Metabolic Syndrome Impairs 3D Mitochondrial Structure, Dynamics, and Function in Swine Mesenchymal Stem Cells

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Metabolic Syndrome Impairs 3D Mitochondrial Structure, Dynamics, and Function in Swine Mesenchymal Stem Cells Rahele A. Farahani 1 & Mohamed C. Farah 1 & Xiang-Yang Zhu 1 & Hui Tang 1 & Ishran M. Saadiq 1 & Lilach O. Lerman 1 & Alfonso Eirin 1

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract Transplantation of autologous mesenchymal stem cells (MSCs) is an effective therapy for several diseases. Mitochondria modulate several important aspects of MSC function, but might be damaged by comorbidities and cardiovascular risk factors. We hypothesized that metabolic syndrome (MetS) compromises 3D mitochondrial structure, dynamics, and function in swine adipose tissue-derived MSCs. Domestic pigs were fed a Lean or MetS diet (n = 6 each) for 16 weeks. MSCs were collected from subcutaneous abdominal fat and their mitochondria analyzed using state-of-the-art Serial Block Face Electron Microscopy and 3D reconstruction. Mitochondrial dynamics (fusion/fission) were assessed by mRNA sequencing and Western blotting, and bioenergetics by membrane potential (TMRE), cytochrome-c oxidase (COX)-IV activity, and Seahorse Analyzer. Expression of mitochondria-associated microRNAs (mitomiRs) was measured by quantitative polymerase chain reaction (qPCR). MetS pigs developed obesity, hypertension, insulin resistance, and hyperlipidemia. Mitochondrial density was similar between the groups, but 3D mitochondrial and matrix volumes were lower in MetS-MSCs versus Lean-MSCs. Mitochondrial fission was higher, but fusion lower in MetS-MSCs versus Lean-MSCs, as were membrane potential, COX-IV activity, and ATP production. Contrarily, expression of the mitomiRs miR15a, miR-137, and miR-181c, which target mitochondrial genes that support mitochondrial structure, energy pathways, and dynamics, was higher in MetS-MSCs compared to Lean-MSCs, suggesting a potential to modulate their expression. MetS damages MSC 3D mitochondrial structure, dynamics, and function, and may modulate genes encoding for mitochondrial proteins. These observations support development of mitoprotective strategies to preserve the regenerative potency of MSCs and their suitability for autologous transplantation in patients with MetS. Keywords Mesenchymal stem cells . Metabolic syndrome . Mitochondria . microRNAs . Mitochondrial dynamics

Introduction Mesenchymal stem/stromal cells (MSCs) are undifferentiated non-embryonic stem cells present in adult tissues, which possess important self-renewal capacity, multi-lineage differentiation, immunomodulatory properties, and potential for tissue repair [1]. These cells can be easily isolated from different sources, including adipose tissue, which makes them an ideal Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12015-020-09988-3) contains supplementary material, which is available to authorized users. * Alfonso Eirin [email protected] 1

Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochest