Multipotent mesenchymal stromal cells enhance insulin secretion from human islets via N-cadherin interaction and prolong function of transplanted encapsulated islets in mice

Abstract

BackgroundMultipotent 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.MethodsHuman 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.ResultsIn 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).ConclusionsMSC improve survival and function of islets of Langerhans by cell-to-cell contact mediated by the adhesion molecule N-cadherin.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0646-7) contains supplementary material, which is available to authorized users.

Alginate/Pluronic F127-based encapsulation supports viability and functionality of human dental pulp stem cell-derived insulin-producing cells

“…porosity, stability and permeability were fulfilled by alginate [50]. Consistent results by several studies were reported that pancreatic islet, ESC-and iPSC-derived IPC encapsulation using alginate could maintain the viability both in vivo and in vitro [51][52][53][54][55][56]. Another study on pancreatic islet cryopreservation incorporated alginate encapsulation reported that alginate encapsulation could maintain both viability and functionality of pancreatic islets [57].…”

Optimizing beta cell function through mesenchymal stromal cell-mediated mitochondria transfer

“…We have identified MSC‐derived soluble secretory products that mimic some of the beneficial effects of MSCs in vitro, and shown that preculturing islets with a defined cocktail of MSC‐secreted ligands also improved islet graft function in vivo, albeit not to the same extent seen with MSC coculture . MSC‐derived extracellular matrix further contributes to the beneficial effects of MSCs on islet function, and a number of studies have highlighted the importance of direct MSC‐islet cell‐cell contact for islet functional survival . Studies in other tissues have also demonstrated the capacity of MSCs to act as mitochondria donors by transferring functional mitochondria directly to adjacent cocultured cells in inflammatory and ischemic disease settings, resulting in the rescue of aerobic respiration .…”

Xenotransplantation: back to the future?

“…Indeed, the use of transgenic pigs led to comparable results in vascularized heterotopic heart xenografts . Another potential strategy, namely encapsulation of pig islets , should also benefit from further development of genetically modified pigs. Of note, islet xenotransplantation from nongenetically modified pig‐to‐human achieved islet survival but no significant clinical improvement .…”