Modeling human embryonic adrenogenesis in pluripotentstem cell-derived corticomedullar-like assembloids

Embryonic development unfolds through two distinct cell lineages within the adrenal gland: cortical cells arising from intermediate mesoderm-derived progenitors and medullary cells generated by neural crest-derived catecholaminergic progenitors. Recreating this dynamic in a human pluripotent stem cell (hPSC) system poses significant hurdles due to the unique cellular origins, signaling environments, and interactions required for the simultaneous emergence and integration of cortical and medullary layers.

Our research team has devised a novel strategy to model the adrenal-gonadal primordium (AGP) in compound organoids, characterized by a gradient of NR5A1 expression. This setup, surprisingly, also integrates SOX10-expressing Schwann cell precursors, which ultimately give rise to chromaffin cells. By examining the paracrine signaling within these AGP-like organoids (AGPLOs), we identified a fibroblast growth factor 9 (FGF9)-driven mechanism that expands bridge cell-like chromaffin progenitors, mirroring the paracrine cues experienced by these cells as they migrate to the cortex in vivo.

Combining NR5A1-expressing cells with chromaffin cell clusters resulted in corticomedullar-like assembloids (CMLAs) that successfully produced steroids and catecholamines and responded to adrenocorticotropic hormone. This breakthrough establishes a platform for studying the complex signaling relationships that govern adrenal gland development and function in both health and disease.

Furthermore, it offers a promising avenue for generating hPSC-derived adrenal cells and tissues, potentially paving the way for therapeutic applications.