Abstract
Islet transplantation is a minimally invasive treatment for severe diabetes. However, it often requires multiple donors to accomplish insulin-independence and the long-term results are not yet satisfying. Therefore, novel ways to overcome these problems have been explored. Isolated islets are fragile and susceptible to pro-apoptotic factors and poorly proliferative. In contrast, mesenchymal stem cells (MSCs) are highly proliferative, anti-apoptotic and pluripotent to differentiate toward various cell types, promote angiogenesis and modulate inflammation, thereby studied as an enhancer of islet function and engraftment. Electrofusion is an efficient method of cell fusion and nuclear reprogramming occurs in hybrid cells between different cell types. Therefore, we hypothesized that electrofusion between MSC and islet cells may yield robust islet cells for diabetes therapy. We establish a method of electrofusion between dispersed islet cells and MSCs in rats. The fusion cells maintained glucose-responsive insulin release for 20 days in vitro. Renal subcapsular transplantation of fusion cells prepared from suboptimal islet mass (1,000 islets) that did not correct hyperglycemia even if co-transplanted with MSCs, caused slow but consistent lowering of blood glucose with significant weight gain within the observation period in streptozotocin-induced diabetic rats. In the fusion cells between rat islet cells and mouse MSCs, RT-PCR showed new expression of both rat MSC-related genes and mouse β-cell-related genes, indicating bidirectional reprogramming of both β-cell and MSCs nuclei. Moreover, decreased caspase3 expression and new expression of Ki-67 in the islet cell nuclei suggested alleviated apoptosis and gain of proliferative capability, respectively. These results show that electrofusion between MSCs and islet cells yield special cells with β-cell function and robustness of MSCs and seems feasible for novel therapeutic strategy for diabetes mellitus.
Highlights
Diabetes mellitus (DM) is a leading cause of morbidity and mortality in industrialized countries, and the number of patients affected is estimated to be 366 million in 2011 with an increase to 552 million by 2030 [1]
Islet transplantation is an effective therapy for Type 1 DM (T1DM), but limited donor sources restrict it from becoming a major treatment option [3,4]
By electrofusion of SYTO11-labeled mesenchymal stem cells (MSCs) and Vybrant Dil-labeled islet cells, cells double positive for SYTO11 and Vybrant Dil were observed after cell fusion, whereas such cells were not observed without cell fusion (Fig. 4)
Summary
Diabetes mellitus (DM) is a leading cause of morbidity and mortality in industrialized countries, and the number of patients affected is estimated to be 366 million in 2011 with an increase to 552 million by 2030 [1]. B-cell reconstruction is currently achieved only by either pancreas or islet transplantation in clinical setting. Clinical trials of encapsulated islets that enable transplantation without immune suppression are on-going [2], these transplantation therapies share common problems of donor scarcity and adverse effects related to immune suppression. Islet transplantation is an effective therapy for T1DM, but limited donor sources restrict it from becoming a major treatment option [3,4]. A diabetic patient often requires two or even three donor pancreata to accomplish insulinindependence in current mainstream protocols, which makes the problem of a donor shortage even more serious [5]. Even though insulin-independence is achieved by islet transplantation, islet graft function is rarely sustained with only 7.5% of these patients remaining insulin-independent at 5 years post transplantation [3]
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