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

• Published in: Stem cells (Dayton, Ohio) Ohio), 2020-04, Vol.38 (4), p.574-584
• Main Authors: Rackham, Chloe L., Hubber, Ella L., Czajka, Anna, Malik, Afshan N., King, Aileen J. F., Jones, Peter M.
• Format: Article
• Language: English
• Subjects: Animals; Beta cells; Cell culture; Cells, Cultured; diabetes; Diabetes Mellitus, Experimental - therapy; Fluorescence; Glucose; Humans; Hypoxia; In vivo methods and tests; Insulin; Insulin secretion; Insulin-Secreting Cells - metabolism; Islet cells; islet transplantation; Islets of Langerhans Transplantation - methods; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; mesenchymal stromal cells; Mesenchyme; Mice; Mitochondria; Mitochondria - metabolism; mitochondrial transfer; Optimization; Pancreatic islet transplantation; Stromal cells; Tissue‐specific Stem Cells; Transplantation
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.3134

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. Human mesenchymal stromal cells (MSCs) transfer their mitochondria to cocultured human islet β‐cells. Fluorescence imaging showed that mitochondrial transfer occurs, at least partially through tunneling nanotube‐like structures. MSC‐mediated mitochondrial donation to islet β‐cells represents a novel mechanism of enhanced islet β‐cell function.