Generation of Glucocorticoid-producing Cells Derived from Human Pluripotent Stem Cells

Overview

Journal Cell Rep Methods

Specialty Cell Biology

Date 2023 Nov 4

PMID 37924815

Authors

Gerard Ruiz-Babot

Ariane Eceiza

Fernando Abollo-Jimenez

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

Affiliations

Soon will be listed here.

Abstract

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.

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