The hedgehog and Wnt/β-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis

Chen, Xiang; Shi, Chaowen; Cao, Honghui; Chen, Ling; Hou, Jiwei; Zou, Xiang; Hu, Kebin; Han, Xiaodong

doi:10.1038/s41419-018-0692-9

Cited by 60 publications

(47 citation statements)

References 56 publications

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“…For example, GLI could bind to promoter of Wnt genes to regulate Wnt/β-catenin signaling [41], and β-catenin could enhance GLI1 transcriptional activity [42]. Recently, crosstalk between Wnt and Hh was shown to be involved in pulmonary fibrosis, and GLI1 was proved to be a potential therapeutic target in pulmonary fibrosis [43]. The present study showed that GLI1 expression was promoted by Wnt activation in LF, and additional knockdown of PRC1 could inhibit GLI1 expression.…”

Section: Discussionmentioning

confidence: 99%

PRC1 promotes GLI1-dependent osteopontin expression in association with the Wnt/β-catenin signaling pathway and aggravates liver fibrosis

Xiang

Huang

et al. 2019

Cell Biosci

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BackgroundPRC1 (Protein regulator of cytokinesis 1) regulates microtubules organization and functions as a novel regulator in Wnt/β-catenin signaling pathway. Wnt/β-catenin is involved in development of liver fibrosis (LF). We aim to investigate effect and mechanism of PRC1 on liver fibrosis.MethodsCarbon tetrachloride (CCl4)-induced mice LF model was established and in vitro cell model for LF was induced by mice primary hepatic stellate cell (HSC) under glucose treatment. The expression of PRC1 in mice and cell LF models was examined by qRT-PCR (quantitative real-time polymerase chain reaction), western blot and immunohistochemistry. MTT assay was used to detect cell viability, and western blot to determine the underlying mechanism. The effect of PRC1 on liver pathology was examined via measurement of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and hydroxyproline, as well as histopathological analysis.ResultsPRC1 was up-regulated in CCl4-induced mice LF model and activated HSC. Knockdown of PRC1 inhibited cell viability and promoted cell apoptosis of activated HSC. PRC1 expression was regulated by Wnt3a signaling, and PRC1 could regulate downstream β-catenin activation. Moreover, PRC1 could activate glioma-associated oncogene homolog 1 (GLI1)-dependent osteopontin expression to participate in LF. Adenovirus-mediated knockdown of PRC1 in liver attenuated LF and reduced collagen deposition.ConclusionsPRC1 aggravated LF through regulating Wnt/β-catenin mediated GLI1-dependent osteopontin expression, providing a new potential therapeutic target for LF treatment.

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Section: Discussionmentioning

confidence: 99%

PRC1 promotes GLI1-dependent osteopontin expression in association with the Wnt/β-catenin signaling pathway and aggravates liver fibrosis

Xiang

Huang

et al. 2019

Cell Biosci

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“…Accumulating evidence suggest that MSC-sourced CM and Exos may represent a compelling alternative to MSCs in the treatment of ALF and liver fibrosis (Table 1) [13,14,15,16,17,18,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88].…”

Section: Experimental Evidence For Therapeutic Potential Of Msc-dementioning

confidence: 99%

“…Beneficial effects of MSC-CM and MSC-Exo-based therapy have been demonstrated in the animal models of ALI, asthma, COPD and IPF (Table 2) [19,20,21,22,83,84,85,86,87,88,89,90,91]. Importantly, MSC-CM and MSC-EVs managed to induce regeneration of injured epithelium, attenuation of inflammation and fibrosis in the lungs in similar manner as transplanted MSCs [19,24,84,85,86,87].…”

Section: Experimental Evidence For Therapeutic Potential Of Msc-dementioning

confidence: 99%

“…Although MSCs can be used for the attenuation of chronic lung inflammation and fibrosis, plenty of evidence suggest that aberrant activation of Wnt/β-catenin and TGF-β signaling pathways in lung resident MSCs may induce their differentiation in miofibroblasts and could, consequently, contribute to the development of IPF [87]. Having in mind that beneficial effects of MSCs in the therapy of IPF were mainly relied on their paracrine effects [88], Shantu and colleagues investigated whether MSC-sourced secretome may attenuate IPF as efficiently as MSCs [89].…”

Section: Experimental Evidence For Therapeutic Potential Of Msc-dementioning

confidence: 99%

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Molecular Mechanisms Responsible for Therapeutic Potential of Mesenchymal Stem Cell-Derived Secretome

Harrell¹,

Fellabaum²,

Jovičić

et al. 2019

Cells

371

300

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Mesenchymal stem cell (MSC)-sourced secretome, defined as the set of MSC-derived bioactive factors (soluble proteins, nucleic acids, lipids and extracellular vesicles), showed therapeutic effects similar to those observed after transplantation of MSCs. MSC-derived secretome may bypass many side effects of MSC-based therapy, including unwanted differentiation of engrafted MSCs. In contrast to MSCs which had to be expanded in culture to reach optimal cell number for transplantation, MSC-sourced secretome is immediately available for treatment of acute conditions, including fulminant hepatitis, cerebral ischemia and myocardial infarction. Additionally, MSC-derived secretome could be massively produced from commercially available cell lines avoiding invasive cell collection procedure. In this review article we emphasized molecular and cellular mechanisms that were responsible for beneficial effects of MSC-derived secretomes in the treatment of degenerative and inflammatory diseases of hepatobiliary, respiratory, musculoskeletal, gastrointestinal, cardiovascular and nervous system. Results obtained in a large number of studies suggested that administration of MSC-derived secretomes represents a new, cell-free therapeutic approach for attenuation of inflammatory and degenerative diseases. Therapeutic effects of MSC-sourced secretomes relied on their capacity to deliver genetic material, growth and immunomodulatory factors to the target cells enabling activation of anti-apoptotic and pro-survival pathways that resulted in tissue repair and regeneration.

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“…Importantly, despite the fact that MSCs can be used for the attenuation of chronic lung inflammation and fibrosis, plenty of evidence suggests that aberrant activation of Wnt/ β -catenin and TGF- β signaling pathways in lung-resident MSCs might induce their differentiation towards myofibroblasts and could, consequently, contribute to the development of IPF [104]. In line with these findings, a pharmacological inhibitor of Wnt/ β -catenin signaling (ICG-001) managed to prevent MSC-myofibroblst transition and protected from bleomycin-induced fibrosis [105].…”

Section: Msc-based Therapy Of Ipfmentioning

confidence: 99%

Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung Diseases: Current Understanding and Future Perspectives

Harrell

Sadikot

Pascual

et al. 2019

Stem Cells International

169

168

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During acute or chronic lung injury, inappropriate immune response and/or aberrant repair process causes irreversible damage in lung tissue and most usually results in the development of fibrosis followed by decline in lung function. Inhaled corticosteroids and other anti-inflammatory drugs are very effective in patients with inflammatory lung disorders, but their long-term use is associated with severe side effects. Accordingly, new therapeutic agents that will attenuate ongoing inflammation and, at the same time, promote regeneration of injured alveolar epithelial cells are urgently needed. Mesenchymal stem cells (MSCs) are able to modulate proliferation, activation, and effector function of all immune cells that play an important role in the pathogenesis of acute and chronic inflammatory lung diseases. In addition to the suppression of lung-infiltrated immune cells, MSCs have potential to differentiate into alveolar epithelial cells in vitro and, accordingly, represent new players in cell-based therapy of inflammatory lung disorders. In this review article, we described molecular mechanisms involved in MSC-based therapy of acute and chronic pulmonary diseases and emphasized current knowledge and future perspectives related to the therapeutic application of MSCs in patients suffering from acute respiratory distress syndrome, pneumonia, asthma, chronic obstructive pulmonary diseases, and idiopathic pulmonary fibrosis.

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The hedgehog and Wnt/β-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis

Cited by 60 publications

References 56 publications

PRC1 promotes GLI1-dependent osteopontin expression in association with the Wnt/β-catenin signaling pathway and aggravates liver fibrosis

PRC1 promotes GLI1-dependent osteopontin expression in association with the Wnt/β-catenin signaling pathway and aggravates liver fibrosis

Molecular Mechanisms Responsible for Therapeutic Potential of Mesenchymal Stem Cell-Derived Secretome

Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung Diseases: Current Understanding and Future Perspectives

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