Schwann Cell Precursors Generate the Majority of Chromaffin Cells in Zuckerkandl Organ and Some Sympathetic Neurons in Paraganglia

Abstract

In humans, neurosecretory chromaffin cells control a number of important bodily functions, including those related to stress response. Chromaffin cells appear as a distinct cell type at the beginning of midgestation and are the main cellular source of adrenalin and noradrenalin released into the blood stream. In mammals, two different chromaffin organs emerge at a close distance to each other, the adrenal gland and Zuckerkandl organ (ZO). These two structures are found in close proximity to the kidneys and dorsal aorta, in a region where paraganglioma, pheochromocytoma and neuroblastoma originate in the majority of clinical cases. Recent studies showed that the chromaffin cells comprising the adrenal medulla are largely derived from nerve-associated multipotent Schwann cell precursors (SCPs) arriving at the adrenal anlage with the preganglionic nerve fibers, whereas the migratory neural crest cells provide only minor contribution. However, the embryonic origin of the ZO, which differs from the adrenal medulla in a number of aspects, has not been studied in detail. The ZO is composed of chromaffin cells in direct contact with the dorsal aorta and the intraperitoneal cavity and disappears through an autophagy-mediated mechanism after birth. In contrast, the adrenal medulla remains throughout the entire life and furthermore, is covered by the adrenal cortex. Using a combination of lineage tracing strategies with nerve- and cell type-specific ablations, we reveal that the ZO is largely SCP-derived and forms in synchrony with progressively increasing innervation. Moreover, the ZO develops hand-in-hand with the adjacent sympathetic ganglia that coalesce around the dorsal aorta. Finally, we were able to provide evidence for a SCP-contribution to a small but significant proportion of sympathetic neurons of the posterior paraganglia. Thus, this cellular source complements the neural crest, which acts as a main source of sympathetic neurons. Our discovery of a nerve-dependent origin of chromaffin cells and some sympathoblasts may help to understand the origin of pheochromocytoma, paraganglioma and neuroblastoma, all of which are currently thought to be derived from the neural crest or committed sympathoadrenal precursors.

Malignant Schwann cell precursors mediate intratumoral plasticity in human neuroblastoma

“…Developmental differentiation of SCPs into the adrenal compartment can produce both neuroendocrine chromaffin and sympathetic neurons 9,10 . The adrenergic cells of neuroblastoma generally resembled sympathoblasts, expressing PRPH and GAP43, and lacked chromaffin markers such as PNMT (Fig 3F).…”

“…Many tumors are known to activate and replay developmental mechanisms to attain plasticity that ultimately promotes resistance to therapy 8 . The neural crest lineage, from which neuroblastoma originates, is remarkably flexible, and can give rise to both mesenchymal and adrenergic lineages during normal development [9][10][11][12][13] . In particular, using lineage tracing experiments in mice, we have recently observed that these adrenergic and mesenchymal cell types share an immediate developmental progenitor, represented by neural crest cells diverging at last towards sympatho-adrenal and mesenchymal sub-lineages 14 .…”

“…In an embryo, neural crest cells settle on the growing nerves and transform into Schwann cell precursors (SCPs), which express the most archetypical part of the neural crest signature and retain neural crest-like multipotency 9,15 . SCPs are retained for a considerable time during development and continuously give rise to chromaffin cells and some sympathetic neurons of the adrenal gland region which, in turn, is the most common anatomical location of neuroblastoma 9,10,16 . Here, by performing in-depth profiling of human neuroblastoma tumor samples at a single-cell level, we show continuous transitions between the two previously identified mesenchymal and adrenergic neuroblastoma subpopulations.…”

Extrinsic innervation of the pelvic organs in the lesser pelvis of human embryos

“…2017; Kastriti et al . 2019) and that to the intrinsic neurons of the colon ~20% (Uesaka et al . 2015), we do not know at present if, and if so to what extent, SCPs contribute to the IHGCs.…”

“…2017; Kastriti et al . 2019). These two agglomerates differ in that the chromaffin cells of the adrenal medulla are positioned dorsolaterally to the coeliac plexus, whereas those of the para‐aortic bodies touch or merge in the midline (Figure A,B), with very few para‐aortic bodies found distal to the umbilical bifurcation (Coupland, 1952, Kruepunga et al ., in press).…”