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Secreted factors from adipose tissue-derived mesenchymal stem cells suppress oxygen/glucose deprivation-induced cardiomyocyte cell death via furin/PCSK-like enzyme activity.

ABSTRACT: Clinical application of mesenchymal stem cells (MSCs) represents a potential novel therapy for currently intractable deteriorating diseases or traumatic injuries, including myocardial infarction. However, the molecular mechanisms of the therapeutic effects have not been precisely revealed. Herein, we report that conditioned media (CM) from rat adipose tissue-derived MSCs (ASCs) protected adult cardiomyocytes from oxygen/glucose deprivation (OGD)-induced cell death. We focused on furin/PCSK protease activity in ASC-CM because many therapeutic factors of MSCs and soluble cardioprotective factors include the PCSK cleavage site. We found that recombinant furin protected cardiomyocytes from OGD-induced cell death. The ASC-CM had potent furin/PCSK protease activity and the cardioprotective effect of the CM from ASCs in the OGD-assay was abolished by an inhibitor of the furin/PCSK-like enzyme. Microarray analysis and Western blot analysis showed PCSK5A, the secreted type of PCSK5, is the most abundantly secreted PCSK among 7 PCSK family members in ASC. Finally, knockdown of PCSK5A in ASCs decreased both the furin/PCSK protease activity and cardioprotective activity in the CM. These findings indicate an involvement of furin/PCSK-type protease(s) in the anti-ischemic activity of ASCs, and suggest a new mechanism of the therapeutic effect of MSCs.

SUBMITTER: Tachida Y

PROVIDER: S-EPMC5613516 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other

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Secreted factors from adipose tissue-derived mesenchymal stem cells suppress oxygen/glucose deprivation-induced cardiomyocyte cell death via furin/PCSK-like enzyme activity.

Tachida Yuki Y Suda Koji K Nagase Hiroyuki H Shimada Kohei K Isono Fujio F Kobayashi Hideki H

Biochemistry and biophysics reports 20160702

Clinical application of mesenchymal stem cells (MSCs) represents a potential novel therapy for currently intractable deteriorating diseases or traumatic injuries, including myocardial infarction. However, the molecular mechanisms of the therapeutic effects have not been precisely revealed. Herein, we report that conditioned media (CM) from rat adipose tissue-derived MSCs (ASCs) protected adult cardiomyocytes from oxygen/glucose deprivation (OGD)-induced cell death. We focused on furin/PCSK prote ...[more]

PMID: 28955916

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Project description:Background: Cerebral ischemia-reperfusion (I/R) injury can lead to severe dysfunction, and its treatment is difficult. It is reported that nucleotide-binding domain and leucine-rich repeat family protein 3 (NLRP3) inflammasome-mediated cell pyroptosis is an important part of cerebral I/R injury and the activation of autophagy can inhibit pyroptosis in some tissue injury. Our previous study found that the protective effects of bone marrow mesenchymal stem cells (BMSCs) in cerebral I/R injury may be associated with the regulation of autophagy. Recent studies have demonstrated that exosomes secreted from BMSCs (BMSC-Exos) may play an essential role in the effective biological performance of BMSCs and the protective mechanism of BMSC-Exos is associated with the activation of autophagy and the remission of inflammation, but it has not been reported in studies of cerebral I/R injury. We aimed to investigate the effects of BMSC-Exos on cerebral I/R injury and determine if the mechanism is associated with the regulation of pyroptosis and autophagic flux. Method: PC12 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to induce cerebral I/R in vitro and were cocultured with BMSC-Exos. Cell viability was determined with CCK-8 and lactate dehydrogenase (LDH) detection kits. Scanning electron microscopy (SEM), Hoechst 33342/propidium iodide (PI) double staining, 2',7'-dichlorodihydrofluorescein diacetate assay, immunofluorescence, Western blot, and Enzyme-linked immunosorbent assay (ELISA) were used to detect cell pyroptosis. Furthermore, transmission electron microscopy (TEM), GFP-RFP-LC3 adenovirus transfection, and Western blot were used to detect autophagic flux and its influence on pyroptosis. Finally, coimmunoprecipitation was used to detect the binding interaction between NLRP3 and LC3. Results: BMSC-Exos increased cell viability in OGD/R. The inhibitory effect of BMSC-Exos on pyroptosis was comparable to the NLRP3 inhibitor MCC950 and was reversed by NLRP3 overexpression. Furthermore, BMSC-Exos promoted autophagic flux through the AMP-activated kinase (AMPK)/mammalian target of the rapamycin pathway, whereas chloroquine, AMPK silencing, and compound C blocked the inhibitory effect on pyroptosis. Conclusions: BMSC-Exos can protect PC12 cells against OGD/R injury via attenuation of NLRP3 inflammasome-mediated pyroptosis by promoting AMPK-dependent autophagic flux.

Dataset Information

Secreted factors from adipose tissue-derived mesenchymal stem cells suppress oxygen/glucose deprivation-induced cardiomyocyte cell death via furin/PCSK-like enzyme activity.

Publications

Secreted factors from adipose tissue-derived mesenchymal stem cells suppress oxygen/glucose deprivation-induced cardiomyocyte cell death via furin/PCSK-like enzyme activity.

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