MCP-1 Feedback Loop Between Adipocytes and Mesenchymal Stromal Cells Causes Fat Accumulation and Contributes to Hematopoietic Stem Cell Rarefaction in the Bone Marrow of Patients With Diabetes
MCP-1 Feedback Loop Between Adipocytes and Mesenchymal Stromal Cells Causes Fat Accumulation and Contributes to Hematopoietic Stem Cell Rarefaction in the Bone Marrow of Patients With Diabetes
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DOI：
10.2337/db18-0044
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发表时间：
2018-07-01
期刊：
影响因子：
7.7
通讯作者：
Madeddu, Paolo
中科院分区：
文献类型：
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作者：
Ferland-McCollough, David;Maselli, Davide;Madeddu, Paolo
糖尿病患者的骨髓(BM)中脂肪积聚。在本研究中，我们探讨了这一现象的机制和后果。与非糖尿病患者的BM-MSCs相比，2型糖尿病患者的骨髓间充质干细胞(BM-MSCs)表达成脂标志物，体外诱导分化为脂肪细胞(ADS)。此外，来自T2D受试者的BM-ADS(T2D BM-ADS)在BM-MSCs中刺激转录成脂程序。T2D BM-AD关键表达的趋化因子MCP-1的拮抗作用可阻止T2D BM-AD分泌体将BM-MSCs转化为ADS。接下来，在肥胖的T2D小鼠模型中对人类数据进行机械验证。全身应用单核细胞趋化蛋白-1可改善代谢控制，减少骨髓脂肪，增加骨细胞密度。它还间接地重建了长期造血干细胞相对于短期造血干细胞的丰度。我们揭示了一个糖尿病反馈环，其中1)BM-MSCs天生倾向于制造ADS，2)成熟的BM-ADS通过分泌MCP-1，无情地将BM-MSC的测定补充到新的脂肪中。药物抑制单核细胞趋化蛋白-1信号可以对抗这种恶性循环，至少在一定程度上恢复了T2D受试者骨髓中脂肪生成和造血之间的平衡。
Fat accumulates in bone marrow (BM) of patients with diabetes. In this study, we investigated the mechanisms and consequences of this phenomenon. BM mesenchymal stromal cells (BM-MSCs) from patients with type 2 diabetes (T2D) constitutively express adipogenic markers and robustly differentiate into adipocytes (ADs) upon in vitro induction as compared with BM-MSCs from subjects without diabetes. Moreover, BM-ADs from subjects with T2D (T2D BM-ADs) paracrinally stimulate a transcriptional adipogenic program in BM-MSCs. Antagonism of MCP-1, a chemokine pivotally expressed in T2D BM-ADs, prevented the T2D BM-AD secretome from converting BM-MSCs into ADs. Mechanistic validation of human data was next performed in an obese T2D mouse model. Systemic antagonism of MCP-1 improved metabolic control, reduced BM fat, and increased osteocyte density. It also indirectly re-established the abundance of long-term versus short-term hematopoietic stem cells. We reveal a diabetic feedback loop in which 1) BM-MSCs are constitutively inclined to make ADs, and 2) mature BM-ADs, via secreted MCP-1, relentlessly fuel BM-MSC determination into new fat. Pharmacological inhibition of MCP-1 signaling can contrast this vicious cycle, restoring, at least in part, the balance between adipogenesis and hematopoiesis in BM from subjects with T2D.