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Oxidative Stress Enhances Autophagy-Mediated Death Of Stem Cells Through Erk1/2 Signaling Pathway – Implications For Neurotransplantations

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Abstract

Stem cell therapies are becoming increasingly popular solutions for neurological disorders. However, there is a lower survival rate of these cells after transplantation. Oxidative stress is linked to brain damage, and it may also impact transplanted stem cells. To better understand how transplanted cells respond to oxidative stress, the current study used H2O2. We briefly illustrated that exogenous H2O2 treatment exaggerated oxidative stress in the human dental pulp and mesenchymal stem cells. 2′,7′-Dichlorofluorescin diacetate (DCFDA), MitoSOX confirms the reactive oxygen species (ROS) involvement, which was remarkably subsided by the ROS inhibitors. The findings showed that H2O2 activates autophagy by enhancing pro-autophagic proteins, Beclin1 and Atg7. Increased LC3II/I expression (which co-localized with lysosomal proteins, LAMP1 and Cathepsin B) showed that H2O2 treatment promoted autophagolysosome formation. In the results, both Beclin1 and Atg7 were observed co-localized in mitochondria, indicating their involvement in mitophagy. The evaluation of Erk1/2 in the presence and absence of Na-Pyruvate, PEG-Catalase, and PD98059 established ROS-Erk1/2 participation in autophagy regulation. Further, these findings showed a link between apoptosis and autophagy. The results conclude that H2O2 acts as a stressor, promoting autophagy and mitophagy in stem cells under oxidative stress. The current study may help understand better cell survival and death approaches for transplanted cells in various neurological diseases.

Graphical abstract

The current study uses human Dental Pulp and Mesenchymal Stem cells to demonstrate the importance of H2O2-driven autophagy in deciding the fate of these cells in an oxidative microenvironment. To summarise, we discovered that exogenous H2O2 treatment causes oxidative stress. Exogenous H2O2  treatment also increased ROS production, especially intracellular H2O2. H2O2 stimulated the ErK1/2 signaling pathway and autophagy. Erk1/2 was found to cause autophagy. Further, the function of mitophagy appeared to be an important factor in the H2O2-induced regulation of these two human stem cell types. In a nutshell, by engaging in autophagy nucleation, maturation, and terminal phase proteins, we elucidated the participation of autophagy in cell dysfunction and death.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

No funding was received—some chemicals from DST-SERB Grant India, Grant no. YSS/2015//1731 were utilized in this project.

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Authors and Affiliations

  1. Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era’s Lucknow Medical College Hospital, Era University, Sarfarazganj, Lucknow, 226003, India

    Ravi Prakash, Eram Fauzia, Abu Junaid Siddiqui, Santosh Kumar Yadav, Neha Kumari & Syed Shadab Raza

  2. Department of Pathology, King George’s Medical University, Lucknow, 226020, India

    Atin Singhai

  3. Era University, Lucknow, 226003, India

    Mohsin Ali Khan

  4. Center for Advanced Imaging Research, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, University of Maryland Baltimore, Baltimore, MD, 21201-1595, USA

    Miroslaw Janowski

  5. Department of Life Science, National Institute of Technology, Rourkela, 769008, India

    Sujit Kumar Bhutia

  6. Department of Stem Cell Biology and Regenerative Medicine, Era University, Lucknow, 14 226003, India

    Syed Shadab Raza

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  1. Ravi Prakash
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All authors contributed to this work in collaboration with SSR. SSR: conceptualized, designed, and supervision.

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Correspondence to Syed Shadab Raza.

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Ravi Prakash and Eram Fauzia shared equal first authorship

Abu Junaid Siddiqui and Santosh Kumar Yadav shared equal second authorship

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Prakash, R., Fauzia, E., Siddiqui, A.J. et al. Oxidative Stress Enhances Autophagy-Mediated Death Of Stem Cells Through Erk1/2 Signaling Pathway – Implications For Neurotransplantations. Stem Cell Rev and Rep 17, 2347–2358 (2021). https://doi.org/10.1007/s12015-021-10212-z

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