The impact of different implantation sites and sex on the differentiation of human pancreatic endoderm cells into insulin-secreting cells in vivo
Few studies have examined the differentiation of human embryonic stem cell (hESC)-derived pancreatic endoderm cells (PECs) in different implantation sites. Here, we investigate the influence of implantation site and recipient sex on the differentiation of hESC-derived PECs in vivo. Male and female mice were implanted with 5x106 hESC-derived PECs either under the kidney capsule, in the gonadal fat pad, or subcutaneously within macroencapsulation (TheraCyteTM) devices. Mice that received PECs within TheraCyteTM devices developed glucose-stimulated human C-peptide secretion faster than cells implanted under the kidney capsule or in the gonadal fat pad. Interestingly, hESC-derived PECs implanted under the kidney capsule in females developed glucose-stimulated human C-peptide faster than in males, and secreted higher levels of arginine-stimulated glucagon and GLP-1 than other implantation sites. Furthermore, hESC-derived grafts collected from the kidney capsule and gonadal fat pad sites displayed a mix of endocrine and ductal cells as well as contained cysts whereas TheraCyteTM device grafts displayed mostly endocrine cells and cysts were not observed. Here we demonstrate that the macroencapsulated subcutaneous site and the female recipient can promote faster differentiation of hESC-derived PECs to endocrine cells in mice.