Tissue Dynamics of the Carotid Body Under Chronic Hypoxia: A Computational Study
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.
KeywordsCarotid body Hypoxia Morphogenesis Mathematical modeling Stem cells Peripheral neurogenesis
- 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
- 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
- Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM (2000) Fate of the mammalian cardiac neural crest. Development 127:1606–1616Google Scholar
- 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
- 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