Transplantation of insulin secreting cells differentiated from human adipose tissue-derived stem cells into type 2 diabetes mice

Abstract

There has been a shift in paradigm about the pathogenesis of type 2 diabetes, from the emphasis on insulin resistance to a depletion of insulin secretion. Although there are various drugs and ways to ameliorate insulin resistance, there are very limited ways to preserve or recover insulin secretory capacity. The purpose of this study was to evaluate the efficacy of cell therapy using insulin secreting cells differentiated from human eyelid adipose tissue-derived stem cells (hEA) into type 2 diabetes mice in terms of glucose lowering effect, survival benefit, and its effect on other metabolic parameters. After differentiating hEA using ISI media, these insulin secreting cells (hEA-ISC) were transplanted into renal capsules of type 2 diabetes mouse model established by a low dose streptozotocin injection followed by a high fat diet. Mice that received differentiated cells (DC group) showed a significant lowering of blood glucose level up to 60 days and improved glucose tolerance compared to those that received undifferentiated cells (UDC group) and sham-operated mice (sham group). There was a survival benefit, with 10 out of 15 mice surviving in DC group while 6 out of 15 in UDC group and none of 8 sham mice survived at 60 days after transplantation. Significantly increased levels of human insulin and human c-peptide were detected in sera of DC group (both p < 0.001), but the combined human and mouse insulin and c-peptide levels were not different among the groups. Human genes were expressed in kidneys of transplanted mice, including insulin, GLUT1, GLUT2, NueroD1, Pdx1, and glucokinase. Immunohistochemical analysis showed co-existence of human and mouse cells in transplanted kidneys, and triple-staining with human insulin (hINS), human nuclear antigen (hNUCLEI), and DAPI (4'',6-diamidino-2-phenylindole) showed co-localization of human insulin and human nuclear antigen. Also, DC and UDC group showed a significantly lower serum IL-6 level compared to sham group (both P < 0.05), and DC group showed a tendency toward lower triglyceride and free fatty levels compared to sham group (P = 0.093 and 0.065, respectively).Cell therapy using differentiated hEAs is effective in lowering blood glucose level in type 2 diabetes mice by increasing circulating insulin level, and it also has a favorable effect on metabolic parameters and IL-6. The cause and effect relationship remains to be determined.