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Taking Neural Crest Stem Cells to New Heights

2007; Cell Press; Volume: 131; Issue: 2 Linguagem: Inglês

10.1016/j.cell.2007.10.006

1097-4172

Erzsebet Kokovay, Sally Temple,

Genetics and Neurodevelopmental Disorders

The carotid body is an organ of the peripheral nervous system that senses oxygen concentration in the blood and responds to changes by regulating breathing. Pardal et al., 2007Pardal R. Ortega-Sáenz P. Durán R. López-Barneo J. Cell. 2007; (this issue)PubMed Google Scholar now report the discovery of carotid body stem cells, which proliferate in response to hypoxia and generate neurons that secrete dopamine. This new source of adult stem cells may be useful in therapies for treating Parkinson's disease. The carotid body is an organ of the peripheral nervous system that senses oxygen concentration in the blood and responds to changes by regulating breathing. Pardal et al., 2007Pardal R. Ortega-Sáenz P. Durán R. López-Barneo J. Cell. 2007; (this issue)PubMed Google Scholar now report the discovery of carotid body stem cells, which proliferate in response to hypoxia and generate neurons that secrete dopamine. This new source of adult stem cells may be useful in therapies for treating Parkinson's disease. When Edmund Hillary climbed with Tenzing Norgay into thin air in their campaign to conquer Everest, little did they know that an intriguing piece of stem cell biology was contributing to their success. In this issue, Pardal et al., 2007Pardal R. Ortega-Sáenz P. Durán R. López-Barneo J. Cell. 2007; (this issue)PubMed Google Scholar reveal that in low-oxygen conditions, a glia-like stem cell population of the carotid body proliferates and generates new dopaminergic neurons that contribute to an increase in ventilation. This is the first finding of in vivo neurogenesis from adult stem cells derived from the neural crest. Moreover, the demonstration that carotid stem cells can be grown in tissue culture opens up an exciting possibility—to expand a patient's own cells ex vivo for autologous cell therapy to treat Parkinson's disease. Neurogenesis is highly restricted in adulthood. In the adult central nervous system (CNS), neurons are formed in the dentate gyrus of the hippocampus and in the subventricular zone surrounding the lateral ventricle. Adult CNS stem cells resemble astrocytes (a major type of glial cell) in their ultrastructural features and expression of glial fibrillary acidic protein (GFAP) (Alvarez-Buylla and Lim, 2004Alvarez-Buylla A. Lim D.A. Neuron. 2004; 41: 683-686Abstract Full Text Full Text PDF PubMed Scopus (1103) Google Scholar, Doetsch et al., 1999Doetsch F. Caille I. Lim D.A. Garcia-Verdugo J.M. Alvarez-Buylla A. Cell. 1999; 97: 703-716Abstract Full Text Full Text PDF PubMed Scopus (3097) Google Scholar). In the peripheral nervous system (PNS), neurogenesis persists in the olfactory neuroepithelium, which produces sensory neurons throughout life for odor detection (Beites et al., 2005Beites C.L. Kawauchi S. Crocker C.E. Calof A.L. Exp. Cell Res. 2005; 306: 309-316Crossref PubMed Scopus (205) Google Scholar). The work by Pardal et al. reveals another location for endogenous neurogenesis—the chemoreceptor carotid body. The ability to adapt to short- and long-term exposure to low-oxygen environments is crucial for mammalian survival, and the carotid body, nestled at the bifurcation of the internal and external carotid arteries, is a key component of the adaptive response (Figure 1). The carotid body consists of two main cell types, the excitable dopaminergic glomus cells and the sustentacular cells that resemble glia of the CNS in their supportive role and GFAP expression. The glomus cells, present in highly vascularized clusters throughout the carotid body, are chemoreceptor cells exquisitely sensitive to changes in oxygen levels in arterial blood. Reduction in available oxygen activates the glomus cells, resulting in membrane depolarization and release of neurotransmitters, including acetylcholine, ATP, and dopamine. These factors bind to sensory fibers that carry a message to the brainstem respiratory center to stimulate ventilation, thereby increasing the availability of oxygen. One intriguing feature of the carotid body is that in addition to its immediate response to acute hypoxia, chronic hypoxia (such as acclimation to high altitudes) results in a dramatic increase in its size. Pardal and colleagues discovered that the increase in size is due to neurogenesis resulting from the proliferation and differentiation of stem cells. Using bromodeoxyuridine (BrdU), a label of proliferative cells, they observed a dramatic increase in cell division in rats exposed to a hypoxic environment. After 5 days of hypoxia, many BrdU+ cells also expressed tyrosine hydroxylase (TH), a marker of dopaminergic neurons. Upon restoration of normoxia, the carotid body displays remarkable plasticity, returning to its normal size with nearly half of the glomus cells being newly generated. The authors then showed that cells extracted from the carotid body and cultured under hypoxic conditions express the progenitor marker Nestin and proliferate to form multicell spheres, a hallmark of neural stem cell activity. A small percentage of these cells self renew, even under these stringent conditions outside the normal niche. The authors tracked sphere growth over time and watched a surprising transformation take place. After a few days, they produced a growing bud of TH+ cells that eventually formed a paired-sphere structure with progenitors on one lobe and differentiated progeny on the other. Importantly, these TH+ cells generated in vitro had essentially the same responses as normal glomus cells: hypoxia caused them to become depolarized and to secrete dopamine. Which cell type is responsible for growth of the carotid body? The observation that almost all GFAP immunoreactivity disappeared following hypoxia and then reappeared under normoxic conditions suggested the glia-like sustentacular cells could be responsible, an idea confirmed using transgenic mice that express lacZ in cells with a history of GFAP expression. Further characterization revealed that GFAP+ sustentacular cells activated by hypoxia give rise to proliferating Nestin+ GFAP− progenitor cells that in turn produce dopaminergic glomus cells, a lineage resembling that of CNS stem cells (Figure 1). Importantly, upon returning to normoxia, the carotid growth regresses and the activated stem cells return to their normal GFAP+ sustentacular cell state. Understanding the mechanism of this reversal could tell us about the relationship between the quiescent and activated states, an issue relevant to other classes of stem cells including tumor stem cells. Using a Wnt1 reporter, the authors showed that the carotid body stem cell is derived from the neural crest. Prior reports of neurons generated from adult neural crest stem cells, in the skin and enteric nervous systems, have been limited to in vitro studies (Fernandes et al., 2007Fernandes K.J. Toma J.G. Miller F.D. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2007; (Published online February 5, 2007)https://doi.org/10.1098/rstb.2006.2020Crossref Scopus (114) Google Scholar, Kruger et al., 2002Kruger G.M. Mosher J.T. Bixby S. Joseph N. Iwashita T. Morrison S.J. Neuron. 2002; 35: 657-669Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). Now that we recognize that neurogenesis of the carotid body requires hypoxia, we speculate that specific injury or stress could induce endogenous neurogenesis from other neural crest stem cells. However, we still need to uncover the mechanism of stem cell activation. Is low availability of oxygen first detected by glomus cells that then signal to the sustentacular cells to activate their stem cell activity, or do the sustentacular cells respond directly to hypoxia? This latter possibility is plausible given in vitro studies showing that when cultured under hypoxic conditions, neural crest and other neural stem cells display enhanced proliferation and generate a higher number of TH+ cells (Pistollato et al., 2007Pistollato F. Chen H.L. Schwartz P.H. Basso G. Panchision D.M. Mol. Cell. Neurosci. 2007; 35: 424-435Crossref PubMed Scopus (115) Google Scholar and references therein). We also should not ignore the possibility of other endogenous signals that come from the vasculature to the stem cells. Given the importance of the vascular niche to a variety of stem cells, understanding the signaling pathway for stem cell activation in the carotid body could have broader implications. Perhaps the most exciting aspect of the discovery of carotid body stem cells is their potential for clinical application. Parkinson's disease is a debilitating neurological disorder characterized by loss of dopaminergic neurons of the substantia nigra that project to the striatum. Intrastriatal grafting of dopamine-producing cells is an attractive therapeutic strategy. Glomus cells are a promising cell source, because they are readily obtained from the carotid body of the patient, thus obviating the need for immunosuppressive therapies that would accompany the transplantation of nonautologous donor cells. Furthermore, these cells thrive in low-oxygen tension, conditions typical of brain parenchyma. Lopez-Barneo and colleagues showed that transplantation of carotid body cell aggregates significantly ameliorates motor deficiency in a rat model of Parkinson's disease (Espejo et al., 1998Espejo E.F. Montoro R.J. Armengol J.A. Lopez-Barneo J. Neuron. 1998; 20: 197-206Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar), and recent clinical trials using cell aggregates derived from the carotid body have reported encouraging results in Parkinson's patients (Minguez-Castellanos et al., 2007Minguez-Castellanos A. Escamilla-Sevilla F. Hotton G.R. Toledo-Aral J.J. Ortega-Moreno A. Mendez-Ferrer S. Martin-Linares J.M. Katati M.J. Mir P. Villadiego J. et al.J. Neurol. Neurosurg. Psychiatry. 2007; 78: 825-831Crossref PubMed Scopus (69) Google Scholar). However, a limitation is the small number of cells that can be extracted from the carotid body. The identification of carotid body stem cells may make it possible to generate sufficient cells ex vivo for transplantation and allow for genetic manipulation of the cells if necessary. Although adult stem cells have been vilified by some, largely due to misrepresentation of their plasticity by crusaders against embryonic stem cells, the findings by Pardal et al. and others point to their promise. Now is the time to embrace the entire breadth of stem cell biology and to celebrate the discovery of new stem cell niches and the growing possibilities of stem cell-related therapies. Glia-like Stem Cells Sustain Physiologic Neurogenesis in the Adult Mammalian Carotid BodyPardal et al.CellOctober 19, 2007In BriefNeurogenesis is known to occur in the specific niches of the adult mammalian brain, but whether germinal centers exist in the neural-crest-derived peripheral nervous system is unknown. We have discovered stem cells in the adult carotid body (CB), an oxygen-sensing organ of the sympathoadrenal lineage that grows in chronic hypoxemia. Production of new neuron-like CB glomus cells depends on a population of stem cells, which form multipotent and self-renewing colonies in vitro. Cell fate mapping experiments indicate that, unexpectedly, CB stem cells are the glia-like sustentacular cells and can be identified using glial markers. Full-Text PDF Open Archive