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

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
Article number115252
Journalbone
Volume133
ISSN8756-3282
DOIs
Publication statusPublished - Apr 2020

Keywords

  • Adipogenesis
  • Antioxidant
  • Bone marrow adiposity
  • Bone marrow skeletal stromal cells
  • Cellular senescence
  • Osteogenesis

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