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Single-cell connectomic analysis of adult mammalian lungs.

ABSTRACT: Efforts to decipher chronic lung disease and to reconstitute functional lung tissue through regenerative medicine have been hampered by an incomplete understanding of cell-cell interactions governing tissue homeostasis. Because the structure of mammalian lungs is highly conserved at the histologic level, we hypothesized that there are evolutionarily conserved homeostatic mechanisms that keep the fine architecture of the lung in balance. We have leveraged single-cell RNA sequencing techniques to identify conserved patterns of cell-cell cross-talk in adult mammalian lungs, analyzing mouse, rat, pig, and human pulmonary tissues. Specific stereotyped functional roles for each cell type in the distal lung are observed, with alveolar type I cells having a major role in the regulation of tissue homeostasis. This paper provides a systems-level portrait of signaling between alveolar cell populations. These methods may be applicable to other organs, providing a roadmap for identifying key pathways governing pathophysiology and informing regenerative efforts.

SUBMITTER: Raredon MSB

PROVIDER: S-EPMC6892628 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Single-cell connectomic analysis of adult mammalian lungs.

Raredon Micha Sam Brickman MSB Adams Taylor Sterling TS Suhail Yasir Y Schupp Jonas Christian JC Poli Sergio S Neumark Nir N Leiby Katherine L KL Greaney Allison Marie AM Yuan Yifan Y Horien Corey C Linderman George G Engler Alexander J AJ Boffa Daniel J DJ Kluger Yuval Y Rosas Ivan O IO Levchenko Andre A Kaminski Naftali N Niklason Laura E LE

Science advances 20191204 12

Efforts to decipher chronic lung disease and to reconstitute functional lung tissue through regenerative medicine have been hampered by an incomplete understanding of cell-cell interactions governing tissue homeostasis. Because the structure of mammalian lungs is highly conserved at the histologic level, we hypothesized that there are evolutionarily conserved homeostatic mechanisms that keep the fine architecture of the lung in balance. We have leveraged single-cell RNA sequencing techniques to ...[more]

PMID: 31840053

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Project description:A secondary function of the respiratory system of the mammals is, during inspiration, to heat the air to body temperature and to saturate it with water before it reaches the alveoli. Relying on a mathematical model, we propose a comprehensive analysis of this function, considering all the terrestrial mammals (spanning six orders of magnitude of the body mass, M) and focusing on the sole contribution of the lungs to this air conditioning. The results highlight significant differences between the small and the large mammals, as well as between rest and effort, regarding the spatial distribution of heat and water exchanges in the lungs, and also in terms of regime of mass transfer taking place in the lumen of the airways. Interestingly, the results show that the mammalian lungs appear to be designed just right to fully condition the air at maximal effort (and clearly over-designed at rest, except for the smallest mammals): all generations of the bronchial region of the lungs are mobilized for this purpose, with calculated values of the local evaporation rate of water from the bronchial mucosa that can be very close to the maximal ability of the serous cells to replenish this mucosa with water. For mammals with a mass above a certain threshold ([Formula: see text] kg at rest and [Formula: see text] g at maximal effort), it appears that the maximal value of this evaporation rate scales as [Formula: see text] at rest and [Formula: see text] at maximal effort and that around 40% (at rest) or 50% (at maximal effort) of the water/heat extracted from the lungs during inspiration is returned to the bronchial mucosa during expiration, independently of the mass, due to a subtle coupling between different phenomena. This last result implies that, above these thresholds, the amounts of water and heat extracted from the lungs by the ventilation scale with the mass such as the ventilation rate does (i.e. as [Formula: see text] at rest and [Formula: see text] at maximal effort). Finally, it is worth to mention that these amounts appear to remain limited, but not negligible, when compared to relevant global quantities, even at maximal effort (4-6%).

Project description:Abstract Alzheimer’s disease (AD) is a severe neurodegenerative disorder that affects a growing worldwide elderly population. Identification of brain functional biomarkers is expected to help determine preclinical stages for targeted mechanistic studies and development of therapeutic interventions to deter disease progression. Connectomic analysis, a graph theory–based methodology used in the analysis of brain-derived connectivity matrices was used in conjunction with percolation theory targeted attack model to investigate the network effects of AD-related amyloid deposition. We used matrices derived from resting-state functional magnetic resonance imaging collected on mice with extracellular amyloidosis (TgCRND8 mice, n = 17) and control littermates (n = 17). Global, nodal, spatial, and percolation-based analysis was performed comparing AD and control mice. These data indicate a short-term compensatory response to neurodegeneration in the AD brain via a strongly connected core network with highly vulnerable or disconnected hubs. Targeted attacks demonstrated a greater vulnerability of AD brains to all types of attacks and identified progression models to mimic AD brain functional connectivity through betweenness centrality and collective influence metrics. Furthermore, both spatial analysis and percolation theory identified a key disconnect between the anterior brain of the AD mice to the rest of the brain network. Author Summary Accurate biomarkers of Alzheimer’s disease (AD) are needed for early diagnosis and treatments. Connectomic analysis, a graph theory approach, coupled with percolation theory, a network attack approach, were applied here to analyze neuroimaging through a quantitative lens. We report a marker of AD vulnerability, which highlighted a core network disconnected from key hubs, notably within the anterior portion of the brain disconnected. Additionally, preliminary models using targeted attacks provide potential pathways of neurodegeneration from the control state to the diseased state. These findings show key differences in brain connectivity due to AD and provide a potential methodology for identifying biomarkers.

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Single-cell connectomic analysis of adult mammalian lungs.

Publications

Single-cell connectomic analysis of adult mammalian lungs.

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