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

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.

Opportunities and Challenges in Tunneling Nanotubes Research: How Far from Clinical Application?

“…So far, the most reported is the protective effect on stressed cells, which usually involves the mitochondria, an important organelle associated with apoptosis. Mitochondria were delivered from mesenchymal stem cells (MSCs) to injured cells in acute lung injury, allergic airway inflammation, blood vessels experiencing chemotherapy stress, or dysfunctional pancreatic islet [ 17 , 18 , 93 , 94 ]. Injured cells could also be rescued by obtaining mitochondria from neighboring healthy cells via TNTs [ 19 ].…”

“…The ability of cells to exploit TNTs as a bridge to help other cells in pathological conditions might be a natural mechanism for tissue self-repairing. When mesenchymal stem cells were introduced into damaged cultures or tissues, the transfer of the mitochondria from these stem cells was shown to save the recipient cells by recovering their cellular metabolism [ 17 , 94 ], rescuing aerobic respiration [ 61 ], or establishing angiogenic capacity [ 93 ]. Alternatively, TNT-like structures could remove damaged organelles or autophagosomes to rescue cystinosin-deficient fibroblasts or prematurely senescent endothelial cells [ 95 , 129 ].…”

Mitochondrial Dysfunction in Pancreatic Alpha and Beta Cells Associated with Type 2 Diabetes Mellitus

“…If the reduced insulin secretion in patients with T2DM is due to impaired mitochondrial bioenergetics, it would be promising to reanimate or even replace the pathologically exhaustive mitochondria. Very recently, Rackham et al [ 70 ] reported for the first time that insulin secretion can be restored by mitochondria transfer into insulin-secreting beta cells of diabetic mouse and human islets. The mitochondria were transferred by mesenchymal stromal cells.…”

“…In the experiments, it has been observed that the mesenchymal stromal cells-derived mitochondria have reached approx. 30% of beta cells, which was sufficient to reinduce a functional phenotype in the intact islets [ 70 ]. This might indicate a new epoch in clinical treatments of T2DM.…”

A preview of selected articles

“…Previous research from the laboratory of Chloe L. Rackham (King's College London, UK) demonstrated the improved curative capacity of grafted islets in diabetic mice following co-culture with MSCs, 12,13 and further extended these encouraging findings to clinically relevant human islets and MSCs. 14,15 In their new STEM CELLS article, 8 Overall, the fascinating study highlights co-culture and cytoplasmic exchange between cells as a potentially exciting means to enhance the benefits of MSC therapy in the damaged brain.…”