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Sirtuin-1 - Mediated NF-κB Pathway Modulation to Mitigate Inflammasome Signaling and Cellular Apoptosis is One of the Neuroprotective Effects of Intra-arterial Mesenchymal Stem Cell Therapy Following Ischemic Stroke

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Abstract

Aim

Stroke results in long term serious disability that affect millions across the globe. Several clinical and preclinical studies have reinforced the therapeutic use of stem cells in stroke patients to enhance their quality of life. Previous studies from our lab have demonstrated that 1*105 allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) when given intraarterially (IA) render neuroprotection by modulating the expression of inflammasomes. Sirtuins are a class of important deacylases having a significant role in cellular functioning. Sirtuin-1 (SIRT-1) is an important enzyme essential for regulating cellular metabolism, which is reduced following an ischemic episode. The present study aims to unviel the role of MSCs in regulating the brain SIRT-1 levels following stroke and the involvement of SIRT-1 in regulating inflammasome signaling to reduce cellular apoptosis towards rendering neuroprotection.

Materials and Methods

6 h post-reversible middle cerebral artery occlusion (MCAo), ovariectomized Sprague Dawley (SD) rats were infused intraarterially with 1*105 MSCs. 24 h after MCAo animals were examined for functional and behavioral outcomes. Brains were collected for assessing size of infarct and neuronal morphology. Molecular and immunofluroscence studies were also performed for assessing changes in gene and protein expressions. Extent of apoptosis was also determined in different groups. Inhibition study with SIRT-1 specific inhibitor EX-527 was also performed.

Results

A reduction in infarct size and improvement in motor functional and behavioral outcomes following infusion of MSCs IA at 6 h post-stroke was observed. Increase in average neuronal density and neuronal length was also seen. Increased expression of SIRT-1, BDNF and concomitant reduction in the expression of different inflammatory and apoptotic markers in the brain cortical regions were observed following MSCs treatment.

Conclusion

Our study provides a preliminary evidence that post-stroke IA MSCs therapy regulates SIRT-1 to modulate NF-κB pathway to mitigate inflammasome signaling and cellular apoptosis. This study using IA approach for administering MSCs is highly relevant clinically. Our study is the first to report that neuroprotective effects of IA MSCs in rodent focal ischemia is mediated by SIRT-1 regulation of inflammasome signaling.

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Data Availability

Available upon reasonable request from the corresponding author.

Code Availability

NA.

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Acknowledgements

Authors acknowledge Ms. Monika Seervi for her help in performing confocal microscopy, Mr. Vishal Gupta and Mr. Pramod Suthar for their assistance during surgery and post-operative animal care and Dr. Shirish Bhatiya, NIPER-A veterinarian, for taking care of animal housing and animal health.

Funding

Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India; National Institute of Pharmaceutical Education and Research (NIPER) -Ahmedabad; Indo French Centre for Promotion of Advanced Research (IFCPAR/CEFIPRA) for Raman Charpak Fellowship 2018 (IFC/4122/RCF 2018/1356) to Ms. Deepaneeta Sarmah; Indian Council of Medical Research, India for Senior research fellowships to Ms. Aishika Datta (45/13/2020-PHA/BMS) and Ms. Harpreet Kaur (5/3/8/16/ITR-F/2019-ITR) and Nanobio project grant to Dr. Pallab Bhattacharya (34/5/2019-TF/Nano/BMS).

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Authors and Affiliations

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

    Deepaneeta Sarmah, Aishika Datta, Harpreet Kaur, Kiran Kalia & Pallab Bhattacharya

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

    Anupom Borah

  3. Université Paris-Est Créteil, INSERM, IMRB, 94010, Créteil, France

    Anne Marie Rodriguez

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

    Dileep R. Yavagal

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  1. Deepaneeta Sarmah
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Contributions

Conception and design of the study: PB. Acquisition of data: DS, AD and HK. Analysis and interpretation of data: DS, AD, KK, AB, AMR, DY and PB. Drafting and revision of the manuscript: DS, KK, AB, AMR, DY and PB. All authors have approved the final manuscript.

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Correspondence to Pallab Bhattacharya.

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Sarmah, D., Datta, A., Kaur, H. et al. Sirtuin-1 - Mediated NF-κB Pathway Modulation to Mitigate Inflammasome Signaling and Cellular Apoptosis is One of the Neuroprotective Effects of Intra-arterial Mesenchymal Stem Cell Therapy Following Ischemic Stroke. Stem Cell Rev and Rep 18, 821–838 (2022). https://doi.org/10.1007/s12015-021-10315-7

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  • DOI: https://doi.org/10.1007/s12015-021-10315-7

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