Abstract
Pretransplant islet culture is associated with the loss of islet cell mass and insulin secretory function. Insulin secretion from islet β‐cells is primarily controlled by mitochondrial ATP generation in response to elevations in extracellular glucose. Coculture of islets with mesenchymal stromal cells (MSCs) improves islet insulin secretory function in vitro, which correlates with superior islet graft function in vivo. This study aimed to determine whether the improved islet function is associated with mitochondrial transfer from MSCs to cocultured islets. We have demonstrated mitochondrial transfer from human adipose MSCs to human islet β‐cells in coculture. Fluorescence imaging showed that mitochondrial transfer occurs, at least partially, through tunneling nanotube (TNT)‐like structures. The extent of mitochondrial transfer to clinically relevant human islets was greater than that to experimental mouse islets. Human islets are subjected to more extreme cellular stressors than mouse islets, which may induce “danger signals” for MSCs, initiating the donation of MSC‐derived mitochondria to human islet β‐cells. Our observations of increased MSC‐mediated mitochondria transfer to hypoxia‐exposed mouse islets are consistent with this and suggest that MSCs are most effective in supporting the secretory function of compromised β‐cells. Ensuring optimal MSC‐derived mitochondria transfer in preculture and/or cotransplantation strategies could be used to maximize the therapeutic efficacy of MSCs, thus enabling the more widespread application of clinical islet transplantation.
Highlights
Allogenic islet transplantation offers the possibility of treating a small subgroup of people with type 1 diabetes (T1D), but the limited availability of human islet material is a major obstacle to the more widespread adoption of islet transplantation as a treatment option for the majority of people with T1D.1 Clinical transplantation of allogeneic human islets necessitates a short-term culture period for safety tests, administration of the transplant recipient to hospital and induction immunotherapy
We have demonstrated mitochondrial transfer from human adipose mesenchymal stromal cells (MSCs) to human islet β-cells in coculture
Heterogeneity in mitochondrial transfer capacity between different MSC tissue sources have been reported,[30] so we investigated the potential for mouse bone marrow (BM)-MSCs to transfer GFP-labeled mitochondria to neighboring mouse islet cells
Summary
Allogenic islet transplantation offers the possibility of treating a small subgroup of people with type 1 diabetes (T1D), but the limited availability of human islet material is a major obstacle to the more widespread adoption of islet transplantation as a treatment option for the majority of people with T1D.1 Clinical transplantation of allogeneic human islets necessitates a short-term culture period for safety tests, administration of the transplant recipient to hospital and induction immunotherapy. Allogenic islet transplantation offers the possibility of treating a small subgroup of people with type 1 diabetes (T1D), but the limited availability of human islet material is a major obstacle to the more widespread adoption of islet transplantation as a treatment option for the majority of people with T1D.1. Clinical transplantation of allogeneic human islets necessitates a short-term culture period for safety tests, administration of the transplant recipient to hospital and induction immunotherapy. Mouse mesenchymal stromal cells (MSCs) derived from multiple tissue sources, including kidney, adipose, and bone marrow (BM), have direct effects on donor islet β-cells to improve their survival and insulin secretory function during the in vitro culture period prior to transplantation.[3,4,5,6,7] These in vitro findings correlate with persistent improvements in subsequent islet post-transplantation function in vivo. Others, have demonstrated that these findings translate to clinically relevant human islets and human MSCs.[5,8,9]
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