Involvement of midkine in the development of pulmonary fibrosis

Misa, Kenichi; Tanino, Yoshinori; Wang, Xintao; Nikaido, Takefumi; Kikuchi, Masami; Sato, Yuki; Togawa, Ryuichi; Tanino, Mishie; Tanaka, Shinya; Kadomatsu, Kenji; Munakata, Mitsuru

doi:10.14814/phy2.13383

Cited by 24 publications

(21 citation statements)

References 50 publications

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“…Again focusing on potential regulatory target genes conserved between the two injury models, SCENIC uncovers 6 genes associated with Rxra and 5 genes associated with Sox4 (Figure S9F). Genes associated with the Sox4 regulon include Mdk and Hmcn1 that have previously been shown to have important roles in fibrosis in other organs (Chowdhury et al., 2014, Misa et al., 2017).…”

Section: Resultsmentioning

confidence: 99%

Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis

et al. 2019

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SummaryIterative liver injury results in progressive fibrosis disrupting hepatic architecture, regeneration potential, and liver function. Hepatic stellate cells (HSCs) are a major source of pathological matrix during fibrosis and are thought to be a functionally homogeneous population. Here, we use single-cell RNA sequencing to deconvolve the hepatic mesenchyme in healthy and fibrotic mouse liver, revealing spatial zonation of HSCs across the hepatic lobule. Furthermore, we show that HSCs partition into topographically diametric lobule regions, designated portal vein-associated HSCs (PaHSCs) and central vein-associated HSCs (CaHSCs). Importantly we uncover functional zonation, identifying CaHSCs as the dominant pathogenic collagen-producing cells in a mouse model of centrilobular fibrosis. Finally, we identify LPAR1 as a therapeutic target on collagen-producing CaHSCs, demonstrating that blockade of LPAR1 inhibits liver fibrosis in a rodent NASH model. Taken together, our work illustrates the power of single-cell transcriptomics to resolve the key collagen-producing cells driving liver fibrosis with high precision.

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Section: Resultsmentioning

confidence: 99%

Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis

et al. 2019

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“…The high expression of inhibitor of MMP in the SCGB3A2 high club cells may contribute to the complex regulation of ECM in IPF. In addition, SCGB3A2 high club cells in IPF expressed many fibrotic growth factors, such as C3, MDK and SPP1 [ 37 – 39 ]. Interestingly, like the MUC5B + club cells, the SCGB3A2 high club cells in the IPF lung also express many mucin-related genes, but with a different repertoire, suggesting the heterogeneity of goblet cell-like club cells in the IPF.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of club cell biology in idiopathic pulmonary fibrosis

et al. 2020

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Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic fibrotic lung disease with an irreversible decline of lung function. “Bronchiolization”, characterized by ectopic appearance of airway epithelial cells in the alveolar regions, is one of the characteristic features in the IPF lung. Based on the knowledge that club cells are the major epithelial secretory cells in human small airways, and their major secretory product uteroglobin (SCGB1A1) is significantly increased in both serum and epithelial lining fluid of IPF lung, we hypothesize that human airway club cells contribute to the pathogenesis of IPF. By assessing the transcriptomes of the single cells from human lung of control donors and IPF patients, we identified two SCGB1A1 + club cell subpopulations, highly expressing MUC5B, a significant genetic risk factor strongly associated with IPF, and SCGB3A2, a marker heterogeneously expressed in the club cells, respectively. Interestingly, the cellular proportion of SCGB1A1 + MUC5B + club cells was significantly increased in IPF patients, and this club cell subpopulation highly expressed genes related to mucous production and immune cell chemotaxis. In contrast, though the cellular proportion did not change, the molecular phenotype of the SCGB1A1 + SCGB3A2 high club cell subpopulation was significantly altered in IPF lung, with increased expression of mucins, cytokine and extracellular matrix genes. The single cell transcriptomic analysis reveals the cellular and molecular heterogeneity of club cells, and provide novel insights into the biological functions of club cells in the pathogenesis of IPF.

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“…Here, we used comparative expression analysis to identify apoptosis-linked genes, including midikine, gremlin1, Spp1,Ptgs2, Bak, Bax, Bcl2, and Fas, in IPF and a mouse model of TGFα-induced pulmonary fibrosis and validated changes in their expression by RT-PCR and found a significant overlap. Among upregulated genes, midikine, Spp1, and gremlin1 were shown to function as positive regulators in IPF and during bleomycin-induced pulmonary fibrosis (Pardo et al, 2005; Koli et al, 2006; Misa et al, 2017). Studies using cancer cell lines further support the hypothesis that increased expression of these genes increases the survival of mesenchymal cells, suggesting their inhibition as an intervention strategy (Tamminen et al, 2013; Muller et al, 2014; Saleh et al, 2016; Xiang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Mesenchymal Cell Survival Pathways in Severe Fibrotic Lung Disease: The Effect of Nintedanib Therapy

et al. 2019

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Impaired apoptotic clearance of myofibroblasts can result in the continuous expansion of scar tissue during the persistent injury in the lung. However, the molecular and cellular mechanisms underlying the apoptotic clearance of multiple mesenchymal cells including fibrocytes, fibroblasts and myofibroblasts in severe fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) remain largely unknown. We analyzed the apoptotic pathways activated in mesenchymal cells of IPF and in a mouse model of TGFα-induced pulmonary fibrosis. We found that fibrocytes and myofibroblasts in fibrotic lung lesions have acquired resistance to Fas-induced apoptosis, and an FDA-approved anti-fibrotic agent, nintedanib, effectively induced apoptotic cell death in both. In support, comparative gene expression analyses suggest that apoptosis-linked gene networks similarly dysregulated in both IPF and a mouse model of TGFα-induced pulmonary fibrosis. TGFα mice treated with nintedanib show increased active caspase 3-positive cells in fibrotic lesions and reduced fibroproliferation and collagen production. Further, the long-term nintedanib therapy attenuated fibrocyte accumulation, collagen deposition, and lung function decline during TGFα-induced pulmonary fibrosis. These results highlight the importance of inhibiting survival pathways and other pro-fibrotic processes in the various types of mesenchymal cells and suggest that the TGFα mouse model is relevant for testing of anti-fibrotic drugs either alone or in combination with nintedanib.

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Involvement of midkine in the development of pulmonary fibrosis

Cited by 24 publications

References 50 publications

Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis

Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis

Dysregulation of club cell biology in idiopathic pulmonary fibrosis

Dysregulation of Mesenchymal Cell Survival Pathways in Severe Fibrotic Lung Disease: The Effect of Nintedanib Therapy

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