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A comparative study on the cellular stressors in mesenchymal stem cells (MSCs) and pancreatic β-cells under hyperglycemic milieu

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Abstract

β-cell dysfunction is a critical determinant for both type 1 diabetes and type 2 diabetes and β-cells are shown to be highly susceptible to cellular stressors. Mesenchymal stem cells (MSCs) on the other hand are known to have immunomodulatory potential and preferred in clinical applications. However, there is paucity of a comparative study on these cells in relation to several cellular stressors in response to hyperglycemia and this forms the rationale for the present study. INS1 β-cells and MSCs were subjected to high-glucose treatment without and with Metformin, Lactoferrin, or TUDCA and assessed for stress signaling alterations using gene expression, protein expression, as well as functional read-outs. Compared to the untreated control cells, INS1 β-cells or MSCs treated with high glucose showed significant increase in mRNA expressions of ER stress, senescence, and proinflammation. This was accompanied by increased miR146a target genes and decreased levels of SIRT1, NRF2, and miR146a in both the cell types. Consistent with the mRNA results, protein expression levels do reflect the same alterations. Notably, the alterations are relatively less extent in MSCs compared to INS1 β-cells. Interestingly, three different agents, viz., Metformin, Lactoferrin, or TUDCA, were found to overcome the high glucose-induced cellular stresses in a concerted and inter-linked way and restored the proliferation and migration capacity in MSCs as well as normalized the glucose-stimulated insulin secretion in INS1 β-cells. While our study gives a directionality for potential supplementation of metformin/lactoferrin/TUDCA in optimization protocols of MSCs, we suggest that in vitro preconditioning of MSCs with such factors should be further explored with in-depth investigations to harness and enhance the therapeutic capacity/potential of MSCs.

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Acknowledgements

The authors acknowledge partial grant support from the Indian Council of Medical Research (ICMR), Govt. of India. Srividhya Raghavan acknowledges the Council of Scientific & Industrial Research (CSIR), New Delhi, India for her financial assistance as Senior Research Fellowship. The work is part of the PhD topic of Srividhya Raghavan from the Madras Diabetes Research Foundation––which is affiliated to the University of Madras for PhD curriculum.

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  1. Department of Cell and Molecular Biology, Dr. Mohan’s Diabetes Specialties Centre, ICMR- Centre for Advanced Research On Diabetes, Madras Diabetes Research Foundation, Gopalapuram, Chennai, 600 086, India

    Srividhya Raghavan, Sarubala Malayaperumal, Viswanathan Mohan & Muthuswamy Balasubramanyam

  2. Medical and Health Sciences (MHS), SRM Institute of Science and Technology (SRMIST), SRM Nagar, Kattankulathur, Kanchipuram, Chennai, 603 203, India

    Muthuswamy Balasubramanyam

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Raghavan, S., Malayaperumal, S., Mohan, V. et al. A comparative study on the cellular stressors in mesenchymal stem cells (MSCs) and pancreatic β-cells under hyperglycemic milieu. Mol Cell Biochem 476, 457–469 (2021). https://doi.org/10.1007/s11010-020-03922-4

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