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Stem cells alleviate OGD/R mediated stress response in PC12 cells following a co-culture: modulation of the apoptotic cascade through BDNF-TrkB signaling

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Cell Stress and Chaperones Aims and scope

Abstract

Apoptosis mediated by endoplasmic reticulum (ER) stress plays a crucial role in several neurovascular disorders, including ischemia/reperfusion injury (I/R injury). Previous in vitro and in vivo studies have suggested that following I/R injury, ER stress is vital for mediating CCAT-enhancer-binding protein homologous protein (CHOP) and caspase-12-dependent apoptosis. However, its modulation in the presence of stem cells and the underlying mechanism of cytoprotection remains elusive. In vivo studies from our lab have reported that post-stroke endovascular administration of stem cells renders neuroprotection and regulates apoptosis mediated by ER stress. In the current study, a more robust in vitro validation has been undertaken to decipher the mechanism of stem cell-mediated cytoprotection. Results from our study have shown that oxygen–glucose deprivation/reoxygenation (OGD/R) potentiated ER stress and apoptosis in the pheochromocytoma 12 (PC12) cell line as evident by the increase of protein kinase R (PKR)-like ER kinase (p-PERK), p-Eukaryotic initiation factor 2α subunit (EIF2α), activation transcription factor 4 (ATF4), CHOP, and caspase 12 expressions. Following the co-culture of PC12 cells with MSCs, ER stress was significantly reduced, possibly via modulating the brain-derived neurotrophic factor (BDNF) signaling. Furthermore, inhibition of BDNF by inhibitor K252a abolished the protective effects of BDNF secreted by MSCs following OGD/R. Our study suggests that inhibition of ER stress-associated apoptotic pathway with MSCs co-culture following OGD/R may help to alleviate cellular injury and further substantiate the use of stem cells as a therapeutic modality toward neuroprotection following hypoxic injury or stroke in clinical settings.

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Data Availability

All data generated are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors also acknowledge the Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Govt. of India and National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, India. The authors would like to acknowledge the Indian Council of Medical Research (ICMR), New Delhi for the senior research fellowship grant of Miss Harpreet Kaur (File No. 5/3/8/16/ITR-F/2019-ITR) for the work on Stem Cell Therapy to Counteract Endoplasmic Reticulum Stress in Ischemic stroke, Servier Medical Art by Servier (licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com/) and  https://biorender.com/ for graphics.

Funding

Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India. Indian Council of Medical Research (ICMR), New Delhi, File No. 5/3/8/16/ITR-F/2019-ITR, for providing a research fellowship to Ms. Harpreet Kaur.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, 382355, India

    Harpreet Kaur, Deepaneeta Sarmah, Aishika Datta & Pallab Bhattacharya

  2. Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, 788011, Assam, India

    Anupom Borah

  3. Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA

    Dileep R. Yavagal

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  1. Harpreet Kaur
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  2. Deepaneeta Sarmah
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Kaur, H., Sarmah, D., Datta, A. et al. Stem cells alleviate OGD/R mediated stress response in PC12 cells following a co-culture: modulation of the apoptotic cascade through BDNF-TrkB signaling. Cell Stress and Chaperones 28, 1041–1051 (2023). https://doi.org/10.1007/s12192-022-01319-4

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