Abstract
Sympathoadrenergic progenitor cells (SAPs) of the peripheral nervous system (PNS) are important for normal development of the sympathetic PNS and for the genesis of neuroblastoma, the most common and often lethal extracranial solid tumor in childhood. However, it remains difficult to isolate sufficient numbers of SAPs for investigations. We therefore set out to improve generation of SAPs by using two complementary approaches, differentiation from murine embryonic stem cells (ESCs) and isolation from postnatal murine adrenal glands. We provide evidence that selecting for GD2 expression enriches for ESC-derived SAP-like cells and that proliferating SAP-like cells can be isolated from postnatal adrenal glands of mice. These advances may facilitate investigations about the development and malignant transformation of the sympathetic PNS.
Highlights
Peripheral sympathoadrenergic cells develop from neural crest cells
A widely used strategy to generate neural progenitor cells (NPCs) from embryonic stem cells (ESCs) involves the formation of embryoid bodies (EBs), followed by culture in serum-free medium with mitogens to induce and expand Neural Progenitor Cells (NPCs) [27,28] (Fig. 1A)
We investigated in detail whether differentiation of ES cells to NPCs cells yields cells expressing markers related to neural crest stem cells (NCSCs) and sympathoadrenergic progenitors (SAPs)
Summary
Peripheral sympathoadrenergic cells develop from neural crest cells. Signals emanating from surrounding cells such as the BMPs (bone morphogenetic proteins), FGF (fibroblast growth factor) and Wnts (wingless-type proteins) induce neural crest markers including SNAIL/SLUG (vertebrate homologs of Drosophila snail gene), PAX3 (paired box 3), SOX9/10 (sex determining region Y-box) [1]. Once in the proximity of the dorsal aorta, BMPs induce a network of transcription factors in NCSCs that specify them to become sympathoadrenergic progenitors (SAPs) [4,5,6] Within this network PHOX2b (paired-like homeobox 2b) is pivotal and MASH1 (mammalian achaete schute homolog 1) is important [7,8]. These transcription factors induce HAND2 (heart- and neural crest derivatives-expressed protein 2) and GATA3 (GATA binding protein 3), which in concert with PHOX2b induce key enzymes of catecholamine biosynthesis, TH (tyrosine hydroxylase) and DBH (dopamine beta-hydroxylase) [9,10,11]. Those factors include glial cell line-derived nerve growth factor (GDNF), neurturin (NTN), brain-derived neurotrophic factor (BDNF), neurotrophin 4 (NT4), activating tyrosine kinase receptor B (TRKB), nerve growth factor (NGF), neurotrophin 3 (NT3) and activating tyrosine kinase receptor A (TRKA) [12,13]
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