Resveratrol inhibits adipocyte differentiation and cellular senescence of human bone marrow stromal stem cells

Dalia Ali; Li Chen; Justyna M Kowal; Meshail Okla; Muthurangan Manikandan; Moayad AlShehri; Yousef AlMana; Reham AlObaidan; Najd AlOtaibi; Rimi Hamam; Nehad M Alajez; Abdullah Aldahmash; Moustapha Kassem; Musaad Alfayez

doi:10.1016/j.bone.2020.115252

Resveratrol inhibits adipocyte differentiation and cellular senescence of human bone marrow stromal stem cells

Bone. 2020 Apr:133:115252. doi: 10.1016/j.bone.2020.115252. Epub 2020 Jan 21.

Authors

Dalia Ali¹, Li Chen², Justyna M Kowal³, Meshail Okla⁴, Muthurangan Manikandan⁵, Moayad AlShehri⁶, Yousef AlMana⁷, Reham AlObaidan⁸, Najd AlOtaibi⁹, Rimi Hamam¹⁰, Nehad M Alajez¹¹, Abdullah Aldahmash¹², Moustapha Kassem¹³, Musaad Alfayez¹⁴

Affiliations

¹ Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology & Metabolism, University Hospital of Odense and University of Southern Denmark, Odense, Denmark. Electronic address: dayesh@health.sdu.dk.
² Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology & Metabolism, University Hospital of Odense and University of Southern Denmark, Odense, Denmark. Electronic address: lchen@health.sdu.dk.
³ Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology & Metabolism, University Hospital of Odense and University of Southern Denmark, Odense, Denmark. Electronic address: jkowal@health.sdu.dk.
⁴ Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia. Electronic address: meokla@ksu.edu.sa.
⁵ Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: coralmani@gmail.com.
⁶ Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: moayadkhalid@gmail.com.
⁷ Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: yousef.almana@gmail.com.
⁸ Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: Re.alobaidan@gmail.com.
⁹ Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: najd.muneef@gmail.com.
¹⁰ Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: rimih@hotmail.com.
¹¹ Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: nalajez@gmail.com.
¹² Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Prince Naif Health Research Center, King Saud University, Riyadh, Saudi Arabia. Electronic address: dahmash@ksu.edu.sa.
¹³ Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology & Metabolism, University Hospital of Odense and University of Southern Denmark, Odense, Denmark; Department of Cellular and Molecular Medicine, Danish Stem Cell Center (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: mkassem@health.sdu.dk.
¹⁴ Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: alfayez@ksu.edu.sa.

PMID: 31978617
DOI: 10.1016/j.bone.2020.115252

Abstract

Bone marrow adipose tissue (BMAT) is a unique adipose depot originating from bone marrow stromal stem cells (BMSCs) and regulates bone homeostasis and energy metabolism. An increased BMAT volume is observed in several conditions e.g. obesity, type 2 diabetes, osteoporosis and is known to be associated with bone fragility and increased risk for fracture. Therapeutic approaches to decrease the accumulation of BMAT are clinically relevant. In a screening experiment of natural compounds, we identified Resveratrol (RSV), a plant-derived antioxidant mediating biological effects via sirtuin- related mechanisms, to exert significant effects of BMAT formation. Thus, we examined in details the effects RSV on adipocytic and osteoblastic differentiation of tolermerized human BMSCs (hBMSC-TERT). RSV (1.0 μM) enhanced osteoblastic differentiation and inhibited adipocytic differentiation of hBMSC-TERT when compared with control and Sirtinol (Sirtuin inhibitor). Global gene expression profiling and western blot analysis revealed activation of a number of signaling pathways including focal adhesion kinase (FAK). Pharmacological inhibition of FAK using (PF-573228) and AKT inhibitor (LY-294002) (5μM), diminished RSV-induced osteoblast differentiation. In addition, RSV reduced the levels of senescence-associated secretory phenotype (SASP), gene markers associated with senescence (P53, P16, and P21), intracellular ROS levels and increased gene expression of enzymes protecting cells from oxidative damage (HMOX1 and SOD3). In vitro treatment of primary hBMSCs from aged patients characterized with high adipocytic and low osteoblastic differentiation ability with RSV, significantly enhanced osteoblast and decreased adipocyte formation when compared to hBMSCs from young donors. RSV targets hBMSCs and inhibits adipogenic differentiation and senescence-associated phenotype and thus a potential agent for treating conditions of increased BMAT formation.

Keywords: Adipogenesis; Antioxidant; Bone marrow adiposity; Bone marrow skeletal stromal cells; Cellular senescence; Osteogenesis.

Publication types

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

MeSH terms

Adipocytes
Adipogenesis
Aged
Bone Marrow Cells
Cell Differentiation
Cellular Senescence
Diabetes Mellitus, Type 2*
Humans
Mesenchymal Stem Cells*
Osteoblasts
Osteogenesis
Resveratrol / pharmacology

Substances

Resveratrol