Postnatal sustentacular cells as chromaffin progenitors and tumor cells of origin in VHL-related paragangliomas.

The cellular source of chromaffin cell regeneration after birth and its relationship to paraganglioma tumorigenesis remains incompletely defined. Here, we identify a postnatal population of SOX2/SOX10-expressing sustentacular glia-like cells in the organ of Zuckerkandl (OZ) and adrenal gland that give rise to chromaffin cells in vivo. These cells differ transcriptionally from embryonic chromaffin progenitors known as Schwann cell precursors and exhibit a unique progenitor signature. Genetic lineage tracing confirms their postnatal contribution to chromaffin cells, and SOX2(+)PHOX2B(+) transitional cells were observed in both human and mouse OZ and adrenal tissues. Single-nuclei RNA-seq and inferCNA analysis of pheochromocytoma and paraganglioma (PPGL) revealed that while most sustentacular cells exhibit a stromal profile, a subset in VHL-mutated PPGLs harbor the hallmark 3p chromosomal loss shared with chief tumor cells, suggesting a clonal origin. In an additional PPGL, widespread SOX2 expression in PHOX2B(+) tumor cells supports this hypothesis. Finally, DLK1-NOTCH signaling was predicted as a central regulator of chromaffin-sustentacular communication, suggesting DLK1 fine-tunes chromaffin regeneration via NOTCH inhibition and may represent a therapeutic target in PPGL.