In healthy individuals, pancreatic β cells secrete insulin in response to nutrients such as glucose, amino acids, and free fatty acids to regulate blood glucose levels and lipid metabolism, whereas β cell failure or impaired function is associated with both type 1 and type 2 diabetes. The continuing challenges in treating diabetes placed the development of transplantable β cells as one of the central goals of stem cell therapy. While human embryonic and pluripotent stem cells (hESCs and hPSCs) offer this potential, it has been difficult to realize this therapeutic promise.
The recent descriptions of embryonic stem-derived β-like cells reflect both the progress and ongoing challenges in achieving functionally mature β cells in vitro. Interestingly, transplantation of these pre-functional cells into mice results in a progressive in vivo maturation, presumably facilitated by the complex internal milieu reflecting a process that may be too complex to achieve in cell culture.
β cells are known to facilitate glucose-stimulated insulin secretion (GSIS) through increased mitochondrial oxidative ATP production. Whereas the cellular components required for GSIS are well established, the key transcriptional networks that regulate β cell metabolism and insulin secretion remain poorly understood.
Nuclear receptors are ligand-dependent transcription factors that play central roles in controlling development, growth, and metabolism. Estrogen-related receptors (ERRs) are orphan nuclear receptors represented by three paralogs in mammals, ERRα (NR3B1, Esrra), ERRβ (NR3B2, Esrrb), and ERRγ (NR3B3, Esrrg). ERRβ is known to play an essential role in embryonic stem cell maintenance whereas ERRα and ERRγ regulate oxidative pathways such as the tricarboxylic acid cycle, the electron transport complex (ETC), and oxidative phosphorylation (OxPhos).
Notably, genetic studies in mice have revealed distinct functions for ERRα and ERRγ. While whole body ERRα knockout (ERRαKO) mice are developmentally normal, they are lean and resistant to high fat diet-induced obesity. In contrast, whole body ERRγ knockout (ERRγKO) mice have significant developmental abnormalities and marked postnatal lethality attributed to defects in energy utilization, severely limiting their experimental utility.
Researchers report that ERRγ is a master regulator of β cell maturation in vivo and that this function can be recapitulated in the in vitro setting. They show that estrogen-related receptor γ (ERRγ) expression as a hallmark of adult, but not neonatal β cells. Authors identify postnatal induction of ERRγ drives a transcriptional network activating mitochondrial oxidative phosphorylation, the electron transport chain, and ATP production needed to drive glucose-responsive insulin secretion.
Mice lacking ERRγ specifically in pancreatic β cells (βERRγKO mice) are glucose intolerant due to impaired insulin secretion. Reciprocally, in vitro expression of ERRγ in human iPSC-derived β-like cells yields functional and transplantable glucose-responsive cells capable of restoring glucose homeostasis in type 1 diabetic mice.
These studies reveal that functional, transplantable β cells can be generated and quantified in vitro without the need for kidney capsule maturation in patients.
Estrogen-related receptor γ (ERRγ) required for functional maturation of pancreatic beta cells
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