多能间充质基质细胞通过 N-钙黏蛋白相互作用增强人胰岛的胰岛素分泌，并延长小鼠体内包被胰岛移植的功能。
Multipotent mesenchymal stromal cells enhance insulin secretion from human islets via N-cadherin interaction and prolong function of transplanted encapsulated islets in mice.
机构信息
Department of Surgery, Geneva University Hospitals and Medical Faculty, 1211, Geneva, Switzerland.
Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
出版信息
Stem Cell Res Ther. 2017 Sep 29;8(1):199. doi: 10.1186/s13287-017-0646-7.
BACKGROUND
Multipotent mesenchymal stromal cells (MSC) enhance viability and function of islets of Langerhans. We aimed to examine the interactions between human MSC and human islets of Langerhans that influence the function of islets.
METHODS
Human MSC and human islets (or pseudoislets, obtained after digestion and reaggregation of islet cells) were cocultured with or without cellular contact and glucose-stimulated insulin secretion assays were performed to assess cell function. The expression of several adhesion molecules, notably ICAM-1 and N-cadherin on islets and MSC, was investigated by qPCR. The role of N-cadherin was analyzed by adding an anti-N-cadherin antibody in islets cultured with or without MSC for 24 h followed by insulin measurements in static incubation assays. Islets and MSC were coencapsulated in new hydrogel microspheres composed of calcium alginate and covalently crosslinked polyethylene glycol. Encapsulated cells were transplanted intraperitoneally in streptozotocin-induced diabetic mice and glycemia was monitored. Islet function was evaluated by the intraperitoneal glucose tolerance test.
RESULTS
In vitro, free islets and pseudoislets cocultured in contact with MSC showed a significantly increased insulin secretion when compared to islets or pseudoislets cultured alone or cocultured without cell-to-cell contact with MSC (p < 0.05). The expression of ICAM-1 and N-cadherin was present on islets and MSC. Blocking N-cadherin prevented the enhanced insulin secretion by islets cultured in contact with MSC whereas it did not affect insulin secretion by islets cultured alone. Upon transplantation in diabetic mice, islets microencapsulated together with MSC showed significantly prolonged normoglycemia when compared with islets alone (median 69 and 39 days, respectively, p < 0.01). The intraperitoneal glucose tolerance test revealed an improved glycemic response in mice treated with islets microencapsulated together with MSC compared to mice transplanted with islets alone (p < 0.001).
CONCLUSIONS
MSC improve survival and function of islets of Langerhans by cell-to-cell contact mediated by the adhesion molecule N-cadherin.
背景
多能间充质基质细胞（MSC）可提高胰岛的活力和功能。我们旨在研究影响胰岛功能的人 MSC 与人胰岛之间的相互作用。
方法
将人 MSC 和人胰岛（或从胰岛细胞消化和重新聚集获得的假胰岛）共培养，有无细胞接触，并进行葡萄糖刺激的胰岛素分泌测定以评估细胞功能。通过 qPCR 检测胰岛和 MSC 上几种粘附分子（特别是 ICAM-1 和 N-钙粘蛋白）的表达。通过在与 MSC 共培养 24 小时的胰岛中添加抗 N-钙粘蛋白抗体，然后在静态孵育测定中测量胰岛素，分析 N-钙粘蛋白的作用。将胰岛和 MSC 共包封在由海藻酸钠和共价交联的聚乙二醇组成的新型水凝胶微球中。将包封的细胞经腹腔内移植入链脲佐菌素诱导的糖尿病小鼠中，并监测血糖。通过腹腔内葡萄糖耐量试验评估胰岛功能。
结果
在体外，与 MSC 接触共培养的游离胰岛和假胰岛与单独培养的胰岛或假胰岛或与 MSC 无细胞接触共培养的胰岛相比，胰岛素分泌显著增加（p<0.05）。ICAM-1 和 N-钙粘蛋白在胰岛和 MSC 上均有表达。阻断 N-钙粘蛋白可阻止与 MSC 接触培养的胰岛的胰岛素分泌增强，而对单独培养的胰岛的胰岛素分泌无影响。在糖尿病小鼠中移植后，与 MSC 共包封的胰岛与单独的胰岛相比，其正常血糖期显著延长（中位数分别为 69 和 39 天，p<0.01）。腹腔内葡萄糖耐量试验显示，与单独移植胰岛的小鼠相比，用与 MSC 共包封的胰岛治疗的小鼠的血糖反应得到改善（p<0.001）。
结论
MSC 通过细胞间接触，即通过粘附分子 N-钙粘蛋白，改善胰岛的存活和功能。
Zotero 插件