Intrapancreatic injection of human bone marrow-derived mesenchymal stem/stromal cells alleviates hyperglycemia and modulates the macrophage state in streptozotocin-induced type 1 diabetic mice.
Intrapancreatic injection of human bone marrow-derived mesenchymal stem/stromal cells alleviates hyperglycemia and modulates the macrophage state in streptozotocin-induced type 1 diabetic mice.
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DOI：
10.1371/journal.pone.0186637
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Izumizaki M
中科院分区：
文献类型：
--
作者：
Murai N;Ohtaki H;Watanabe J;Xu Z;Sasaki S;Yagura K;Shioda S;Nagasaka S;Honda K;Izumizaki M
1型糖尿病是一种进行性疾病，由胰腺β细胞破坏引起，导致胰岛素依赖和高血糖。虽然移植的骨髓间充质干细胞(BMMSCs)已被探索为治疗疾病的替代方法，但移植途径的选择可能是决定其可持续性的关键因素。本研究评价胰腺内和静脉注射人骨髓间充质干细胞(HBMMSCs)对链脲佐菌素(STZ)诱导的1型糖尿病小鼠模型的影响。C57/BL6小鼠第0天腹腔注射链脲佐菌素115 mg/kg。第7天将hBMMSCs(1×106细胞)或赋形剂注入胰腺或颈静脉。与相同途径的赋形剂相比，胰腺内注射hBMMSC在第28天显著降低血糖水平，而静脉注射hBMMSC不显著。作为异种移植对照，胰腺内注射人成纤维细胞不会引起这种降糖作用。胰腺内注射荧光标记的hBMMSCs位于胰腺小叶内和小叶外间隙，静脉注射的细胞位于肺区，但在注射后2周内细胞数量大多减少。对于第7天和第28天向胰腺区域注射两次的hBMMSCs，注射的小鼠在第56天进一步将血糖降低到接近糖尿病的水平。两次注射hBMMSCs的大鼠血浆胰岛素水平、胰岛数目和大小、胰岛素阳性细胞占总胰腺面积的比例和胰岛素染色强度均高于赋形剂注射组。我们发现胰岛IBA1阳性细胞减少，内分泌和外分泌胰腺CD206阳性细胞增加。注射hBMMSC还减少了胰岛CD40阳性细胞和胰岛高血糖素免疫反应阳性细胞的数量。这些结果提示，胰腺内注射hBMMSCs可能是治疗1型糖尿病的较好途径。
Type 1 diabetes mellitus is a progressive disease caused by the destruction of pancreatic β-cells, resulting in insulin dependency and hyperglycemia. While transplanted bone marrow-derived mesenchymal stem/stromal cells (BMMSCs) have been explored as an alternative therapeutic approach for diseases, the choice of delivery route may be a critical factor determining their sustainability. This study evaluated the effects of intrapancreatic and intravenous injection of human BMMSCs (hBMMSCs) in streptozotocin (STZ)-induced type 1 diabetic mouse model. C57/BL6 mice were intraperitoneally injected with 115 mg/kg STZ on day 0. hBMMSCs (1 × 106 cells) or vehicle were injected into the pancreas or jugular vein on day 7. Intrapancreatic, but not intravenous, hBMMSC injection significantly reduced blood glucose levels on day 28 compared with vehicle injection by the same route. This glucose-lowering effect was not induced by intrapancreatic injection of human fibroblasts as the xenograft control. Intrapancreatically injected fluorescence-labeled hBMMSCs were observed in the intra- and extra-lobular spaces of the pancreas, and intravenously injected cells were in the lung region, although the number of cells mostly decreased within 2 weeks of injection. For hBMMSCs injected twice into the pancreatic region on days 7 and 28, the injected mice had further reduced blood glucose to borderline diabetic levels on day 56. Animals injected with hBMMSCs twice exhibited increases in the plasma insulin level, number and size of islets, insulin-positive proportion of the total pancreas area, and intensity of insulin staining compared with vehicle-injected animals. We found a decrease of Iba1-positive cells in islets and an increase of CD206-positive cells in both the endocrine and exocrine pancreas. The hBMMSC injection also reduced the number of CD40-positive cells merged with glucagon immunoreactions in the islets. These results suggest that intrapancreatic injection may be a better delivery route of hBMMSCs for the treatment of type 1 diabetes mellitus.
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