Characterization of the Effects of Mesenchymal Stromal Cells on Mouse and Human Islet Function.

Islet transplantation has the potential to cure type 1 diabetes, but current transplantation protocols are not optimal and there is extensive loss of islet ß-cell insulin secretory function during the immediate post-transplantation period. Studies using experimental models of diabetes have shown that the coculture of islets with mesenchymal stromal cells (MSCs) prior to transplantation improves graft function, but several variables differed among research groups (e.g., type of MSCs used and the treatment conditions). We have therefore assessed the effects of MSCs on mouse and human islets by investigating the importance of tissue source for MSCs, the coculture protocol configuration and length, the effect of activated MSCs, and different ß-cell secretory stimuli. MSCs derived from adipose tissue (aMSCs) were the most effective at supporting ß-cell insulin secretion in both mouse and human islets, in a direct contact coculture configuration. Preculture with aMSCs enhanced both phases of glucose-induced insulin secretion and further enhanced secretory responses to the non-nutrients carbachol and arginine. These effects required a coculture period of 48-72 hours and were not dependent on activation of the MSCs. Thus, direct contact coculture with autologous, adipose-derived MSCs for a minimum of 48 hours before implantation is likely to be an effective addition to human islet transplantation protocols. Stem Cells Translational Medicine 2019;8:935&944.

Using Mesenchymal Stromal Cells in Islet Transplantation.

Islet transplantation has the potential to cure type 1 diabetes, but current clinical transplantation protocols are inefficient because of the extensive loss of functional islets during the immediate post-transplantation period. Studies in rodent models have demonstrated that co-transplanting mesencyhmal stromal cells (MSCs) with islets improves graft functional survival and transplantation outcomes, and some of the beneficial effects of MSCs are attributable to bioactive molecules secreted by MSCs. Clinical islet transplantation is almost exclusively via the hepatic portal vein, which does not facilitate co-engraftment of islets and MSCs, so attention is currently focused on using cell-free cocktails of MSC-derived products to treat islets prior to transplantation. This approach has the potential to overcome many of the technical and regulatory hurdles associated with using MSCs as an adjuvant therapy for human islet transplantation. Stem Cells Translational Medicine 2018;7:559-563.

Mesenchymal stromal cells improve human islet function through released products and extracellular matrix.

AIMS: The aims of the present study were (i) to determine whether the reported beneficial effects of mesenchymal stromal cells (MSCs) on mouse islet function extend to clinically relevant human tissues (islets and MSCs), enabling translation into improved protocols for clinical human islet transplantation; and (ii) to identify possible mechanisms through which human MSCs influence human islet function. MATERIALS AND METHODS: Human islets were co-cultured with human adipose tissue-derived MSCs (hASCs) or pre-treated with its products - extracellular matrix (ECM) and annexin A1 (ANXA1). Mouse islets were pre-treated with mouse MSC-derived ECM. Islet insulin secretory function was assessed in vitro by radioimmunoassay. Quantitative RT-PCR was used to screen human adipMSCs for potential ligands of human islet G-protein-coupled receptors. RESULTS: We show that co-culture with hASCs improves human islet secretory function in vitro, as measured by glucose-stimulated insulin secretion, confirming previous reports using rodent tissues. Furthermore, we demonstrate that these beneficial effects on islet function can be partly attributed to the MSC-derived products ECM and ANXA1. CONCLUSIONS: Our results suggest that hASCs have the potential to improve the quality of human islets isolated for transplantation therapy of Type 1 diabetes. Furthermore, it may be possible to achieve improvements in human islet quality in a cell-free culture system by using the MSC-derived products ANXA1 and ECM.