Journal of Neural Transmission

, Volume 116, Issue 8, pp 975–982 | Cite as

The neurogenic niche in the carotid body and its applicability to antiparkinsonian cell therapy

  • José López-Barneo
  • Ricardo Pardal
  • Patricia Ortega-Sáenz
  • Rocío Durán
  • Javier Villadiego
  • Juan José Toledo-Aral
Movement Disorders - Review Article
First Online:
Received:
Accepted:

Abstract

The carotid body (CB) is a neural crest-derived organ whose major function is to sense changes in arterial O2 tension to elicit hyperventilation during hypoxia. The CB is composed of clusters of neuron-like glomus, or type I, cells that are highly dopaminergic and contain large amounts of the glial cell line-derived neurotrophic factor (GDNF). Glomus cells are enveloped by glia-like sustentacular, or type II, cells. In chronic hypoxia the CB grows with increase in glomus cell number. This adaptive response depends on a collection of neural progenitors that can be isolated and induced to form clonal neurospheres in vitro. CB neurospheres contain numerous newly differentiated glomus cells, which maintain their functional properties and the ability to synthesize dopamine and GDNF. Intrastriatal CB transplants have been assayed in animal models of Parkinson’s disease (PD) to test whether they increase the striatal dopamine levels and/or exert a neuroprotective action on the nigrostriatal pathway. Two pilot safety studies performed on PD patients subjected to CB autotransplantation have suggested that a major limitation of this technique is the small size of the organ. This could, however, be overcome by the in vitro formation of new CB tissue derived from adult CB stem cells.

Keywords

Carotid body Chronic hypoxia Stem cells Parkinson’s disease Transplantation Neuroprotection GDNF 
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Notes

Acknowledgments

This research has been supported by the Instituto de Salud Carlos III (Ciberned and Red de Terapia Celular), The Spanish Ministry of Science, and the Juan March and Marcelino Botín Foundations.

References

  1. Arenas E, Trupp M, Akerud P et al (1995) GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo. Neuron 15:1465–1473PubMedCrossRefGoogle Scholar
  2. Arias-Stella J, Valcarcel J (1976) Chief cell hyperplasia in the human carotid body at high altitudes; physiologic and pathologic significance. Hum Pathol 7:361–373PubMedCrossRefGoogle Scholar
  3. Arjona V, Mínguez-Castellanos A, Montoro RJ et al (2003) Autotransplantation of human carotid body cell aggregates for treatment of Parkinson’s disease. Neurosurgery 53:321–328PubMedCrossRefGoogle Scholar
  4. Belzunegui S, Izal-Azcárate A, San Sebastián W et al (2008) Striatal carotid body graft promotes differentiation of neural progenitor cells into neurons in the olfactory bulb of adult hemiparkisonian rats. Brain Res 1217:213–220PubMedCrossRefGoogle Scholar
  5. Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedCrossRefGoogle Scholar
  6. Choi-Lundberg DL, Lin Q, Chang YN et al (1997) Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science 275:838–841PubMedCrossRefGoogle Scholar
  7. Duchen MR, Caddy KWT, Kirby GC et al (1988) Biophysical studies of the cellular elements of the rabbit carotid body. Neuroscience 26:291–311PubMedCrossRefGoogle Scholar
  8. Edwards C, Heath D, Harris P (1971) The carotid body in emphysema and left ventricular hypertrophy. J Pathol 104:1–13PubMedCrossRefGoogle Scholar
  9. Erickson JT, Brosenitsch TA, Katz DM (2001) Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor are required simultaneously for survival of dopaminergic primary sensory neurons in vivo. J Neurosci 21:581–589PubMedGoogle Scholar
  10. Espejo EF, Montoro RJ, Armengol JA et al (1998) Cellular and functional recovery of Parkinsonian rats after intrastriatal transplantation of carotid body cell aggregates. Neuron 20:197–206PubMedCrossRefGoogle Scholar
  11. Espejo M, Cutillas B, Arenas TE, Ambrosio S (2000) Increased survival of dopaminergic neurons in striatal grafts of fetal ventral mesencephalic cells exposed to neurotrophin-3 or glial cell line-derived neurotrophic factor. Cell Transpl 9:45–53Google Scholar
  12. Frim DM, Uhler TA, Galpern WR et al (1994) Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat. Proc Natl Acad Sci USA 91:5104–5108PubMedCrossRefGoogle Scholar
  13. García-Fernández M, Ortega-Sáenz P, Castellano A et al (2007) Mechanisms of low-glucose sensitivity in carotid body glomus cells. Diabetes 56:2893–2900PubMedCrossRefGoogle Scholar
  14. Gash DM, Zhang Z, Ovadia A et al (1996) Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380:252–255PubMedCrossRefGoogle Scholar
  15. Hao G, Yao Y, Wang J et al (2002) Intrastriatal grafting of glomus cells ameliorates behavioral defects of Parkinsonian rats. Physiol Behav 77:519–525PubMedCrossRefGoogle Scholar
  16. Heath D, Smith P, Jago R (1982) Hyperplasia of the carotid body. J Pathol 138:115–127PubMedCrossRefGoogle Scholar
  17. Kirik D, Georgievska B, Björklund A (2004) Localized striatal delivery of GDNF as a treatment for Parkinson disease. Nature Neurosci 7:105–110PubMedCrossRefGoogle Scholar
  18. Leitner ML, Wang LH, Osborne PA et al (2005) Expression and function of GDNF family ligands and receptors in the carotid body. Exp Neurol Suppl 1:S68–S79CrossRefGoogle Scholar
  19. Levivier M, Przedborski S, Bencsics C, Kang UJ (1995) Intrastriatal implantation of fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevents degeneration of dopaminergic neurons in a rat model of Parkinson’s disease. J Neurosci 15:7810–7820PubMedGoogle Scholar
  20. Lin LF, Doherty DH, Lile JD et al (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130–1132PubMedCrossRefGoogle Scholar
  21. Li JY, Englund E, Holton JL, Soulet D et al (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503PubMedCrossRefGoogle Scholar
  22. López-Barneo J (2003) Oxygen and glucose sensing by carotid body glomus cells. Curr Opin Neurobiol 13:493–499PubMedCrossRefGoogle Scholar
  23. López-Barneo J, López-López JR, Ureña J et al (1988) Chemotransduction in the carotid body: K+ current modulated by pO2 in type I chemoreceptor cells. Science 241:580–582PubMedCrossRefGoogle Scholar
  24. López-Barneo J, Ortega-Sáenz P, Pardal R et al (2008a) Carotid body oxygen sensing. Eur Respir J 32:1386–1398PubMedCrossRefGoogle Scholar
  25. López-Barneo J, Mínguez-Castellanos A, Toledo-Aral J (2008b) Cell therapy for Parkinson’s disease and other neurodegenerative disorders. In: García Olmo D, García-Verdugo JM, Alemany J, González MA, Gutiérrez-Fuentes JA et al (eds) Cell therapy. Mc-Graw Hill Interamericana, BasauriGoogle Scholar
  26. Luquin MR, Montoro RJ, Guillén J et al (1999) Recovery of chronic parkinsonian monkeys by autotransplants of carotid body cell aggregates into putamen. Neuron 22:743–750PubMedCrossRefGoogle Scholar
  27. McGregor KH, Gil J, Lahiri S (1984) A morphometric study of the carotid body in chronically hypoxic rats. J Appl Physiol 57:1430–1438PubMedGoogle Scholar
  28. Mínguez-Castellanos A, Escamilla-Sevilla F, Hotton GR et al (2007) Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study. J Neurol Neurosurg Psychiatry 78:825–831PubMedCrossRefGoogle Scholar
  29. Montoro RJ, Ureña J, Fernández-Chacón R et al (1996) Oxygen sensing by ion channels and chemotransduction in single glomus cells. J Gen Physiol 107:133–143PubMedCrossRefGoogle Scholar
  30. Nosrat CA, Tomac A, Lindqvist E et al (1996) Cellular expression of GDNF mRNA suggests multiple functions inside and outside the nervous system. Cell Tissue Res 286:191–207PubMedCrossRefGoogle Scholar
  31. Nurse CA (2005) Neurotransmission and neuromodulation in the chemosensory carotid body. Auton Neurosci 120:1–9PubMedCrossRefGoogle Scholar
  32. Nurse CA, Vollmer C (1997) Role of basic FGF and oxygen in control of proliferation, survival, and neuronal differentiation in carotid body chromaffin cells. Dev Biol 184:197–206PubMedCrossRefGoogle Scholar
  33. Ortega-Sáenz P, Pascual A, Gómez-Díaz R et al (2006) Acute oxygen sensing in heme oxygenase-2 null mice. J Gen Physiol 128:405–411PubMedCrossRefGoogle Scholar
  34. Pardal R, López-Barneo J (2002) Low glucose-sensing cells in the carotid body. Nature Neurosci 5:197–198PubMedCrossRefGoogle Scholar
  35. Pardal R, Ludewig U, García-Hirschfeld J et al (2000) Secretory responses of intact glomus cells in thin slices of rat carotid body to hypoxia and tetraethylammonium. Proc Natl Acad Sci USA 97:2361–2366PubMedCrossRefGoogle Scholar
  36. Pardal R, Ortega-Sáenz P, Durán R et al (2007) Glia-like stem cells sustain physiologic neurogenesis in the adult mammalian carotid body. Cell 131:364–377PubMedCrossRefGoogle Scholar
  37. Pascual A, Hidalgo-Figueroa M, Piruat JI et al (2008) Absolute requirement of GDNF for adult catecholaminergic neuron survival. Nature Neurosci 11:755–761PubMedCrossRefGoogle Scholar
  38. Peers C, Buckler KJ (1995) Transduction of chemostimuli by the type I carotid body cell. J Membr Biol 144:1–9PubMedGoogle Scholar
  39. Sánchez MP, Silos-Santiago I, Frisén J et al (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382:70–73PubMedCrossRefGoogle Scholar
  40. Shukla S, Agrawal AK, Chaturvedi RK et al (2004) Co-transplantation of carotid body and ventral mesencephalic cells as an alternative approach towards functional restoration in 6-hydroxydopamine-lesioned rats: implications for Parkinson’s disease. J Neurochem 91:274–284PubMedCrossRefGoogle Scholar
  41. Toledo-Aral JJ, Méndez-Ferrer S, Pardal R et al (2003) Trophic restoration of the nigrostriatal dopaminergic pathway in long-term carotid body-grafted parkinsonian rats. J Neurosci 23:141–148PubMedGoogle Scholar
  42. Ureña J, López-López J, González C et al (1989) Ionic currents in dispersed chemoreceptor cells of the mammalian carotid body. J Gen Physiol 93:979–999PubMedCrossRefGoogle Scholar
  43. Ureña J, Fernández-Chacón R, Benot AR et al (1994) Hypoxia induces voltage-dependent Ca2+ entry and quantal dopamine secretion in carotid body glomus cells. Proc Natl Acad Sci USA 91:10208–10211PubMedCrossRefGoogle Scholar
  44. Villadiego J, Méndez-Ferrer S, Valdés-Sánchez T et al (2005) Selective glial cell line-derived neurotrophic factor production in adult dopaminergic carotid body cells in situ and after intrastriatal transplantation. J Neurosci 25:4091–4098PubMedCrossRefGoogle Scholar
  45. Wang ZY, Bisgard GE (2002) Chronic hypoxia-induced morphological and neurochemical changes in the carotid body. Microsc Res Tech 59:168–177PubMedCrossRefGoogle Scholar
  46. Weir EK, López-Barneo J, Buckler KJ et al (2005) Acute oxygen-sensing mechanisms. N Engl J Med 353:2042–2055PubMedCrossRefGoogle Scholar
  47. Yu G, Xu L, Hadman M et al (2004) Intracerebral transplantation of carotid body in rats with transient middle cerebral artery occlusion. Brain Res 1015:50–56PubMedCrossRefGoogle Scholar
  48. Zarow C, Lyness SA, Mortimer JA et al (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60:337–341PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • José López-Barneo
    • 1
    • 2
  • Ricardo Pardal
    • 1
    • 2
  • Patricia Ortega-Sáenz
    • 1
    • 2
  • Rocío Durán
    • 1
    • 2
  • Javier Villadiego
    • 1
    • 2
  • Juan José Toledo-Aral
    • 1
    • 2
  1. 1.Instituto de Biomedicina de Sevilla (IBiS), Edificio de Laboratorios, 2a plantaHospital Universitario Virgen del Rocío, CSIC, Universidad de SevillaSevilleSpain
  2. 2.Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)SevilleSpain

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