Heterogeneity of Pulmonary Stem Cells

Lynch, Thomas J.; Ievlev, Vitaly; Parekh, Kalpaj R.

doi:10.1007/978-3-030-24108-7_6

Cited by 11 publications

(11 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As expected, slingshot trajectory of AT1s and AT2s in our data illustrated transition from AT2s to AT1s (Fig. 4A), supporting the capability of AT2s to self-renew and differentiate into AT1s (29), which was reconfirmed by the enrichment of AT2s in earlier trajectory along the pseudo-timeline compared with AT1s (Supplementary Fig. S1).…”

Section: Resultssupporting

confidence: 85%

See 1 more Smart Citation

Single-cell transcriptomics reveal cell type-specific molecular changes and altered intercellular communications in chronic obstructive pulmonary disease

Huang

Wang

Shen

et al. 2021

Preprint

View full text Add to dashboard Cite

Chronic obstructive pulmonary disease (COPD) is a common and heterogeneous respiratory disease, the molecular complexity of which remains poorly understood, as well as the mechanisms by which aging and smoking facilitate COPD development. Here, using single-cell RNA sequencing of more than 65,000 cells from COPD and age-stratified control lung tissues of donors with different smoking histories, we identified monocytes, club cells, and macrophages as the most disease-, aging-, and smoking-relevant cell types, respectively. Notably, we found these highly cell-type specific changes under different conditions converged on cellular dysfunction of the alveolar epithelium. Deeper investigations revealed that the alveolar epithelium damage could be attributed to the abnormally activated monocytes in COPD lungs, which could be amplified via exhaustion of club cell stemness as ages. Moreover, the enhanced intercellular communications in COPD lungs as well as the pro-inflammatory interaction between macrophages and endothelial cells indued by smoking could facilitate signaling between monocyte and the alveolar epithelium. Our findings complement the existing model of COPD pathogenesis by emphasizing the contributions of the previously less appreciated cell types, highlighting their candidacy as potential therapeutic targets for COPD.

show abstract

Section: Resultssupporting

confidence: 85%

“…Increased alveolar wall destruction in COPD lungs has long been attributed to the reduction in both quantity and regenerative capacity of airway stem/progenitor cells including AT2s and club cells (29). As expected, slingshot trajectory of AT1s and AT2s in our data illustrated transition from AT2s to AT1s (Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell transcriptomics reveal cell type-specific molecular changes and altered intercellular communications in chronic obstructive pulmonary disease

Huang

Wang

Shen

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…5 C). Given that club cells are multifunctional bronchoalveolar epithelial progenitor cells that are of great importance to airway epithelium maintenance [ 39 ], such negative correlations raised the possibility that the autoimmunity of aged club cells may compromise their stemness through the modulation of FGF signaling, as was reported in other types of progenitor cells and stem cells [ 35 ]. Concordantly, we further identified an autoimmune-prone sub-cluster unique to aged club cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell transcriptomics highlights immunological dysregulations of monocytes in the pathobiology of COPD

et al. 2022

View full text Add to dashboard Cite

Background Chronic obstructive pulmonary disease (COPD) is a common respiratory disease, whose pathogenetic complexity was strongly associated with aging/smoking and poorly understood. Methods Here we performed single-cell RNA sequencing (scRNA-seq) analysis of 66,610 cells from COPD and age-stratified control lung tissues of donors with different smoking histories to prioritize cell types most perturbed in COPD lungs in aging/smoking dependent or independent manner. By performing an array of advanced bioinformatic analyses, such as gene set enrichment analysis, trajectory analysis, cell–cell interactions analysis, regulatory potential analysis, weighted correlation network analysis, functional interaction analysis, and gene set variation analysis, we integrated cell-type-level alterations into a system-level malfunction and provided a more clarified COPD pathological model containing specific mechanisms by which aging and smoking facilitate COPD development. Finally, we integrated the publicly available scRNA-seq data of 9 individuals, resulting in a total of 110,931 cells, and replicated the analyses to enhance the credibility of our findings. Results Our study pointed to enrichment of COPD molecular alteration in monocytes, which further induced a previously unrecognized pro-inflammatory effect on alveolar epithelial cells. In addition, aged monocytes and club cells facilitated COPD development via maintaining an autoimmune airway niche. Unexpectedly, macrophages, whose defect to resolve inflammation was long-recognized in COPD pathogenesis, primarily induced an imbalance of sphingolipids rheostat in a smoking-dependent way. These findings were validated in a meta-analysis including other public single-cell transcriptomic data. Conclusions In sum, our study provided a clarified view of COPD pathogenesis and demonstrated the potential of targeting monocytes in COPD diagnosis and treatment.

show abstract

“…The large airway epithelium is a pseudostratified columnar epithelium consisting of basal cells in the basal layer, and secretory and ciliated cells residing in an apical/surface layer. Basal cells function as progenitors of other epithelial cells (Boers et al, 1998; Hong et al, 2004a, b; Lynch et al, 2019; Rock et al, 2009) and regulate adhesion of the epithelium to the basement membrane (Evans and Plopper, 1988; Hawkins et al, 2021; Nakajima et al, 1998). Secretory cells can be further divided into two subtypes, club cells and goblet cells.…”

Section: Introductionmentioning

confidence: 99%

“…basal to ciliated prior to birth (Daniely et al, 2004), goblet cell development (Boucherat et al, 2013; Engelhardt et al, 1995; Evans et al, 2004; Hayashi et al, 2004; Pardo-Saganta et al, 2013; Reader et al, 2003; Turner et al, 2011; Tyner et al, 2006). Additionally, the cell types present in different airway locations vary between mice and humans: club cells are present in the trachea and bronchi of mice but only in bronchioles in humans (Plopper et al, 1980a; Plopper et al, 1980b, c), and basal cells are only present in trachea of mice but extend to both large and small airways in humans (Hogan et al, 2014; Rock et al, 2011; Rock et al, 2009), reviewed in (Lynch et al, 2019; Tata and Rajagopal, 2017). Even less well understood is the contribution of rare cells such as ionocytes to small airway epithelial function.…”

Section: Introductionmentioning

confidence: 99%

Topography-dependent gene expression and function of common cell archetypes in large and small porcine airways

Pezzulo

Thurman

et al. 2021

Preprint

View full text Add to dashboard Cite

The small airways of humans are affected early in several lung diseases. However, because they are relatively inaccessible, little is known about the epithelial cells that line these airways. We performed a single cell RNA-seq census of small and large airways of wild-type pigs and pigs with disrupted cystic fibrosis transmembrane conductance regulator (CFTR) gene. The sequencing data showed that small airway epithelia had similar major cell types as large airways but no ionocytes; moreover, lack of CFTR expression had minimal effect on the transcriptome. Small airway epithelial cells expressed a different transcriptome than large airway cells. Quantitative immunohistochemistry showed that small airway basal cells participate in epithelial barrier function. Finally, sequencing data and in vitro electrophysiologic studies suggest that small airway epithelia have a water and ion transport advantage. Our data highlight the archetypal nature of basal, secretory, and ciliated airway cells with location-dependent gene expression and function.

show abstract

Heterogeneity of Pulmonary Stem Cells

Cited by 11 publications

References 91 publications

Single-cell transcriptomics reveal cell type-specific molecular changes and altered intercellular communications in chronic obstructive pulmonary disease

Single-cell transcriptomics reveal cell type-specific molecular changes and altered intercellular communications in chronic obstructive pulmonary disease

Single-cell transcriptomics highlights immunological dysregulations of monocytes in the pathobiology of COPD

Topography-dependent gene expression and function of common cell archetypes in large and small porcine airways

Contact Info

Product

Resources

About