The Sympathoadrenal Progenitor of the Neural Crest: Basic Biology and Therapeutic Potential

Abstract

The development of successful cell-replacement therapies in the nervous system would be enhanced by an understanding of the basic biology of embryonic neural progenitor cells. The sympathoadrenal (SA) progenitor of the peripheral nervous system is among the best-characterized of such progenitors, in vertebrates. This cell, which derives from the neural crest, has a restricted developmental program that allows it to develop into a chromaffin cell or a sympathetic neuron, depending upon the environment to which it migrates. The extracellular signals that control the fate of SA progenitors have been identified, using both primary cultures of cells isolated from fetal rat adrenal glands and immortalized cell lines (MAH cells) derived from these primary progenitors. These studies have suggested that glucocorticoid hormones secreted by the adrenal cortex promote the development of SA progenitors into chromaffin cells, whereas fibroblast growth factor (FGF) and nerve growth factor (NGF) promote their development into sympathetic neurons. FGF and NGF appear to act sequentially; the former factor promotes neurite outgrowth and proliferation while the latter factor supports the survival of post-mitotic neurons. In addition to choosing between neuronal and endocrine fates, SA progenitors must also express an appropriate neurotransmitter phenotype. Although ordinarily noradrenergic, sympathetic neurons are able to convert to a cholinergic phenotype in response to specific inducing factors. This cholinergic potential is already present in uncommitted SA progenitors, as evidenced by their ability to synthesize acetylcholine. Recent studies suggest that these cells may have additional developmental capacities besides the chromaffin, noradrenergic and cholinergic sympathetic phenotypes, including the ability to generate serotonergic enteric neurons. The SA progenitor may therefore be a “master” neuroendocrine progenitor for the peripheral nervous system. Because it is multipotential, this progenitor (or immortalized lines derived from it) may be useful in heterologous cell transplantation therapies for a variety of neurodegenerative diseases.