Dataset Information

Effect of hCMSCs and liraglutide combination in ALI through cAMP/PKAc/β-catenin signaling pathway.

ABSTRACT:

Background

ALI/ARDS is the major cause of acute respiratory failure in critically ill patients. As human chorionic villi-derived MSCs (hCMSCs) could attenuate ALI in the airway injury model, and liraglutide, glucagon-like peptide 1 (GLP-1) agonist, possesses anti-inflammatory and proliferation promotion functions, we proposed to probe the potential combinatory effect of hCMSCs and liraglutide on ALI.

Methods

We examined the time- and dose-dependent manner of GLP-1R, SPC, Ang-1, and FGF-10 with LPS via western blot and qRT-PCR. Western blot and chromatin immunoprecipitation assay detected the effects of liraglutide on GLP-1R, SPC, Ang-1, and FGF-10 through PKAc/β-catenin pathway and cAMP pathway. In the ALI animal model, we detected the effects of MSC and liraglutide combination on ALI symptoms by H&E staining, western blot, ELISA assays, calculating wet-to-dry ratio of the lung tissue, and counting neutrophils, leukocytes, and macrophages in mouse bronchoalveolar lavage fluid (BALF).

Results

The data demonstrated that LPS reduced hCMSC proliferation and GLP-1R, SPC, Ang-1, and FGF-10 levels in a dose- and time-dependent manner. Liraglutide significantly dampened the reduction of GLP-1R, SPC, Ang-1, and FGF-10 and reversed the effect of LPS on hCMSCs, which could be regulated by GLP-1R and its downstream cAMP/PKAc/β-catenin-TCF4 signaling. Combination of hCMSCs with liraglutide showed more therapeutic efficacy than liraglutide alone in reducing LPS-induced ALI in the animal model.

Conclusions

These results reveal that the combination of hCMSCs and liraglutide might be an effective strategy for ALI treatment.

SUBMITTER: Feng Y

PROVIDER: S-EPMC6942368 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Effect of hCMSCs and liraglutide combination in ALI through cAMP/PKAc/β-catenin signaling pathway.

Feng Yun Y Wang Linlin L Ma Xiaoying X Yang Xiaotong X Don Ocholi O Chen Xiaoyan X Qu Jieming J Song Yuanlin Y

Stem cell research & therapy 20200103 1

<h4>Background</h4>ALI/ARDS is the major cause of acute respiratory failure in critically ill patients. As human chorionic villi-derived MSCs (hCMSCs) could attenuate ALI in the airway injury model, and liraglutide, glucagon-like peptide 1 (GLP-1) agonist, possesses anti-inflammatory and proliferation promotion functions, we proposed to probe the potential combinatory effect of hCMSCs and liraglutide on ALI.<h4>Methods</h4>We examined the time- and dose-dependent manner of GLP-1R, SPC, Ang-1, an ...[more]

PMID: 31900217

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Project description:BackgroundMesenchymal stem cells (MSCs) have been widely studied to alleviate acute lung injury (ALI) due to their paracrine function. However, the microenvironment of inflammatory outbreaks significantly restricted the factors secreted from MSCs like keratinocyte growth factor (KGF). KGF is a growth factor with tissue-repaired ability. Is there a better therapeutic prospect for MSCs in combination with compounds that promote their paracrine function? Through compound screening, we screened out isoxazole-9 (ISX-9) to promote MSCs derived KGF secretion and investigated the underlying mechanisms of action.MethodsCompounds that promote KGF secretion were screened by a dual-luciferase reporter gene assay. The TMT isotope labeling quantitative technique was used to detect the differential proteins upon ISX-9 administrated to MSCs. The expressions of NGFR, ERK, TAU, and β-catenin were detected by Western blot. In the ALI model, we measured the inflammatory changes by HE staining, SOD content detection, RT-qPCR, immunofluorescence, etc. The influence of ISX-9 on the residence time of MSCs transplantation was explored by optical in vivo imaging.ResultsWe found out that ISX-9 can promote the expression of KGF in MSCs. ISX-9 acted on the membrane receptor protein NGFR, upregulated phosphorylation of downstream signaling proteins ERK and TAU, downregulated phosphorylation of β-catenin, and accelerated β-catenin into the nucleus to further increase the expression of KGF. In the ALI model, combined ISX-9 with MSCs treatments upgraded the expression of KGF in the lung, and enhanced the effect of MSCs in reducing inflammation and repairing lung damage compared with MSCs alone.ConclusionsISX-9 facilitated the secretion of KGF from MSCs both in vivo and in vitro. The combination of ISX-9 with MSCs enhanced the paracrine function and anti-inflammatory effect of MSCs compared with MSCs applied alone in ALI. ISX-9 played a contributive role in the transplantation of MSCs for the treatment of ALI.

Project description:Insulin and liraglutide have been demonstrated to control blood glucose and exert neuroprotective effects. However, the impact of liraglutide or insulin alone or in combination on brain pathology in type 1 diabetes mellitus (T1DM) and their underlying mechanisms are unclear. In the present study, diabetes mellitus (DM) was induced via intraperitoneal injection of streptozotocin in mice and subsequently mice were treated with insulin, liraglutide, a combination of the two drugs or saline. Changes in body weight and blood glucose were assessed weekly. The pathological changes in the brain tissue and the apoptosis of neurons were assessed using H&E staining and TUNEL staining. The mRNA and protein expression levels of apoptosis-related proteins were detected using reverse transcription-quantitative PCR (RT-qPCR) and western blotting, respectively. Moreover, Ki67 protein expression was analyzed using immunohistochemistry and the mRNA and protein expression levels of Wnt/β-catenin signaling pathway-related proteins were examined using RT-qPCR and western blotting, respectively. The results of the present study suggested that DM mice developed hyperglycemia and weight loss and also exhibited significantly increased neural cell apoptosis and significantly reduced numbers of Ki67-positive cells. Liraglutide significantly decreased blood glucose levels in DM mice, whereas both insulin and the combination of the two drugs failed to control blood glucose well. Insulin, liraglutide and their combination also failed to control body weight well, but significantly attenuated brain pathological changes and activation of the pro-apoptotic proteins Caspase-3 and Bax, which may have resulted in the significant increase in the expression levels of Wnt/β-catenin signaling pathway-associated molecules such as Wnt3a and S9-pGSK-3β. Liraglutide also promoted the protein expression of the neurogenesis marker of Ki67 and the antiapoptotic factor Bcl-2. These results suggested that insulin and liraglutide may improve brain damage via upregulation of the Wnt/β-catenin signaling pathway and could be of therapeutic relevance for improvement of cognitive impairment in patients with DM.

Dataset Information

Effect of hCMSCs and liraglutide combination in ALI through cAMP/PKAc/β-catenin signaling pathway.

Background

Methods

Results

Conclusions

Publications

Effect of hCMSCs and liraglutide combination in ALI through cAMP/PKAc/β-catenin signaling pathway.

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