Transplantation of Heterospheroids of Islet Cells and Mesenchymal Stem Cells for Effective Angiogenesis and Antiapoptosis

Abstract

Although islet transplantation has been suggested as an alternative therapy for type 1 diabetes, there are efficiency concerns that are attributed to poor engraftment of transplanted islets. Hypoxic condition and delayed vasculogenesis induce necrosis and apoptosis of the transplanted islets. To overcome these limitations in islet transplantation, heterospheroids (HSs), which consist of rat islet cells (ICs) and human bone marrow-derived mesenchymal stem cells (hMSCs), were transplanted to the kidney and liver. The HSs cultured under the hypoxic condition system exhibited a significant increase in antiapoptotic gene expression in ICs. hMSCs in the HSs secreted angiogenic and antiapoptotic proteins. With the HS system, ICs and hMSCs were successfully located in the same area of the liver after transplantation of HSs through the portal vein, whereas the transplantation of islets and the dissociated hMSCs did not result in localization of transplanted ICs and hMSCs in the same area. HS transplantation resulted in an increase in angiogenesis at the transplantation area and a decrease in the apoptosis of transplanted ICs after transplantation into the kidney subcapsule compared with transplantation of islet cell clusters (ICCs). Insulin production levels of ICs were higher in the HS transplantation group compared with the ICC transplantation group. The HS system may be a more efficient transplantation method than the conventional methods for the treatment of type 1 diabetes.

Human mesenchymal‐stem‐cells‐derived exosomes are important in enhancing porcine islet resistance to hypoxia

“…Mesenchymal stem cells have shown many unique functions, including release of trophic factors with diverse effects such as improved tissue repair, the reduction of apoptosis, and the promotion of neovascularization . Therefore, they have been used to provide protection for islets from hypoxia‐mediated cell death in islet transplantation .…”

“…Mesenchymal stem cells have shown many unique functions, including release of trophic factors with diverse effects such as improved tissue repair, the reduction of apoptosis, and the promotion of neovascularization. [40][41][42][43] Therefore, they have been used to provide protection for islets from hypoxia-mediated cell death in islet transplantation. 23,[44][45][46] Some studies showed that MSC co-transplantation had a positive effect on islets to tolerate poor oxygenation, but most of these studies focused on accelerating revascularization, rather than directly combating hypoxic damage.…”

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

“…This is particularly important in islet transplantation in type-1 diabetic patients. The hypoxic response in the transplanted islets may slow their rate decay until revascularized in their new milieu (Linn et al, 2006;Shin et al, 2015).…”

Stromal cell-derived factor-1-directed bone marrow mesenchymal stem cell migration in response to inflammatory and/or hypoxic stimuli

“…This observation is particularly true when cells are systemically administered because the efficacy of this approach is limited by the quantity of viable cells that reach an injured tissue. [5][6][7] Unfortunately, previous investigations have uniformly demonstrated poor engraftment of transplanted cells. In the absence of ex vivo pretreatment or modification, less than 3% of transplanted cells typically engraft following their introduction into the body.…”