SIRT3 Enhances Mesenchymal Stem Cell Longevity and Differentiation

Abstract

Mesenchymal stem cells (MSCs) are multipotent cells that are currently being investigated in a wide variety of clinical trials for their anti-inflammatory and immunomodulatory properties as well as their osteogenic and chondrogenic capabilities. However, there are considerable interdonor variability and heterogeneity of MSC populations, making it challenging to compare different products. Furthermore, proliferation, differentiation, and immunomodulation of MSCs decrease with aging and ex vivo expansion. The sirtuins have emerged as a class of protein deacylases involved in aging, oxidative stress, and metabolism. Sirtuin 3 (SIRT3) is the major mitochondrial deacetylase involved in reducing oxidative stress while preserving oxidative metabolism, and its levels have been shown to decrease with age. This study investigated the role of SIRT3 in MSC differentiation and aging. As MSCs were expanded ex vivo, SIRT3 levels decreased. In addition, SIRT3 depletion reduced MSC differentiation into adipocytes and osteoblasts. Furthermore, overexpression of SIRT3 in later-passage MSCs reduced aging-related senescence, reduced oxidative stress, and enhanced their ability to differentiate. These data suggest that overexpressing SIRT3 might represent a strategy to increase the quality and quantity of MSCs utilized for clinical applications.

Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges

“…119 Not only does MSC senescence in vitro correlate with diminished function, but it may also explain why MSCs from older donors are less effective for in vitro immunopotency assays. 120 A possible candidate to reverse MSC age-related senescence is SIRT3. SIRT3 expression is reduced upon MSC expansion.…”

“…Increasing SIRT3 expression reverses this decline and improves MSC longevity and differentiation capacity. 120 Does the age of the recipient limit the response to cell therapy? 83,121,122 In the Transendocardial Autologous Cells in Ischemic Heart Failure Trial (TAC-HFT) and POSEIDON trial, older patients with chronic ischemic cardiomyopathy (ICM) were administered allogeneic or autologous MSCs via a transendocardial route.…”

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

“…Sirt3 (the principal mitochondrial deacetylase involved in reducing oxidative stress) expression level plays an essential role in delaying MSC cellular senescence, as it is involved in mitochondrial homeostasis maintenance and oxidative stress regulation [163]. Sirt3 decreases during MSC expansion in vitro and, conversely, its overexpression in late passage MSCs reduces senescence, oxidative stress, and enhances differentiation ability [164]. Severe oxidative stress reduces Sirt3 levels in young human MSCs and, conversely, Sirt3 overexpression, by activating MnSOD and catalase (CAT), protects human MSCs from apoptosis under stress.…”

Roles of Mitochondrial Sirtuins in Mitochondrial Function, Redox Homeostasis, Insulin Resistance and Type 2 Diabetes

“…Replicative senescence decreases the SIRT3 level and impairs the capacity of adipogenesis and osteogenesis in human bone marrow-derived stem cells. Moreover, restoration of the SIRT3 level not only rescues the senescence phenotype and reduces the intracellular levels of ROS but also improves the differentiation potential of senescent stem cells [54]. Myocytes and adipocytes are the two major cell types involved in the regulation of whole-body metabolism of glucose and lipids, and their dysfunction contributes to the pathogenesis of insulin resistance and type 2 diabetes.…”