Dysregulated lineage commitment of mesenchymal stem cells(MSCs)contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis.The intrinsic cellula...Dysregulated lineage commitment of mesenchymal stem cells(MSCs)contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis.The intrinsic cellular mechanism that regulates MSC commitment remains unclear.Here,we identified Cullin 4B(CUL4B)as a critical regulator of MSC commitment.CUL4B is expressed in bone marrow MSCs(BMSCs)and downregulated with aging in mice and humans.Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation.Moreover,depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy.In addition,CUL4B deficiency in MSCs reduced bone strength.Mechanistically,CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδexpression,respectively.The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription.Collectively,this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs,which has therapeutic implications in osteoporosis.展开更多
There is a lack of understanding of both the conversion of an unstable glass into a metastable supercooled liquid(MSL) upon heating and the metastability of MSLs. In this study, we investigated the time-and temperatur...There is a lack of understanding of both the conversion of an unstable glass into a metastable supercooled liquid(MSL) upon heating and the metastability of MSLs. In this study, we investigated the time-and temperature-dependent metastability of an MSL using an advanced nano-calorimetric technique. The chosen Au-based metallic glass(Au MG) allowed adequate probing of its MSL in a temperature range between 10 and 70 K above the standard glass transition temperature. We found that the survival time of the MSL state is a quadratic function of temperature. Beyond this duration threshold, the sample undergoes fast crystallization even if it is below the crystallization temperature that is measured using differential scanning calorimetry.Employing transmission electron microscopy, we observed the formation of clusters with a partially ordered lattice structure during relaxation in the Au MG sample fabricated using a nano-calorimeter. The atomic ordering within the clusters was enhanced by increasing time and temperature in the MSL region. Once the as-produced glass entered the MSL stage upon heating followed by a quenching stage at a given rate, the mechanical properties of the quenched glass remained the same regardless of its holding temperature and duration within the MSL region. This work provides insights into the glass-MSL-crystal transformation and offers guidance for designing standard metallic glasses for property characterizations.展开更多
基金supported by grants from the National Key R&D Program of China(2022YFC2703700,2022YFC2703701 to Y.G.and 2022YFC2703700,2022YFC2703703 to G.S.)National Natural Science Foundation of China(31872810,82171851 to Y.G.+3 种基金31970559 to B.J.31970781 to G.S.)Key Research and Development Program of Shandong Province(2016GSF201143 to B.J.)Young Scholars Program of Shandong University(to B.J.)。
文摘Dysregulated lineage commitment of mesenchymal stem cells(MSCs)contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis.The intrinsic cellular mechanism that regulates MSC commitment remains unclear.Here,we identified Cullin 4B(CUL4B)as a critical regulator of MSC commitment.CUL4B is expressed in bone marrow MSCs(BMSCs)and downregulated with aging in mice and humans.Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation.Moreover,depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy.In addition,CUL4B deficiency in MSCs reduced bone strength.Mechanistically,CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδexpression,respectively.The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription.Collectively,this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs,which has therapeutic implications in osteoporosis.
基金supported by the Songshan Lake Materials Laboratory (Grant No. 2021SLABFN05)the National Natural Science Foundation of China (Grant Nos. 51971120, 51901139)+2 种基金the Taishan Scholars Program of Shandong Province (Grant No. tsqn201909010)the Key Basic and Applied Research Program of Guangdong Province(Grant No. 2019B030302010)the Sao Paulo Research Foundation–FAPESP (Grant No.#2013/07793-6)。
文摘There is a lack of understanding of both the conversion of an unstable glass into a metastable supercooled liquid(MSL) upon heating and the metastability of MSLs. In this study, we investigated the time-and temperature-dependent metastability of an MSL using an advanced nano-calorimetric technique. The chosen Au-based metallic glass(Au MG) allowed adequate probing of its MSL in a temperature range between 10 and 70 K above the standard glass transition temperature. We found that the survival time of the MSL state is a quadratic function of temperature. Beyond this duration threshold, the sample undergoes fast crystallization even if it is below the crystallization temperature that is measured using differential scanning calorimetry.Employing transmission electron microscopy, we observed the formation of clusters with a partially ordered lattice structure during relaxation in the Au MG sample fabricated using a nano-calorimeter. The atomic ordering within the clusters was enhanced by increasing time and temperature in the MSL region. Once the as-produced glass entered the MSL stage upon heating followed by a quenching stage at a given rate, the mechanical properties of the quenched glass remained the same regardless of its holding temperature and duration within the MSL region. This work provides insights into the glass-MSL-crystal transformation and offers guidance for designing standard metallic glasses for property characterizations.
