학술논문
Generation of glucocorticoid-producing cells derived from human pluripotent stem cells
Document Type
article
Author
Gerard Ruiz-Babot; Ariane Eceiza; Fernando Abollo-Jiménez; Maria Malyukov; Diana L. Carlone; Kleiton Borges; Alexandra Rodrigues Da Costa; Shamma Qarin; Takuya Matsumoto; Ryuji Morizane; William C. Skarnes; Barbara Ludwig; Paul J. Chapple; Leonardo Guasti; Helen L. Storr; Stefan R. Bornstein; David T. Breault
Source
Cell Reports: Methods, Vol 3, Iss 11, Pp 100627- (2023)
Subject
Language
English
ISSN
2667-2375
Abstract
Summary: Adrenal insufficiency is a life-threatening condition resulting from the inability to produce adrenal hormones in a dose- and time-dependent manner. Establishing a cell-based therapy would provide a physiologically responsive approach for the treatment of this condition. We report the generation of large numbers of human-induced steroidogenic cells (hiSCs) from human pluripotent stem cells (hPSCs). Directed differentiation of hPSCs into hiSCs recapitulates the initial stages of human adrenal development. Following expression of steroidogenic factor 1, activation of protein kinase A signaling drives a steroidogenic gene expression profile most comparable to human fetal adrenal cells, and leads to dynamic secretion of steroid hormones, in vitro. Moreover, expression of the adrenocorticotrophic hormone (ACTH) receptor/co-receptor (MC2R/MRAP) results in dose-dependent ACTH responsiveness. This protocol recapitulates adrenal insufficiency resulting from loss-of-function mutations in AAAS, which cause the enigmatic triple A syndrome. Our differentiation protocol generates sufficient numbers of hiSCs for cell-based therapy and offers a platform to study disorders causing adrenal insufficiency. Motivation: Adrenal insufficiency is a life-threatening condition resulting from the inability to produce steroid hormones in a dose and time-dependent manner. The ability to generate cells that produce cortisol in response to adrenocorticotrophic hormone (ACTH), the main regulator of glucocorticoid production in humans, combined with the development of encapsulation and immunoprotecting technologies, will open future opportunities to treat this condition using cell-based therapies. Current protocols have demonstrated the generation of fetal-like steroid-producing cells from hPSCs. However, the resulting cells fail to secrete cortisol, the main glucocorticoid in humans. We therefore sought to develop a protocol that enables the generation of billions of cells that produce cortisol and can respond to ACTH stimulation.