Pluripotent human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating patients with diabetes. compared with SCID-beige mice indicating that the host recipient can greatly influence the fate of immature pancreatic progenitor cells post-transplantation. Introduction Patients with type 1 diabetes suffer from a severe deficiency in insulin production by pancreatic islets as a result of immune-mediated destruction of pancreatic β cells. Insulin independence can be achieved by transplantation of cadaveric human islets (Shapiro 2011 but because of the scarcity of donor tissue the field is exploring the potential use of scalable human embryonic stem cell (hESC)-derived pancreatic cells as an alternative cell source. We have demonstrated previously that hESC-derived pancreatic progenitor cells develop over several months in?vivo into insulin-secreting cells capable of reversing hyperglycemia in a mouse model of type 1 diabetes (Rezania et?al. 2012 Rezania et?al. 2013 Bruin et?al. 2013 Interestingly the maturation process was accelerated when mice were exposed to chronic hyperglycemia but unaffected by exposure to long-term insulin therapy short-term exendin-4 treatment oral anti-diabetic medications or high-fat diets (Bruin et?al. 2013 Bruin et?al. 2015 In addition we recently reported a revised differentiation protocol that generated glucose-responsive insulin-secreting cells in?vitro and required a much shorter maturation period (～6?weeks) following transplantation to reverse hyperglycemia in mice (Rezania et?al. 2014 Given the uncertainty surrounding the complex host environment and variables that may affect the maturation process in? vivo advancing the differentiation protocols in? vitro prior to transplantation may be advantageous. Nevertheless hESC-derived pancreatic progenitor cells are currently being tested for safety tolerability and efficacy in a phase 1/2 clinical trial by Viacyte (ClinicalTrials.gov identifier “type”:”clinical-trial” attrs :”text”:”NCT02239354″ term_id :”NCT02239354″NCT02239354). Therefore although newer differentiation protocols have been reported (Pagliuca et?al. 2014 Rezania et?al. 2014 Russ et?al. 2015 it remains important to understand the development of pancreatic progenitor cells in?vivo because clinical trials are underway in patients with diabetes. There are several obvious differences between the pre-clinical transplant recipients tested to date (immunodeficient mice) and the target patient population including the species distinct metabolic profiles and large size difference. Although rats are not Sesamoside directly comparable with humans their physiology is reportedly more similar to humans than mice particularly in terms of cardiovascular parameters (Davies and Morris 1993 We have demonstrated previously that hESC-derived grafts were capable of robust glucose-stimulated insulin secretion (GSIS) after just 14?weeks in nude rats whereas GSIS was not observed until after 30?weeks in similar studies with severe combined immunodeficiency (SCID)-beige mice (Rezania et?al. 2012 However these studies were performed at Sesamoside different facilities and with different batches of cells so we could not make direct comparisons between species. Interestingly others have reported that hESC-derived pancreatic progenitor cells did not efficiently differentiate into pancreatic endocrine tissue following transplantation in nude rats (Matveyenko et?al. 2010 The authors speculated that the nude rat may be a less accommodating host environment compared with immunodeficient mice (Matveyenko et?al. 2010 To address these conflicting observations we performed a carefully controlled study within a single research facility to directly compare the in?vivo development of hESC-derived pancreatic progenitor cells from the same preparation and Rabbit polyclonal to AKAP5. transplanted in parallel into Sesamoside either immunodeficient nude rats or SCID-beige mice. Results hESC-Derived Insulin-Producing Cells Develop Faster and Function Better Sesamoside in Rats Than in Mice Pluripotent H1 cells were differentiated into pancreatic progenitor cells over 14?days resulting in a population containing 17% endocrine cells (synaptophysin+). Chromogranin+ endocrine cells coexpressed NKX2.2 but were largely negative for NKX6.1 a sign of immaturity (Figure?S1). The differentiated cells were ～80% PDX1+ ～50% NKX6.1+ ～18% PAX6+ and ～15% Ki67+ (Figure?S1). Pluripotent cells (OCT3/4+) were not detected in the differentiated population at the time of transplantation (Figure?S1). Sesamoside This preparation of.