Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis

Xu, Yan; Mizuno, Takako; Sridharan, Anusha; Du, Yina; Guo, Minzhe; Tang, Jie; Wikenheiser-Brokamp, Kathryn A.; Perl, Anne‐Karina T.; Funari, Vincent; Gokey, Jason J.; Stripp, Barry R.; Whitsett, Jeffrey A.

doi:10.1172/jci.insight.90558

Cited by 451 publications

(474 citation statements)

References 49 publications

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“…In line with the study by KUSKO et al [17], single-cell RNA sequencing analysis of IPF and control lungs identified the cross-talk of four distinct lung epithelial cell subtypes (alveolar type 2, goblet, basal and indeterminate) [18]. XU et al [18] showed that cells isolated from IPF patients express genes associated with activation of canonical transforming growth factor (TGF)-β, HIPPO/YAP, PI3K/AKT, p53 and WNT signalling cascades, which are activated in an integrated network [18]. Myofibroblast differentiation and massive ECM deposition are both ideal targetable phenomena in fibrotic diseases [19].…”

Section: Genomics and Transcriptomicssupporting

confidence: 72%

Systems medicine advances in interstitial lung disease

2017

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Fibrotic lung diseases involve subject-environment interactions, together with dysregulated homeostatic processes, impaired DNA repair and distorted immune functions. Systems medicine-based approaches are used to analyse diseases in a holistic manner, by integrating systems biology platforms along with clinical parameters, for the purpose of understanding disease origin, progression, exacerbation and remission.Interstitial lung diseases (ILDs) refer to a heterogeneous group of complex fibrotic diseases. The increase of systems medicine-based approaches in the understanding of ILDs provides exceptional advantages by improving diagnostics, unravelling phenotypical differences, and stratifying patient populations by predictable outcomes and personalised treatments. This review discusses the state-of-the-art contributions of systems medicine-based approaches in ILDs over the past 5 years.

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Section: Genomics and Transcriptomicssupporting

confidence: 72%

Systems medicine advances in interstitial lung disease

2017

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“…A seminal study employing single cell RNAseq analysis of epithelial cells isolated from normal and IPF lung samples demonstrated the co-expression of basal cell markers (i.e. KRT5 and TP63) and the mesenchymal marker, vimentin, in IPF but not normal epithelial cells[42]. Collectively, these studies raise the possibility that alveolar type II and basal epithelial cells might give rise to collagen 1, vimentin and/or S100A4 expressing fibroblasts, but there is no conclusive evidence for these cells also giving rise to αSMA-expressing myofibroblasts.…”

Section: Fibroblast and Myofibroblasts Heterogeneity In Injured Murinmentioning

confidence: 99%

Heterogeneity of Fibroblasts and Myofibroblasts in Pulmonary Fibrosis

Habiel

Hogaboam

2017

Curr Pathobiol Rep

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Purpose of review Idiopathic Pulmonary Fibrosis (IPF) is the most common form of interstitial lung diseases of unknown eathiopathogenesis, mean survival of 3-5 years and limited therapeutics. Characterized by a loss of alveolar type II epithelial cells and aberrant activation of stromal cells, considerable effort was undertaken to characterize the origin and activation mechanisms of fibroblasts and myofibroblasts in IPF lungs. In this review, the origin and contribution of fibroblast and myofibroblasts in lung fibrosis will be summarized. Recent findings Lineage tracing experiments suggested that interstitial lung fibroblasts and lipofibroblasts, pericytes and mesothelial cells differentiate into myofibroblasts. However, epithelial and bone marrow derived cells may give rise to collagen expressing fibroblasts but do not differentiate into myofibroblasts. Summary There is great heterogeneity in fibroblasts and myofibroblasts in fibrotic lungs. Further, there is evidence for the expansion of pericyte derived myofibroblasts and loss of lipofibroblasts and lipofibroblast derived myofibroblasts in IPF.

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“…Because this precise spatiotemporal segregation of Sox2 and Sox9 as canonical proximal and distal lung markers, respectively, has been described in developing mouse lungs it remains somewhat unclear whether these markers may be similarly used as equally faithful proximal-distal epithelial patterning markers in early human lung development. However, recent studies have demonstrated low levels of SOX2 in the human distal lung and high levels in the proximal airways (Kim et al, 2016; Xu et al, 2016), and a variety of additional markers of proximal and distal epithelial differentiation in humans is emerging in single-cell RNA sequencing studies (Xu et al, 2016) to facilitate the study of airway patterning in early human development.…”

Section: Introductionmentioning

confidence: 99%

Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling

et al. 2017

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SUMMARY Effective derivation of functional airway organoids from induced pluripotent stem cells (iPSCs) would provide valuable models of lung disease and facilitate precision therapies for airway disorders such as cystic fibrosis. However, limited understanding of human airway patterning has made this goal challenging. Here, we show that cyclical modulation of the canonical Wnt signaling pathway enables rapid directed differentiation of human iPSCs via an NKX2-1+ progenitor intermediate into functional proximal airway organoids. We find that human NKX2-1+ progenitors have high levels of Wnt activation but respond intrinsically to decreases in Wnt signaling by rapidly patterning into proximal airway lineages at the expense of distal fates. Using this directed approach, we were able to generate cystic fibrosis patient-specific iPSC-derived airway organoids with a defect in forskolin-induced swelling that is rescued by gene editing to correct the disease mutation. Our approach has many potential applications in modeling and drug screening for airway diseases.

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Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis

Cited by 451 publications

References 49 publications

Systems medicine advances in interstitial lung disease

Systems medicine advances in interstitial lung disease

Heterogeneity of Fibroblasts and Myofibroblasts in Pulmonary Fibrosis

Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling

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