Research Article

Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla

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Science  07 Jul 2017:
Vol. 357, Issue 6346, eaal3753
DOI: 10.1126/science.aal3753

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Following the yellow brick road

The adrenal glands affect a variety of processes such as stress responses and metabolism. The mature adrenal gland is formed from multiple tissue sources, including cells of neural origin. Furlan et al. traced the origins of these cells. The cells first become Schwann cell precursors and follow along nerves to travel from the dorsal root ganglia of the spine to the adrenal gland. Once there, the cells differentiate into chromaffin cells. The authors used singlecell transcriptomics to reveal the shifts in functional programs during migration, development, and differentiation.

Science, this issue p. eaal3753

Structured Abstract

INTRODUCTION

Circulating adrenaline can have profound effects on the body’s “inner world,” adjusting levels depending on demand to maintain organ and bodily homeostasis during daily living. In the more extreme fight-or-flight response, the surge of adrenaline is “energizing” through effects on organs and tissues, including increased heart rate and blood glucose levels, and redirecting oxygen and glucose to limb muscles. Chromaffin cells located in the adrenal medulla constitute the main hormonal component of the autonomic nervous system and are the principal source for release of catecholamines, including adrenaline, in the systemic circulation. Understanding the cellular origin and biological processes by which the adrenal medulla is formed during development is needed for mechanistic insights into how the hormonal component of the autonomic nervous system is formed and its relation to the rest of the autonomic nervous system.

RATIONALE

Adrenergic chromaffin cells in the adrenal medulla are thought to originate from a common sympathoadrenal lineage close to the dorsal aorta, where these cells split in a dorsoventral direction, forming the sympathetic chain and adrenal medulla, respectively. Revisiting this dogma, we examined the cell type origin of chromaffin cells, lineage segregation of sympathoblasts and chromaffin cells, the gene programs driving specification of chromaffin cells from progenitors, and the proliferative dynamics by which the adrenal medulla is formed.

RESULTS

We found that chromaffin cells of the adrenal medulla are formed from peripheral glia stem cells, termed Schwann cell precursors. Genetic cell lineage tracing revealed that most chromaffin cells arise from Schwann cell precursors, and consistently, genetic ablation of Schwann cell precursors results in marked depletion of chromaffin cells. Genetic ablation of the preganglionic nerve, on which Schwann cell precursors migrate, similarly leads to marked deficiencies of chromaffin cells, and fate-tracing cells unable to differentiate into chromaffin cells reveal an accumulation of glia cells in the region of the adrenal medulla. Experiments reveal that sympathetic and adrenergic lineages diverge at an unexpectedly early stage during embryonic development. Embryonic development of the adrenal medulla relies on recruitment of numerous Schwann cell precursors with limited cell expansion. Thus, the large majority of chromaffin cells arise from Schwann cell precursors migrating on preganglionic nerves innervating the adrenal medulla. Unexpectedly, single-cell RNA sequencing revealed a complex gene-regulatory mechanism during differentiation of Schwann cell precursors to chromaffin cells, whereby Schwann cell precursors enter into a gene expression program unique for a transient cellular state. Subsequently, this gene program and chromaffin cell gene networks suppress glial gene programs, advancing cells into the chromaffin cell identity.

CONCLUSION

By revisiting development of the adrenergic sympathetic system, we discovered a new cellular origin of this nervous system component. The adrenergic medulla is built from both neural crest cells and Schwann cell precursors, with a major contribution from Schwann cell precursors in rodents. A cellular origin from Schwann cell precursors highlights the importance of peripheral nerves as a stem cell niche and transportation routes for progenitors essential for neuroendocrine development. These results and mechanisms of differentiation through a transient intermediate cell type may also be helpful in advancing our knowledge on neuroblastoma and pheochromocytoma, because these most often arise from the adrenal gland region.

Adrenal medulla largely originates from Schwann cell precursors.

Overview of adrenal medulla development resulting from lineage tracing and nerve ablation experiments. SCP, Schwann cell precursor; AG, adrenal gland; NT, neural tube; n, notochord; DRG, dorsal root ganglion; IML, intermediolateral column; NCC, neural crest cells; NC, neural crest; DA, dorsal aorta; SRG, suprarenal sympathetic ganglion. Red encodes early NCCs and their derivatives. Blue encodes late neural crest and SCP-derived cell types.

Abstract

Adrenaline is a fundamental circulating hormone for bodily responses to internal and external stressors. Chromaffin cells of the adrenal medulla (AM) represent the main neuroendocrine adrenergic component and are believed to differentiate from neural crest cells. We demonstrate that large numbers of chromaffin cells arise from peripheral glial stem cells, termed Schwann cell precursors (SCPs). SCPs migrate along the visceral motor nerve to the vicinity of the forming adrenal gland, where they detach from the nerve and form postsynaptic neuroendocrine chromaffin cells. An intricate molecular logic drives two sequential phases of gene expression, one unique for a distinct transient cellular state and another for cell type specification. Subsequently, these programs down-regulate SCP-gene and up-regulate chromaffin cell–gene networks. The AM forms through limited cell expansion and requires the recruitment of numerous SCPs. Thus, peripheral nerves serve as a stem cell niche for neuroendocrine system development.

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