The Cellular and Physiological Basis for Lung Repair and Regeneration: Past, Present, and Future

Basil, Maria C.; Katzen, Jeremy; Engler, Andrea; Guo, Minzhe; Herriges, Michael J.; Kathiriya, Jaymin J.; Windmueller, Rebecca; Ysasi, Alexandra B.; Zacharias, William J.; Chapman, Harold A.; Kotton, Darrell N.; Rock, Jason R.; Snoeck, Hans Willem; Vunjak‐Novakovic, Gordana; Whitsett, Jeffrey A.; Morrisey, Edward E.

doi:10.1016/j.stem.2020.03.009

Cited by 272 publications

(308 citation statements)

References 229 publications

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“…Single cell RNA sequencing studies have shown that increased transcriptional noise and upregulation of a core group of age-associated molecular mechanisms -including protein processing-and inflammation-associated genes -are correlated with ageing across mouse cell and tissue types, but additional processes are unique to particular cell types within specific organs, including the lungs (Angelidis et al, 2019;Kimmel et al, 2019). However, to date such studies have not profiled the trachea, which has distinct composition and stem cell biology to the more distal airways (Basil et al, 2020), in detail. During murine tracheal ageing, epithelial cell density is reduced and the proportion of basal cells within the epithelium is slightly decreased, but there is no obvious decline in their in vitro clonogenic potential or differentiation capacity (Wansleeben et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Cell-intrinsic differences between human airway epithelial cells from children and adults

Nigro

Pennycuick

Gowers

et al. 2020

Preprint

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The airway epithelium is a key protective barrier whose integrity is preserved by the selfrenewal and differentiation of basal progenitor cells. Epithelial cells are central to the pathogenesis of multiple lung diseases. In chronic diseases, increasing age is a principle risk factor. In acute diseases, such as COVID-19, children suffer less severe symptoms than adults and have a lower rate of mortality. Few studies have explored differences between airway epithelial cells in children and adults to explain this age dependent variation in diseases. Here, we perform bulk RNA sequencing studies in laser-capture microdissected whole epithelium, FACS-sorted basal cells and cultured basal cells, as well as in vitro cell proliferation experiments, to address the intrinsic molecular differences between paediatric and adult airway basal cells. We find that, while the cellular composition of the paediatric and adult tracheobronchial epithelium is broadly similar, in cell culture, paediatric airway epithelial cells displayed higher colony forming ability, better in vitro growth and outcompeted adult cells in competitive proliferation assays. In RNA sequencing experiments, we observed potentially important differences in airway epithelial gene expression between samples from children and adults. However, genes known to be associated with SARS-CoV-2 infection were not differentially expressed between children and adults. Our results chart cell-intrinsic differences in transcriptional profile and regenerative capacity between proximal airway epithelial cells of children and adults.

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Section: Introductionmentioning

confidence: 99%

Cell-intrinsic differences between human airway epithelial cells from children and adults

Nigro

Pennycuick

Gowers

et al. 2020

Preprint

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“…The lung mesenchyme remains poorly defined without any one marker that demarcates a population with unique features. Advances in nextgeneration sequencing and analysis may add novel dimensions and complexity to how we understand lung mesenchymal subtypes and how they differentially contribute to lung fibrosis and repair [51].…”

Section: Discussionmentioning

confidence: 99%

Origin of Myofibroblasts in Lung Fibrosis

Hung

2020

Curr. Tissue Microenviron. Rep.

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Purpose of Review In this brief review, we will highlight important observational and experimental data in the literature that address the origin of scar-forming cells in lung fibrosis. Recent Findings Several cellular sources of activated scar-forming cells (myofibroblasts) have been postulated including alveolar epithelial cells; circulating fibrocytes; and lung stromal cell subpopulations including resident fibroblasts, pericytes, and resident mesenchymal stem cells. Recent advances in lineage-tracing models, however, fail to provide experimental evidence for epithelial and fibrocyte origins of lung myofibroblasts. Resident mesenchymal cells of the lung, which include various cell types including resident fibroblasts, pericytes, and resident mesenchymal stem cells, appear to be important sources of myofibroblasts in murine models of lung injury and fibrosis. Summary Lung myofibroblasts likely originate from multiple sources of lung-resident mesenchymal cells. Their relative contributions may vary depending on the type of injury. Although lineage-tracing experiments have failed to show significant contribution from epithelial cells or fibrocytes, they may play important functional roles in myofibroblast activation through paracrine signaling.

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“…The respiratory system in humans is co-developed with the cardiovascular system via crosstalk and integration of multiple cellular populations (Morrisey and Hogan, 2010). Adult human lungs have functional gas exchange surfaces of about 70 m 2 with a tremendous compensation ability (Basil et al, 2020). Under conditions of repairing cellular loss or lung function deficiency, the alveolar cells are able to self-renew and proliferate to restore normal alveolar structure and gas exchange function, which are regulated via an integrated network of mesenchymal, endothelial, and epithelial cells and other components (Barkauskas et al, 2013;Lee et al, 2017).…”

Section: Improving Alveolar Gas Exchange By Hdr-induced Vasculature Mmentioning

confidence: 99%

“…In addition, the lung microvasculature is shown to contain heterogenic endothelial subpopulations with various vasculogenic capacities coordinately contributing to lung injury response (Niethamer et al, 2020;Stevens et al, 2008). Notably, proliferation of the lung endothelial cell subpopulation is enhanced during influenza-mediated lung injury (Basil et al, 2020;Niethamer et al, 2020). On the other hand, cutaneous low-dose radiation has been shown to increase tissue vascularity through upregulation of angiogenic and vasculogenic pathways (Thanik et al, 2010).…”

Section: Improving Alveolar Gas Exchange By Hdr-induced Vasculature Mmentioning

confidence: 99%

Mitigating Coronavirus-Induced Acute Respiratory Distress Syndrome by Radiotherapy

Li¹

2020

iScience

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The acute respiratory distress syndrome (ARDS) induced by SARS-CoV-2-mediated cytokine storm (CS) in lungs leads to the high mortality in COVID-19 patients. To reduce ARDS, an ideal approach is to diminish virus loading by activating immune cells for CS prevention or to suppress the overactive cytokine-releasing immune cells for CS inhibition. Here, a potential radiation-mediated CS regulation is raised by reevaluating the radiation-mediated pneumonia control in the 1920s, with the following latent advantages of lung radiotherapy (LR) in treatment of COVID-19: (1) radiation accesses poorly circulated tissue more efficiently than blood-delivered medications; (2) low-dose radiation (LDR)mediated metabolic rewiring and immune cell activation inhibit virus loading; (3) pre-consumption of immune reserves by LDR decreases CS severity; (4) higherdose radiation (HDR) within lung-tolerable doses relieves CS by eliminating in situ overactive cytokine-releasing cells. Thus, LDR and HDR or combined with antiviral and life-supporting modalities may mitigate SARS-CoV-2 and other virus-mediated ARDS.

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The Cellular and Physiological Basis for Lung Repair and Regeneration: Past, Present, and Future

Cited by 272 publications

References 229 publications

Cell-intrinsic differences between human airway epithelial cells from children and adults

Cell-intrinsic differences between human airway epithelial cells from children and adults

Origin of Myofibroblasts in Lung Fibrosis

Mitigating Coronavirus-Induced Acute Respiratory Distress Syndrome by Radiotherapy

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