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The Delta Opioid Peptide DADLE Represses Hypoxia-Reperfusion Mimicked Stress Mediated Apoptotic Cell Death in Human Mesenchymal Stem Cells in Part by Downregulating the Unfolded Protein Response and ROS along with Enhanced Anti-Inflammatory Effect

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Abstract

Hypoxia-reperfusion (H/R) emblems a plethora of pathological conditions which is potent in contributing to the adversities encountered by human mesenchymal stem cells (hMSCs) in post-transplant microenvironment, resulting in transplant failure. D-Alanine 2, Leucine 5 Enkephaline (DADLE)-mediated delta opioid receptor (DOR) activation is well-known for its recuperative properties in different cell types like neuronal and cardiomyocytes. In the current study its effectiveness in assuaging hMSC mortality under H/R-like insult has been delineated. The CoCl2 mimicked H/R conditions in vitro was investigated upon DOR activation, mediated via DADLE. hMSCs loss of viability, reactive oxygen species (ROS) production, inflammatory responses and disconcerted unfolded protein response (UPR) were assessed using AnnexinV/PI flow cytometry, fluorescence imaging, mitochondrial complex 1 assay, quantitative PCR, immunoblot analysis and ELISA. H/R like stress induced apoptosis of hMSCs was significantly mitigated by DADLE via modulation of the apoptotic regulators (Bcl-2/Bax) along with significant curtailment of ROS and mitochondrial complex 1 activity. DADLE concomitantly repressed the misfolded protein aggregation, alongside the major UPR sensors: PERK/BiP/IRE-1α /ATF-6, evoked due to the H/R mimicked endoplasmic reticulum stress. Undermined phosphorylation of the Akt signalling pathway was observed, which concerted its effect onto regulating both the pro and anti-inflammatory cytokines, actuated as a response to the H/R-like insult. The effects of DADLE were subdued by naltrindole (specific DOR antagonist) reaffirming the involvement of DOR in the process. Taken together these results promulgate the role of DADLE-induced DOR activation on improved hMSC survival, which signifies the plausible implications of DOR-activation in cell-transplantation therapies and tissue engineering aspect.

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Fig. 1: Characterization of hMSCs.
Fig. 2: Cell viability assessment (MTT) of hMSCs on H/R injury.
Fig. 3: Effect of DOR activation on hMSC survival via DADLE under H/R conditions.
Fig. 4: DADLE-mediated DOR activation curtails the H/R-induced intra-cellular ROS.
Fig. 5: DADLE mediated DOR activation palliates H/R-induced ROS via suppression of the mitochondrial complex 1 activity.
Fig. 6: DADLE mediated DOR activation represses the UPR and corresponding protein aggregation under H/R.
Fig. 7: DADLE mediated DOR activation alters the expression levels of Bcl-2 and Bax under H/R.
Fig. 8: DADLE mediated DOR activation mitigates the phosphorylation of levels of p-Akt and MAPK under H/R.
Fig. 9: DADLE mediated DOR activation regulates the secretion of cytokines (human) in the hMSC-macrophage co-culture supernatants.
Fig. 10: DADLE mediated DOR activation regulates the secretion of cytokines (murine) in the hMSC-macrophage co-culture supernatants
Fig. 11: A concise schematic representation of the hypothesized mechanism of DOR-mediated hMSC survival under H/R

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Abbreviations

hMSC:

human mesenchymal stem cells

H/R:

Hypoxia-reperfusion

DADLE:

d-Ala2, d-Leu5 enkephalin

DOR:

Delta opioid receptor

ER:

Endoplasmic reticulum

UPR:

Unfolded protein response

CMH2DCFDA:

chloro-methyl derivative 2′,7′-dichlorofluorescein

PERK:

PRKR-like ER kinase

ATF-6:

Activating transcription factor 6α

IRE-1α:

Inositol-requiring protein 1α

BiP:

immunoglobulin heavy-chain binding protein

MAPK:

Mitogen activated protein kinase

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Acknowledgements

Centre for Stem Cell Research, Christian Medical College, Vellore, India for providing access to flow cytometry and fluorescence microscope.

Funding

This work was supported by a start-up fund from VIT, Vellore given to DS. DS is also supported by a Indian Council of Medical Research (ICMR) Funded Project (Sanction Order No.NCD/Ad-hoc/66/2016–17) and a ‘Fast Track Young Scientist’ grant (YSS/2014/000027) from the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India.

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  1. Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology (VIT), Vellore, TN, 632014, India

    Madhubanti Mullick & Dwaipayan Sen

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  1. Madhubanti Mullick
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MM has carried out experiments, analyzed data and wrote the paper. DS conceptualized, wrote the paper and analysed the data.

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Correspondence to Dwaipayan Sen.

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Mullick, M., Sen, D. The Delta Opioid Peptide DADLE Represses Hypoxia-Reperfusion Mimicked Stress Mediated Apoptotic Cell Death in Human Mesenchymal Stem Cells in Part by Downregulating the Unfolded Protein Response and ROS along with Enhanced Anti-Inflammatory Effect. Stem Cell Rev and Rep 14, 558–573 (2018). https://doi.org/10.1007/s12015-018-9810-4

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  • DOI: https://doi.org/10.1007/s12015-018-9810-4

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