The fate of neural crest stem cells: nature vs nurture

Molecular Psychiatry (2003) 8, 129–130 & 2003 Nature Publishing Group All rights reserved 1359-4184/03 $25.00 www.nature.com/mp

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The fate of neural crest stem cells: nature vs nurture Molecular Psychiatry (2003) 8, 129–130. doi:10.1038/ sj.mp.4001300 Neural stem cells have received a great deal of attention in the last decade. Stem cells in the central nervous system (CNS) have been the focus of most of the work that has been done; their cousins in the peripheral nervous system have received short shrift. The cells that make up the peripheral nervous system arise in the neural crest. During formation of the neural tube from ectoderm, a group of cells separate from the tube to form a mass along its dorsal–lateral margin. These cells give rise to the neural crests. Cells of the neural crest migrate to different locations in the body to form the paravertebral and prevertebral ganglionic chain as well as chromaffin tissues that later form the adrenal medulla. The neural crest generates the dorsal root ganglia, autonomic ganglia, cranial nerve ganglia, enteric ganglia, Schwann cells and satellite cells as well as some nonneural tissues.1 Diverse progenitor cells make up the neural crest stem cell (NCSC) population; over time they gradually become more restricted in their fates. Thus, their phenotypic repertoire seems to decrease with embryonic age. The factors (intrinsic and extrinsic) that influence this delicate process have been studied in some detail. LaBonne and Bronner-Fraser2 review the factors that are involved in lineage segregation of NCSCs during embryonic development. Prior to the onset of migration of NCSCs, single dorsal neural tube cells can give rise to both CNS neural stem cells and neural crest derivatives, suggesting that their fate is not sealed. The differentiation of NCSCs into diverse cell types (sensory and autonomic ganglion cells, adrenal medulla, paraganglia, cranial nerve ganglia, Schwann cells, satellite cells, dermis, odontoblasts, melanoblasts, chondroblasts) may be driven by both extrinsic and intrinsic factors.3 Bixby et al4 were interested in the latter. They isolated NCSCs from the gut and the sciatic nerve of E14 embryos and examined their response to factors that are known to determine lineage choices. They found in vitro that NCSCs isolated from the sciatic nerve were very sensitive to the gliogenic effects of neuregulin and Notch ligands, while NCSCs that originated in the gut were very sensitive to the neurogenic effects of BMP4 (bone morphogenetic protein 4). In spite of their lineage biases, both populations of cells were capable of Correspondence: E´ Mezey, NIH, NINDS, Bethesda, MD, USA

differentiating into glia and neuron. To determine the relevance of these observations in vivo, NCSCs from both sources were transplanted into the hindlimb bud somites of stage 18 chick embryos. Nerve-derived NCSCs gave rise to glia in the peripheral nerve, but gave rise to neurons in Remak’s ganglion of the chick. Gut-derived NCSCs on the other hand gave rise to neurons in the peripheral nerves. It seems that NCSCs vary in their sensitivity to environmental factors that determine lineage. This difference is intrinsic; perhaps DNA microarrays might help one find the transcripts responsible, but one should bear in mind that the environmental factors can overcome these differences. We still have a lot to learn about the factors driving cell fate switches, the timing of these events, and the plasticity or rigidity of fetal and postnatal stem cells. Although the existence of neural stem cells in the CNS and adult neurogenesis has finally been accepted,5,6 there were no data indicating that similar progenitor cells might be available for the peripheral nervous system. Over 50 years ago Benninghoff,7 a German scientist, described a rather interesting experiment. He partially ligated the small intestine of rodents and examined the enteric ganglionic cells 4 weeks later. Based on classical histological stains and morphology of all nuclei, he concluded that there was a five-fold increase in the number of ganglionic cells upstream from the ligation, while downstream there was a decrease in cell numbers as well as nuclear volume. He suggested that there must be division of ganglion cells in response to injury, but did not discuss how this might happen. One wonders whether the recent findings by Kruger et al8 might explain the results of Benninghoff’s experiments. Kruger et al used flow cytometry and p75 and a-integrin as markers to isolate NCSCs from the intestine of 5–15-day-old and adult rats. These cells are self-renewing in culture and are capable of forming neurons, glial cells and myofibroblasts, suggesting that there are multipotential progenitor cells in the adult gastrointestinal tract. The number of multipotential cells decreases with age and they become more and more fate restricted. In an elegant in vivo experiment, the authors also demonstrated that when these progenitor cells are transplanted into developing chick nerves, the NCSCs derived from E14.5 embryo intestine will give rise to primarily neurons, while those taken from P22 gut primarily generate glial cells. It is interesting that these changes reflect age-related needsFin the embryo, there is much more gut to be grown that will need innervation and many neuronal cellsFwhile in

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the adult (or close to adult) the gastrointestinal system has fully developed and all neurons are in place, so it is the reproduction of nonneuronal cells (with possibly more frequent turnover rate) that will be needed. It will also be interesting to examine these cells in the case of an injuryFwhen ganglionic cells are destroyed, or when they are genetically missing or are dysfunctional. These cells were suggested to have a common precursor with neural stem cells.9 Finding a source for NCSCs (ES cells, CNS neural stem cells, NCSC isolated from gut, bone marrow stromal cells) might help treat diseases of the peripheral nervous system. We all hope that finding out more about the existence and apparent plasticity of NCSCs in the adult organism might enable us to help delay or heal diseases such as mild Hirshprung’s disease or the

Molecular Psychiatry

incurable familial dysautonomia (Riley–Day syndrome). E´ Mezey NIH, NINDS, Bethesda, MD, USA

1 Mathers LH. The Peripheral Nervous System, Addison-Wesley Publishing Company Inc.: Menlo Park, CA, 1985. 2 LaBonne C, Bronner-Fraser M. Annu Rev Cell Dev Biol 1999; 15: 81–112. 3 Paratore C et al. Int J Dev Biol 2002; 46(1 Spec No): 193–200. 4 Bixby S et al. Neuron 2002; 35: 643–656. 5 Kennea NL, Mehmet H. J Pathol 2002; 197: 536–550. 6 Gage FH. Science 2000; 287: 1433–1438. 7 Benninghoff A. Z Naturforsch 1951; 6: 38–44. 8 Kruger GM et al. Neuron 2002; 35: 657–669. 9 Mujtaba T et al. Dev Biol 1998; 200: 1–15.