Resveratrol counteracts bone loss via mitofilin-mediated osteogenic improvement of mesenchymal stem cells in senescence-accelerated mice

Abstract

Rational: Senescence of mesenchymal stem cells (MSCs) and the related functional decline of osteogenesis have emerged as the critical pathogenesis of osteoporosis in aging. Resveratrol (RESV), a small molecular compound that safely mimics the effects of dietary restriction, has been well documented to extend lifespan in lower organisms and improve health in aging rodents. However, whether RESV promotes function of senescent stem cells in alleviating age-related phenotypes remains largely unknown. Here, we intend to investigate whether RESV counteracts senescence-associated bone loss via osteogenic improvement of MSCs and the underlying mechanism.Methods: MSCs derived from bone marrow (BMMSCs) and the bone-specific, senescence-accelerated, osteoblastogenesis/osteogenesis-defective mice (the SAMP6 strain) were used as experimental models. In vivo application of RESV was performed at 100 mg/kg intraperitoneally once every other day for 2 months, and in vitro application of RESV was performed at 10 μM. Bone mass, bone formation rates and osteogenic differentiation of BMMSCs were primarily evaluated. Metabolic statuses of BMMSCs and the mitochondrial activity, transcription and morphology were also examined. Mitofilin expression was assessed at both mRNA and protein levels, and short hairpin RNA (shRNA)-based gene knockdown was applied for mechanistic experiments.Results: Chronic intermittent application of RESV enhances bone formation and counteracts accelerated bone loss, with RESV improving osteogenic differentiation of senescent BMMSCs. Furthermore, in rescuing osteogenic decline under BMMSC senescence, RESV restores cellular metabolism through mitochondrial functional recovery via facilitating mitochondrial autonomous gene transcription. Molecularly, in alleviating senescence-associated mitochondrial disorders of BMMSCs, particularly the mitochondrial morphological alterations, RESV upregulates Mitofilin, also known as inner membrane protein of mitochondria (Immt) or Mic60, which is the core component of the mitochondrial contact site and cristae organizing system (MICOS). Moreover, Mitofilin is revealed to be indispensable for mitochondrial homeostasis and osteogenesis of BMMSCs, and that insufficiency of Mitofilin leads to BMMSC senescence and bone loss. More importantly, Mitofilin mediates resveratrol-induced mitochondrial and osteogenic improvements of BMMSCs in senescence.Conclusion: Our findings uncover osteogenic functional improvements of senescent MSCs as critical impacts in anti-osteoporotic practice of RESV, and unravel Mitofilin as a novel mechanism mediating RESV promotion on mitochondrial function in stem cell senescence.

Osteogenesis and aging: lessons from mesenchymal stem cells

“…Activation of autophagy by rapamycin can restore bone loss in aged mice and osteogenesis of MSCs possibly by regulating ROS levels [ 40 ]. Resveratrol, a polyphenolic compound found in red wine, has been found to promote in vivo bone formation and counteract bone loss in SAMP6 mice, a premature aging mouse model, and in naturally aging mice as well [ 56 ]. Moreover, resveratrol treatment in vitro rescued the osteogenic decline of MSCs from the aged mice mentioned above.…”

NDRG2 suppression as a molecular hallmark of photoreceptor-specific cell death in the mouse retina

“…Total intracellular ROS contents were measured using the fluorescent probe Dichlorodihydrofluorescein Diacetate (DCFH) 75 . Briefly, 25-mM DCFH was added to cells at indicated time points, and was incubated for an additional 30 min at 37 ℃.…”

Resveratrol improves human umbilical cord-derived mesenchymal stem cells repair for cisplatin-induced acute kidney injury

“…Res, a natural small-molecule compound, is a phytophenol with multifarious properties and possesses therapeutic activities in various diseases 31 – 33 . Res generally acknowledged as anti-aging or stem cell-protection substances, which promoted MSCs proliferation, maintained differentiation potential of MSCs, and delayed MSCs senescence 34 , 35 . Co-administration of Res and MSCs could augment therapeutic efficiency of MSCs in autoimmune encephalomyelitis 36 and cardiomyopathy 37 , suggesting improving effects of Res infusion on MSCs-based therapy.…”