Cellular properties and chemosensory responses of the human carotid body

Abstract

Key points• The carotid body (CB) is a key chemoreceptor organ that mediates the hyperventilatory response to hypoxia, and contributes to the process of acclimatisation to chronic hypoxaemia.• Knowledge of CB physiology at the cellular and molecular levels has advanced considerably in recent times thanks to studies on lower mammals; however, information on humans is practically absent. Here we describe the properties of human CB cells in slice preparations or after enzymatic dispersion.• Besides glomus (type I) and glia-like, sustentacular (type II) cells, adult human CBs contain nestin-positive neural progenitor cells. The human CB also expresses high levels of glial cell line-derived neurotrophic factor. These properties are maintained at an advanced age.• Human glomus cells contain a relatively high density of voltage-dependent Na + , Ca 2+ and K + channels. Membrane depolarisation with high extracellular K + induces an increase of cytosolic [Ca 2+ ] and quantal catecholamine release.• Human glomus cells are responsive to hypoxia and hypoglycaemia, both of which induce an increase in cytosolic [Ca 2+ ] and transmitter release. Chemosensory responses of glomus cells are also preserved at an advanced age.• These findings on the cellular and molecular physiology of the CB provide novel perspectives for the systematic study of pathologies involving this organ in humans.Abstract The carotid body (CB) is the major peripheral arterial chemoreceptor in mammals that mediates the acute hyperventilatory response to hypoxia. The CB grows in response to sustained hypoxia and also participates in acclimatisation to chronic hypoxaemia. Knowledge of CB physiology at the cellular level has increased considerably in recent times thanks to studies performed on lower mammals, and rodents in particular. However, the functional characteristics of human CB cells remain practically unknown. Herein, we use tissue slices or enzymatically dispersed cells to determine the characteristics of human CB cells. The adult human CB parenchyma contains clusters of chemosensitive glomus (type I) and sustentacular (type II) cells as well as nestin-positive progenitor cells. This organ also expresses high levels of the dopaminotrophic glial cell line-derived neurotrophic factor (GDNF). We found that GDNF production and the number of progenitor and glomus cells were preserved in the CBs of human subjects of advanced age. qualitatively similar to those reported in lower mammals. These cells responded to hypoxia with an external Ca 2+ -dependent increase of cytosolic Ca 2+ and quantal catecholamine secretion, as reported for other mammalian species. Interestingly, human glomus cells are also responsive to hypoglycaemia and together these two stimuli can potentiate each other's effects. The chemosensory responses of glomus cells are also preserved at an advanced age. These new data on the cellular and molecular physiology of the CB pave the way for future pathophysiological studies involving this organ in humans.

Neurotrophic Properties, Chemosensory Responses and Neurogenic Niche of the Human Carotid Body

“…Nonetheless, other authors have failed to fi nd any responsiveness of explanted whole CB preparations to low glucose (Bin-Jaliah et al 2004 ;Conde et al 2007 ) or any signifi cant changes in cytosolic [Ca 2+ ] in dispersed glomus cells in response to rapid glucose removal (Gallego-Martin et al 2012 ). In contrast to these last observations, we have found that, as in the rat (Garcia-Fernandez et al 2007 ), human glomus cells can also depolarize and release transmitters in response to a decrease in the extracellular glucose concentration (Ortega-Saenz et al 2013 ). Under normoxic conditions (PO 2 ~ 150 mmHg), removal of extracellular glucose produced membrane depolarization, an increase in cytosolic [Ca 2+ ] and a secretory response in human glomus cells similar to that obtained in rodent cells subjected to the same experimental protocol (Fig.…”

“…The estimated volume of the adult human CB in our cohort is 20.7 ± 3.8 mm 3 (n = 16 carotid bodies; 11 donors), a value within the range reported by other studies (Heath et al 1970 ;Shamblin et al 1971 ;Arias-Stella and Valcarcel 1976 ). However, large differences in sizes are observed among the different individuals or even between the right and left CBs of the same subject (Ortega-Saenz et al 2013 ). Although there is a trend for CBs from males to be larger than those of females, no statistically signifi cant differences was found associated to sex (Fig.…”

“…Although the protocol designed to obtain dispersed cells from human CB is still susceptible to improvement, we were able to get some cultures of healthy isolated human glomus cells in which hypoxia-evoked a robust increase in cytosolic [Ca 2+ ]. Nonetheless, the time courses of the Ca 2+ signals greatly varied from cell to cell (Ortega-Saenz et al 2013 ). In cells with spontaneous Ca 2+ oscillations, hypoxia normally elicited a sustained elevation of [Ca 2+ ] that was reversibly abolished by 0.5 mM extracellular Cd 2+ ( Fig.…”

“…However, with the exception of two recent publications on the gene expression profi le of the human CB (Fagerlund et al 2010 ;Mkrtchian et al 2012 ), its functional characteristics have remained practically unknown. Herein we summarize and discuss the data recently obtained by our group regarding the basic anatomical, neurochemical and physiological properties of CBs dissected from human cadavers, of different age and gender, registered with the Organ Donation Program at our institution (Ortega-Saenz et al 2013 ).…”

Increased Cardiometabolic Risk and Worsening Hypoxemia at High Altitude

“…Chronic activation of the sympathetic nervous system may be a pathway toward the development of metabolic syndrome (Brotman et al, 2002). Alternatively, new findings suggest that hypoglycemia stimulates and hyperglycemia inhibits peripheral chemoreceptor responsiveness, and may imply that serum glucose is a driver for sympathetic tone thereby affecting oxygenation through respiratory drive (Ortega-Saenz et al, 2013).…”