Abstract
Mesenchymal stem cells (MSCs) are multi-potent cells that can differentiate into osteoblasts, adipocytes, chondrocytes and myocytes. This potential declines with aging. We investigated whether the sirtuin SIRT1 had a function in MSCs by creating MSC specific SIRT1 knock-out (MSCKO) mice. Aged MSCKO mice (2.2 years old) showed defects in tissues derived from MSCs; i.e. a reduction in subcutaneous fat, cortical bone thickness and trabecular volume. Young mice showed related but less pronounced effects. MSCs isolated from MSCKO mice showed reduced differentiation towards osteoblasts and chondrocytes in vitro, but no difference in proliferation or apoptosis. Expression of β-catenin targets important for differentiation was reduced in MSCKO cells. Moreover, while β-catenin itself (T41A mutant resistant to cytosolic turnover) accumulated in the nuclei of wild-type MSCs, it was unable to do so in MSCKO cells. However, mutating K49R or K345R in β-catenin to mimic deacetylation restored nuclear localization and differentiation potential in MSCKO cells. We conclude that SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus leading to transcription of genes for MSC differentiation.
Highlights
Mesenchymal stem cells (MSCs) are multipotent cells that can be isolated from bone marrow, can proliferate in vitro with fibroblast-like morphology, and can be induced to differentiate into a variety of mesenchymal tissues, including bone, cartilage, tendon, fat, bone marrow stroma and muscle (Pittenger et al, 1999; Prockop, 1997; Uccelli et al, 2008)
Phenotypes of MSCKO mice To test the role of SIRT1 in mesenchymal progenitor cells we generated MSC specific SIRT1 knock-out (MSCKO) mice by crossing mice with cre recombinase expression driven by the Prx-1 promoter (Logan et al, 2002) with SIRT1 floxed exon 4 mice (Cheng et al, 2003; Fig 1A)
Several studies suggest an effect of SIRT1 on promoting osteogenesis and decreasing adipogenesis of MSCs (Backesjoet al, 2006; Li et al, 2011; Peltz et al, 2012; Puri et al, 2012; Tseng et al, 2011)
Summary
Mesenchymal stem cells (MSCs) are multipotent cells that can be isolated from bone marrow, can proliferate in vitro with fibroblast-like morphology, and can be induced to differentiate into a variety of mesenchymal tissues, including bone, cartilage, tendon, fat, bone marrow stroma and muscle (Pittenger et al, 1999; Prockop, 1997; Uccelli et al, 2008). Osteogenic, adipogenic, chondrogenic and myogenic potential is compromised in MSCs of aged rats (Asumda & Chase, 2011). The number of MSCs with osteogenic, chondrogenic and adipocyte potential has been reported to decline in aging potentially contributing to age-related osteoporosis, osteoarthritis and loss of sub-cutaneous fat (Cartwright et al, 2007; Chang et al, 2011; D’Ippolito et al, 1999). Aging compromises the efficacy of MSC differentiation to myocytes and regeneration of damaged myocardial tissue (Asumda & Chase, 2011; Khan et al, 2011), leading to muscle wasting and increased frailty (Goldspink, 2012). Aging causes an inappropriate shift of MSC commitment in bone from the osteoblast to the adipocyte lineage (Moerman et al, 2004), resulting in an increase in bone marrow adipogenesis (Jiang et al, 2008)
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