Sex Differences in Maturation of Human Embryonic Stem Cell–Derived β Cells in Mice

Abstract

Pancreatic progenitors derived from human embryonic stem cells (hESCs) are now in clinical trials for insulin replacement in patients with type 1 diabetes. Animal studies indicate that pancreatic progenitor cells can mature into a mixed population of endocrine cells, including glucose-responsive β cells several months after implantion. However, it remains unclear how conditions in the recipient may influence the maturation and ultimately the function of these hESC-derived cells. Here, we investigated the effects of (1) pregnancy on the maturation of human stage 4 (S4) pancreatic progenitor cells and (2) the impact of host sex on both S4 cells and more mature stage 7 (S7) pancreatic endocrine cells implanted under the kidney capsule of immunodeficient SCID-beige mice. Pregnancy led to increased proliferation of endogenous pancreatic β cells, but did not appear to affect proliferation or maturation of S4 cells at midgestation. Interestingly, S4 and S7 cells both acquired glucose-stimulated C-peptide secretion in females before males. Moreover, S4 cells lowered fasting blood glucose levels in females sooner than in males, whereas the responses with S7 cells were similar. These data indicate that the host sex may impact the maturation of hESC-derived cells in vivo and that this effect can be minimized by more advanced differentiation of the cells before implantation.

Encapsulation boosts islet-cell signature in differentiating human induced pluripotent stem cells via integrin signalling

“…The cellular and molecular basis of the process driving this in vivo terminal differentiation is not yet completely understood 11 . Different potential scenarios include the involvement of circulating factors [12][13][14][15] , nervous system association [16][17][18] and the presence of a 3D niche 19,20 , amongst others. Discriminating the exact contribution of each of these potential scenarios on the transplanted hPSC-derived cells is difficult due to the inherent complexity of the organism environment.…”

In vivo Environment Swiftly Restricts Human Pancreatic Progenitors Toward Mono-Hormonal Identity via a HNF1A/HNF4A Mechanism

“…Nevertheless, it is, however, expected that a very brief in vivo exposure, such as the one used in this study, will be insufficient to promote any meaningful/detectable improvement in the functionality of the transplanted cells. Indeed, previous studies reported improved functionality and glucose stimulated insulin secretion in similar setups only after about 60 days post xenotransplantation (Rezania et al, 2014;Saber et al, 2018), thus involving longer exposure times.…”

“…In addition, xeno-transplantation into living hosts, such as mice, has been shown to significantly increase the yield and functionality of the differentiating hPS-derived cells (Kroon et al, 2008;Rezania et al, 2012Rezania et al, , 2014Pagliuca et al, 2014). Indeed, after extensive periods of time (2-6 months), the xenotransplantation of circa two million in vitro differentiated cells was able to normalize the glycemia in diabetic mice (Pagliuca et al, 2014;Rezania et al, 2014;Agulnick et al, 2015;Vegas et al, 2016;Bochenek et al, 2018;Saber et al, 2018). Although these experiments highlighted the importance of the in vivo environment and its systemic factors in promoting islet cell fate, the signals governing this process are largely unknown.…”

Pluripotent Stem Cell-Derived Pancreatic Progenitors and β-Like Cells for Type 1 Diabetes Treatment

“…This suggests that a more committed population may provide faster glycemic control in clinical settings. Well-designed studies have also described the in vivo maturation of hESC-derived PPs in various settings: 1) with and without encapsulation (9,42,64), 2) in male vs. female hosts (67), 3) in rats vs. mice (8), 4) in high-fat diet (10), 5) during pregnancy (67), and 6) in a model of hypothyroidism (11). These studies suggest that host environment, sex differences, and disease conditions may play crucial roles in PP maturation in vivo.…”