确定为慢周期BM-MSC群体的Lin(-)/ckit(-)/CD106(+)/CD44(-) BM群体的患病率也有所下降。此外，在链脲佐菌素诱导的1型DM模型（DM1）中，成纤维细胞的CFU和Lin（-）/ckit（-）/CD106（+）/CD44（-）BM群体的患病率也显着下降。 RAGE 敲除 (KO) 小鼠中的 BM-MSC 对链脲佐菌素治疗诱导的这种减少具有抵抗力，表明慢性 RAGE 信号传导恶化了 BM-MSC 的维持机制。在体外培养条件下，与野生型 BM-MSC 相比，RAGE-KO 小鼠的 BM-MSC 表现出较少的增殖，并且表达显着更多的 Nanog 和 Oct-4，这是多能性的关键因素。此外，RAGE-KO BM-MSC 显示出更强的分化为间充质谱系（例如脂肪细胞和骨细胞）的能力。这些数据表明 RAGE 信号传导抑制对于体外维持 BM-MSC 很有用。总之，我们的研究结果表明，慢性 RAGE 信号传导可以部分解释 DM 中 BM-MSC 的扰动，并且靶向 RAGE 信号通路是在慢性病理条件下维持 BM-MSC 的可行方法。
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.