Impact of type 2 diabetes mellitus on the immunoregulatory characteristics of adipose tissue-derived mesenchymal stem cells

Nourhan Abu-Shahba; Marwa Mahmoud; Alaa Mohammed El-Erian; Mohamed Ibrahim Husseiny; Ghada Nour-Eldeen; Iman Helwa; Khalda Amr; Mahmoud ElHefnawi; Amel Ibrahim Othman; Sherif Abdelaziz Ibrahim; Osama Azmy

doi:10.1016/j.biocel.2021.106072

Impact of type 2 diabetes mellitus on the immunoregulatory characteristics of adipose tissue-derived mesenchymal stem cells

Int J Biochem Cell Biol. 2021 Nov:140:106072. doi: 10.1016/j.biocel.2021.106072. Epub 2021 Aug 26.

Authors

Affiliations

¹ Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, Cairo, Egypt; Department of Medical Molecular Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt. Electronic address: nm.diaa@nrc.sci.eg.
² Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, Cairo, Egypt; Department of Medical Molecular Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
³ Department of Endocrine Surgery, National Institute of Diabetes and Endocrinology, Cairo, Egypt.
⁴ Department of Translational Research and Cellular Therapeutics, Arthur Riggs DMRI, Beckman Research Institute, City of Hope, National Medical Center, Durate, CA, USA; Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
⁵ Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, Cairo, Egypt; Department of Molecular Genetics and Enzymology, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
⁶ Department of Immunogenetics, Human Genetics and Genome Research Division, National Resrearch Centre, Egypt.
⁷ Department of Medical Molecular Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
⁸ Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt.
⁹ Department of Zoology, Faculty of Science, Cairo University, 12613, Giza, Egypt.
¹⁰ Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, Cairo, Egypt; Department of Reproductive Health Research, Medical Research Division, National Research Centre, Cairo, Egypt; Egypt Center for Research and Regenerative Medicine, Cairo, Egypt.

PMID: 34455058
DOI: 10.1016/j.biocel.2021.106072

Abstract

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder associated with several complications. Adipose tissue-derived mesenchymal stem cells (AT-MSCs) represent an emerging type of MSCs with high plasticity and immunoregulatory capabilities and are useful for treating inflammation-related disorders such as T2DM. However, the pathogenic microenvironment of T2DM may affect their therapeutic potential. We aimed to examine the impact of the diabetic milieu on the immunomodulatory/anti-inflammatory potential of AT-MSCs.

Methods: We assessed the proliferation potential, cell surface expression of MSC-characteristic markers and immunomodulatory markers, along with the gene expression and protein secretion of pro-inflammatory and anti-inflammatory cytokines and adipokines in AT-MSCs derived from T2DM patients (dAT-MSCs) vs. those derived from non-diabetic volunteers (ndAT-MSCs). Furthermore, we evaluated the IFN-γ priming effect on both groups.

Results: Our data revealed comparable proliferative activities in both groups. Flow cytometric analysis results showed a lower expression of CD200 and CD276 on dAT-MSCs vs. ndAT-MSCs. qPCR demonstrated upregulation of IL-1β associated with a downregulation of IL-1RN in dAT-MSCs vs. ndAT-MSCs. IFN-γ priming induced an elevation in CD274 expression associated with IDO1 and ILRN overexpression and IL-1β downregulation in both groups. ELISA analysis uncovered elevated levels of secreted IL-1β, TNF, and visfatin/NAMPT in dAT-MSCs, whereas IL-1RA and IDO levels were reduced. ELISA results were also evident in the secretome of dAT-MSCs upon IFN-γ priming.

Conclusions: This study suggests that the T2DM milieu alters the immunomodulatory characteristics of AT-MSCs with a shift towards a proinflammatory phenotype which may restrain their autologous therapeutic use. Furthermore, our findings indicate that IFN-γ priming could be a useful strategy for enhancing dAT-MSC anti-inflammatory potential.

Keywords: Adipose tissue-derived mesenchymal stem cells; IFN-γ priming; Immunomodulatory/anti-inflammatory potential; Interleukin-1 beta; Type 2 diabetes mellitus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus, Type 2*
Immunomodulation
Interferon-gamma
Mesenchymal Stem Cell Transplantation
Mesenchymal Stem Cells
Secretome

Substances

Interferon-gamma