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Tissue Dynamics of the Carotid Body Under Chronic Hypoxia: A Computational Study

  • Andrea PorzionatoEmail author
  • Diego Guidolin
  • Veronica Macchi
  • Gloria Sarasin
  • Andrea Mazzatenta
  • Camillo Di Giulio
  • José López-Barneo
  • Raffaele De Caro
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 860)

Abstract

The carotid body (CB) increases in volume in response to chronic continuous hypoxia and the mechanisms underlying this adaptive response are not fully elucidated. It has been proposed that chronic hypoxia could lead to the generation of a sub-population of type II cells representing precursors, which, in turn, can give rise to mature type I cells. To test whether this process could explain not only the observed changes in cell number, but also the micro-anatomical pattern of tissue rearrangement, a mathematical modeling approach was devised to simulate the hypothetical sequence of cellular events occurring within the CB during chronic hypoxia. The modeling strategy involved two steps. In a first step a “population level” modeling approach was followed, in order to estimate, by comparing the model results with the available experimental data, “macroscopic” features of the cell system, such as cell population expansion rates and differentiation rates. In the second step, these results represented key parameters to build a “cell-centered” model simulating the self-organization of a system of CB cells under a chronic hypoxic stimulus and including cell adhesion, cytoskeletal rearrangement, cell proliferation, differentiation, and apoptosis. The cell patterns generated by the model showed consistency (from both a qualitative and quantitative point of view) with the observations performed on real tissue samples obtained from rats exposed to 16 days hypoxia, indicating that the hypothesized sequence of cellular events was adequate to explain not only changes in cell number, but also the tissue architecture acquired by CB following a chronic hypoxic stimulus.

Keywords

Carotid body Hypoxia Morphogenesis Mathematical modeling Stem cells Peripheral neurogenesis 

References

  1. Bassingthwaighte JB (2000) Strategies for the physiome project. Ann Biomed Eng 28:1043–1058PubMedCrossRefPubMedCentralGoogle Scholar
  2. Bauer AL, Jackson TL, Jiang Y (2007) A cell-based model exhibiting branching and anastomosis during tumor-induced angiogenesis. Biophys J 92:3105–3121PubMedCrossRefPubMedCentralGoogle Scholar
  3. Boas SEM, Merks RMH (2014) Synergy of cell-cell repulsion and vacuolation in a computational model of lumen formation. J R Soc Interface 11:20131049PubMedCrossRefPubMedCentralGoogle Scholar
  4. Chaturvedi R, Huang C, Izaguirre JA, Newman SA, Glazier JA (2004) A hybrid discrete-continuum model for 3D skeletogenesis of the vertebrate limb. LNCS 3305:543–552Google Scholar
  5. Clarke JA, Daly MB, Marshall JM, Ead HW, Hennessy EM (2000) Quantitative studies of the vasculature of the carotid body in the chronically hypoxic rat. Braz J Med Biol Res 33:331–340Google Scholar
  6. Cickovski T, Aras K, Alber MS, Izaguirre JA, Swat M, Glazier JA, Merks RM, Glimm T, Hentschel HG, Newman SA (2007) From genes to organisms via the cell: a problem-solving environment for multicellular development. Comput Sci Eng 9:50–60PubMedCrossRefPubMedCentralGoogle Scholar
  7. De Caro R, Macchi V, Sfriso MM, Porzionato A (2013) Structural and neurochemical changes in the maturation of the carotid body. Respir Physiol Neurobiol 185:9–19PubMedCrossRefGoogle Scholar
  8. Di Giulio C, Zara S, Cataldi A, Porzionato A, Pokorski M, De Caro R (2012) Human carotid body HIF and NGB expression during human development and aging. Adv Exp Med Biol 758:265–271PubMedCrossRefGoogle Scholar
  9. Donovan D, Brown NJ, Bishop ET, Lewis CE (2001) Comparison of three in vitro human ‘angiogenesis’ assays with capillaries formed in vivo. Angiogenesis 4:113–121PubMedCrossRefGoogle Scholar
  10. Duchesne L, Octeau V, Bearon RN, Beckett A, Prior IA, Lounis B, Fernig DG (2012) Transport of fibroblast growth factor 2 in the pericellular matrix is controlled by the spatial distribution of its binding sites in heparin sulfate. PLoS Biol 10:e1001361PubMedCrossRefPubMedCentralGoogle Scholar
  11. Glazier JA, Graner F (1993) Simulation of the differential adhesion driven rearrangement of biological cells. Phys Rev E 47:2128–2154CrossRefGoogle Scholar
  12. Guidolin D, Albertin A (2012) Tube formation in vitro angiogenesis assay. Methods Cell Biol 112:281–293CrossRefGoogle Scholar
  13. Guidolin D, Vacca A, Nussdorfer GG, Ribatti D (2004) A new image analysis method based on topological and fractal parameters to evaluate the angiostatic activity of docetaxel by using the Matrigel assay in vitro. Microvasc Res 67:117–124PubMedCrossRefGoogle Scholar
  14. Guidolin D, Nico B, Belloni AS, Nussdorfer GG, Vacca A, Ribatti D (2007) Morphometry and mathematical modeling of the capillary-like patterns formed in vitro by bone marrow macrophages of patients with multiple myeloma. Leukemia 21:2201–2203PubMedCrossRefGoogle Scholar
  15. Guidolin D, Albertin G, Sorato E, Oselladore B, Mascarin A, Ribatti D (2009) Mathematical modeling of capillary-like pattern generated by adrenomedullin-treated human vascular endothelial cells in vitro. Dev Dyn 238:1951–1963PubMedCrossRefGoogle Scholar
  16. Guidolin D, Rebuffat P, Albertin G (2011) Cell-oriented modeling of angiogenesis. Sci World J 11:1735–1748CrossRefGoogle Scholar
  17. Guidolin D, Porzionato A, Tortorella C, Macchi V, De Caro R (2014) Fractal analysis of the structural complexity of the connective tissue in human carotid bodies. Front Physiol 5:432PubMedCrossRefPubMedCentralGoogle Scholar
  18. Heat D, Smith P, Jago R (1982) Hyperplasia of the carotid body. J Pathol 138:115–127CrossRefGoogle Scholar
  19. Jenné R, Banadda EN, Smets I, Deurinck J, Van Impe J (2007) Detection of filamentous bulking problems: developing an image analysis system for sludge composition monitoring. Microsc Microanal 13:36–41PubMedCrossRefGoogle Scholar
  20. Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM (2000) Fate of the mammalian cardiac neural crest. Development 127:1606–1616Google Scholar
  21. Joels N, Neil E (1963) The excitation mechanisms of the carotid body. Br Med Bull 19:21–24PubMedGoogle Scholar
  22. Kirby GC, McQueen DS (1984) Effects of the antagonists MDL 7222 and ketanserin on responses of cat carotid body chemoreceptors to 5-hydroxytryptamine. Br J Pharmacol 83:259–269PubMedCrossRefPubMedCentralGoogle Scholar
  23. Lagendijk AK, Szabo A, Merks RHM, Bakkers J (2013) Hyaluronan: a critical regulator of endothelial-to-mesenchimal transition during cardiac valve formation. Trends Cardiovasc Med 23:135–142PubMedCrossRefGoogle Scholar
  24. Lahiri S (2000) Plasticity and multiplicity in the mechanisms of oxygen sensing. Adv Exp Med Biol 475:13–23PubMedGoogle Scholar
  25. LeVeque RJ (2007) Finite difference methods for ordinary and partial differential equations: steady state and time-dependent problems. SIAM, PhiladelphiaCrossRefGoogle Scholar
  26. López-Barneo J, Lopez-Lopez JR, Urena J, Gonzales C (1988) Chemotransduction in the carotid body: K+ current modulated by PO2 in type I chemoreceptor cells. Science 241:580–582PubMedCrossRefGoogle Scholar
  27. Mahoney AW, Smith BG, Flann NS, Podgorski GJ (2008) Discovering novel cancer therapies: a computational modeling and search approach. In: Proceedings of the IEEE symposium on computational intelligence in bioinformatics and computational biology, (CIBCB’08), pp 233–240Google Scholar
  28. Merks RMH, Glazier JA (2005) A cell-centered approach to developmental biology. Phys A 352(1):113–130CrossRefGoogle Scholar
  29. Merks RM, Brodsky SV, Goligorksy MS, Newman SA, Glazier JA (2006) Cell elongation is key to in silico replication of in vitro vasculogenesis and subsequent remodeling. Dev Biol 289:44–54PubMedCrossRefPubMedCentralGoogle Scholar
  30. Mills L, Nurse C (1993) Chronic hypoxia in vitro increases volume of dissociated carotid body chemoreceptors. NeuroReport 4:619–622PubMedCrossRefGoogle Scholar
  31. Mombach JCM, Glazier JA (1996) Single cell motion in aggregates of embryonic cells. Phys Rev Lett 76:3032–3035PubMedCrossRefGoogle Scholar
  32. Ortega-Sáenz P, Pardal R, Levitsky K, Villadiego J, Muñoz-Manchado AB, Durán R, Bonilla-Henao V, Arias-Mayenco I, Sobrino V, Ordóñez A, Oliver M, Toledo-Aral JJ, López-Barneo J (2013) Cellular properties and chemosensory responses of the human carotid body. J Physiol 591:6157–6173PubMedCrossRefPubMedCentralGoogle Scholar
  33. Pardal R, Ortega-Sàenz P, Duràn R, Lòpez-Barneo J (2007) Glia-like stem cells sustain physiologic neurogenesis in the adult mammalian carotid body. Cell 131:364–377PubMedCrossRefGoogle Scholar
  34. Pequignot JM, Hellstrom S, Johansson C (1984) Intact and sympathectomized carotid bodies of long-term hypoxic rats: a morphometric ultrastructural study. J Neurocytol 13:481–493PubMedCrossRefGoogle Scholar
  35. Platero-Luengo A, Gonzàlez-Granero S, Duràn R, Dìaz-Castro B, Piruat JI, Garcìa-Verdugo JM, Pardal R, Lòpez-Barneo J (2014) An O2-sensitive glomus cell-stem cell synapse induces carotid body growth in chronic hypoxia. Cell 156:291–303PubMedCrossRefGoogle Scholar
  36. Porzionato A, Macchi V, Belloni AS, Parenti A, De Caro R (2006) Adrenomedullin immunoreactivity in the human carotid body. Peptides 27:69–73PubMedCrossRefGoogle Scholar
  37. Porzionato A, Macchi V, Parenti A, Matturri L, De Caro R (2008a) Peripheral chemoreceptors: postnatal development and cytochemical findings in Sudden Infant Death Syndrome. Histol Histopathol 23:351–365PubMedGoogle Scholar
  38. Porzionato A, Macchi V, Parenti A, De Caro R (2008b) Trophic factors in the carotid body. Int Rev Cell Mol Biol 269:1–58PubMedCrossRefGoogle Scholar
  39. Porzionato A, Rucinski M, Macchi V, Stecco C, Castagliuolo I, Malendowicz LK, De Caro R (2011) Expression of leptin and leptin receptor isoforms in the rat and human carotid body. Brain Res 1385:56–67PubMedCrossRefGoogle Scholar
  40. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675PubMedCrossRefGoogle Scholar
  41. Smith TG, Lange GD, Marks WB (1996) Fractal methods and results in cellular morphology – dimensions, lacunarity and multifractals. J Neurosci Methods 69:123–136PubMedCrossRefGoogle Scholar
  42. Tse A, Yan L, Lee AK, Tse FW (2012) Autocrine and paracrine actions of ATP in rat carotid body. Can J Physiol Pharmacol 90:705–711PubMedCrossRefGoogle Scholar
  43. Wang ZY, Bisgard GE (2002) Chronic hypoxia-induced morphological and neurochemical changes in the carotid body. Microsc Res Tech 59:168–177PubMedCrossRefGoogle Scholar
  44. Zara S, Pokorski M, Cataldi A, Porzionato A, De Caro R, Antosiewicz J, Di Giulio C (2013) Development and aging are oxygen-dependent and correlate with VEGF and NOS along life span. Adv Exp Med Biol 756:223–228PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Andrea Porzionato
    • 1
    Email author
  • Diego Guidolin
    • 1
  • Veronica Macchi
    • 1
  • Gloria Sarasin
    • 1
  • Andrea Mazzatenta
    • 2
  • Camillo Di Giulio
    • 2
  • José López-Barneo
    • 3
  • Raffaele De Caro
    • 1
  1. 1.Section of Human Anatomy, Department of Molecular MedicineUniversity of PadovaPadovaItaly
  2. 2.Department of Neurosciences, Imaging and Clinical ScienceUniversity ‘G. d’Annunzio’ of Chieti–PescaraChietiItaly
  3. 3.Instituto de Biomedicina de Sevilla (IBiS)Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSevilleSpain

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