Hepatocyte growth factor secreted by bone marrow stem cell reduce ER stress and improves repair in alveolar epithelial II cells

Nita, Gelu M.; Hostettler, Katrin; Tamò, Luca; Medová, Michaela; Bombaci, Giuseppe; Zhong, Jun; Allam, Ramanjaneyulu; Zimmer, Yitzhak; Roth, Michael; Geiser, Thomas; Gazdhar, Amiq

doi:10.1038/srep41901

Cited by 29 publications

(19 citation statements)

References 56 publications

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“…The observation that MSC act upon one specific pathway was unexpected as MSC have been shown to substantially decrease other ER stress pathways, including ER stress‐induced apoptosis, in other models . Previous studies have reported a decrease in the mRNA levels of various ER stress markers other than PERK or Nrf2 by MSC in young mouse models or AEC . The discrepancy with our results might rely on important differences in the models, such as the age of the mice, sample origin or timing and origin of the therapeutic intervention, leading to different outcomes.…”

Section: Discussioncontrasting

confidence: 95%

“…30 Previous studies have reported a decrease in the mRNA levels of various ER stress markers other than PERK or Nrf2 by MSC in young mouse models or AEC. 31,32 The discrepancy with our results might rely on important differences in the models, such as the age of the mice, sample origin or timing and origin of the therapeutic intervention, leading to different outcomes. However, in a model of stress-induced senescence in fibroblasts, only the PERK pathway was upregulated with H 2 O 2, 33 which suggests that the senescence-associated ER stress response might be specific for each stressor.…”

Section: Discussioncontrasting

confidence: 90%

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Mesenchymal stem cells reduce ER stress via PERK‐Nrf2 pathway in an aged mouse model

et al. 2019

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Background and objective Mesenchymal stem cells (MSC) have been shown to ameliorate the deleterious effects of bleomycin in murine models. However, the mechanism responsible for protection from pulmonary fibrosis by stem cell therapy is still poorly understood, especially in terms of endoplasmic reticulum (ER) stress. We hypothesized that during bleomycin‐induced lung injury, markers of ER stress, specifically the activation of the unfolded protein response (UPR), increase during injury, resembling the kinetics of collagen deposition in the lung described for the bleomycin model. We aimed to elucidate the possible role of MSC in ER stress modulation. Methods To determine the kinetics of ER stress in aged mice, the expression of ER stress markers after bleomycin lung injury was measured in old mice at different time points (days 0, 3, 7, 14 and 21). To evaluate the consequences of systemic delivery of MSC on lung ER stress in the bleomycin model, we evaluated changes in body weight, lung histology and protein expression of ER stress markers. Results The level of expression of UPR transcription factor XBP‐1 and its regulator BiP was elevated at day 7 and progressively increased up to day 21. MSC inhibited BiP expression in bleomycin‐induced ER stress, attenuating ER stress via the protein kinase RNA‐like ER kinase (PERK)‐Nrf2 pathway. The expression levels of other ER stress markers were not perturbed by MSC. Conclusion Our data suggest that MSC operate on ER stress via several pathways, but the PERK‐Nrf2 pathway revealed to be the main functioning pathway in our bleomycin model.

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Section: Discussioncontrasting

confidence: 95%

Section: Discussioncontrasting

confidence: 90%

Mesenchymal stem cells reduce ER stress via PERK‐Nrf2 pathway in an aged mouse model

et al. 2019

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“…Also, it is possible that one or more factors from hAT-MSCs may contribute to the suppression of ER stress-induced apoptosis. Hepatocyte growth factor secreted by bone marrow-derived mesenchymal stem cells was shown to reduce ER stress in alveolar epithelial cells [ 55 ]. Further studies are warranted to investigate if NF-κB inhibitors affect the ER stress pathway after hAT-MSC administration.…”

Section: Discussionmentioning

confidence: 99%

TSG-6 secreted by human adipose tissue-derived mesenchymal stem cells ameliorates severe acute pancreatitis via ER stress downregulation in mice

Song

Ryu

et al. 2018

Stem Cell Res Ther

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BackgroundThrough recent studies, the onset of acute pancreatitis in pancreatic acinar cells (PACs) and the regulatory role of PACs in severe acute pancreatitis (SAP) have been revealed. During the early stages of pancreatitis, the endoplasmic reticulum (ER) in PACs undergoes significant changes, including swelling and vacuolization. In response to an increase in the extracellular stress in ER, PACs lose their functions, leading to cell apoptosis and inflammation response. The beneficial effects of human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) on SAP have been well documented in previous studies. However, the underlying mechanism of their action remains controversial.MethodsIn this study, the therapeutic effects of intraperitoneally administered hAT-MSCs in a caerulein (50 μg/kg)- and lipopolysaccharide (LPS) (10 mg/kg)-co-induced SAP mouse model were evaluated. Inflammatory response and ER stress were measured in pancreatic tissue samples, and the beneficial effects were evaluated through quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunofluorescence analysis.ResultsInflammatory response and ER stress were ameliorated following hAT-MSC injection, and the beneficial effects were observed in the absence of significant engraftment of hAT-MSCs. hAT-MSCs transfected with siRNA-targeting tumour necrosis factor-α-induced gene/protein 6 (TSG-6) were unable to inhibit ER stress and inflammation. In addition, TSG-6 from hAT-MSCs significantly suppressed ER stress-induced apoptosis and nuclear factor kappa B (NF-κB) activity in SAP model mice.ConclusionsTSG-6 secreted by hAT-MSCs protects PACs in SAP model mice via the inhibition of ER stress, as well as inflammatory responses. This study has revealed a new area for ER stress-targeted therapy in SAP patients.Graphical abstract Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1009-8) contains supplementary material, which is available to authorized users.

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“…The HGF/c-Met signaling pathway has been shown to be involved in tumor progression and is linked to the stemness and migration ability of cancer stem cells (Comoglio, Trusolino, & Boccaccio, 2018;Frisch et al, 2016;Nita et al, 2017;Yiwen Liu et al, 2011). A recent study showed that the MAPK/ERK1/2 signaling is vital for the selfrenewal of mouse male germline stem cells (Niu, Mu, Zhu, Wu, & Hua, 2017 BMP/Smad1/5/8 signaling is typically involved in bone formation, heterotopic calcification, and stem cell osteogenic differentiation (Salazar, Gamer, & Rosen, 2016), and we found that it is highly activated during TDSC differentiation in vitro (Han et al, 2017).…”

Section: The Balance Between Tenogenic and Osteogenic Differentiation Ofmentioning

confidence: 99%

Hepatocyte growth factor plays a dual role in tendon‐derived stem cell proliferation, migration, and differentiation

Han

Cui

et al. 2019

Journal Cellular Physiology

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Heterotopic ossification is common in tendon healing after trauma, but the detailed mechanisms remain unknown. Tendon‐derived stem cells (TDSCs) are a type of progenitor cell found in the tendon niche, and their incorrect differentiation after trauma may lead to tendon calcification. The expression of hepatocyte growth factor (HGF) presents drastic fluctuations in serum/tissue after trauma and was found to activate quiescent stellate cells and contribute to wound healing; however, its potential role in TDSCs remains elusive. In this study, TDSCs isolated from rats were cultured in media containing HGF with or without a signaling inhibitor, and the proliferation, migration, and differentiation ability of TDSCs were measured to determine the role and mechanism of HGF in TDSCs. We showed that HGF promotes TDSC proliferation and migration but inhibits TDSC osteogenic differentiation ability. HGF activated‐HGF/c‐Met, mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2), and phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) signaling, which was positively correlated with TDSCs proliferation and migration but negatively related to TDSC osteogenic differentiation ability. The phosphorylation of Smad1/5/8 was also negatively related to HGF/c‐Met, MAPK/ERK1/2, and PI3K/AKT signaling, which demonstrated that the inhibition of osteogenic differentiation was dependent on BMP/Smad1/5/8 signaling. Overall, we showed that HGF could promote TDSCs proliferation and migration and inhibit osteogenic differentiation in vitro, suggesting a potential role for HGF as a cytokine treatment of tendon trauma.

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Hepatocyte growth factor secreted by bone marrow stem cell reduce ER stress and improves repair in alveolar epithelial II cells

Cited by 29 publications

References 56 publications

Mesenchymal stem cells reduce ER stress via PERK‐Nrf2 pathway in an aged mouse model

Mesenchymal stem cells reduce ER stress via PERK‐Nrf2 pathway in an aged mouse model

TSG-6 secreted by human adipose tissue-derived mesenchymal stem cells ameliorates severe acute pancreatitis via ER stress downregulation in mice

Hepatocyte growth factor plays a dual role in tendon‐derived stem cell proliferation, migration, and differentiation

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