An integrated single-cell analysis of human adrenal cortex development

Abstract

The adrenal glands synthesize and release essential steroid hormones such as cortisol and aldosterone, but many aspects of human adrenal gland development are not well understood. Here, we combined single-cell and bulk RNA sequencing, spatial transcriptomics, IHC, and micro-focus computed tomography to investigate key aspects of adrenal development in the first 20 weeks of gestation. We demonstrate rapid adrenal growth and vascularization, with more cell division in the outer definitive zone (DZ). Steroidogenic pathways favored androgen synthesis in the central fetal zone, but DZ capacity to synthesize cortisol and aldosterone developed with time. Core transcriptional regulators were identified, with localized expression of HOPX (also known as Hop homeobox/homeobox-only protein) in the DZ. Potential ligand-receptor interactions between mesenchyme and adrenal cortex were seen (e.g., RSPO3 / LGR4 ). Growth-promoting imprinted genes were enriched in the developing cortex (e.g., IGF2 , PEG3 ). These findings reveal aspects of human adrenal development and have clinical implications for understanding primary adrenal insufficiency and related postnatal adrenal disorders, such as adrenal tumor development, steroid disorders, and neonatal stress.

Single-cell and spatial transcriptomics in endocrine research

“…Human adrenal cortex development was studied using scRNA-seq, which demonstrated the longitudinal transcriptional changes of diverse cell types included in the developing adrenal gland. In the study, ligand-receptor analysis revealed the potential bidirectional interactions between mesenchyme and adrenal cortex, such as DLK1-NOTCH2 (cortex to mesenchyme) and RSPO3-LGR4 (mesenchyme to cortex) [116]. These techniques have been used in several studies to examine pancreases.…”