Tendon heterotopic ossification(HO)is characterized by bone formation inside tendon tissue,which severely debilitates people in their daily life.Current therapies fail to promote functional tissue repair largely due t...Tendon heterotopic ossification(HO)is characterized by bone formation inside tendon tissue,which severely debilitates people in their daily life.Current therapies fail to promote functional tissue repair largely due to our limited understanding of HO pathogenesis.Here,we investigate the pathological mechanism and propose a potential treatment method for HO.Immunofluorescence assays showed that the Mohawk(MKX)expression level was decreased in human tendon HO tissue,coinciding with spontaneous HO and the upregulated expression of osteochondrogenic and angiogenic genes in the tendons of Mkx^(−/−)mice.Single-cell RNA sequencing analyses of wild-type and Mkx^(−/−)tendons identified three cell types and revealed the excessive activation of osteochondrogenic genes during the tenogenesis of Mkx^(−/−)tendon cells.Single-cell analysis revealed that the gene expression program of angiogenesis,which is strongly associated with bone formation,was activated in all cell types during HO.Moreover,inhibition of angiogenesis by the small-molecule inhibitor BIBF1120 attenuated bone formation and angiogenesis in the Achilles tendons of both Mkx mutant mice and a rat traumatic model of HO.These findings provide new insights into the cellular mechanisms of tendon HO and highlight the inhibition of angiogenesis with BIBF1120 as a potential treatment strategy for HO.展开更多
Articular cartilage damage is a universal health problem.Despite recent progress,chondrocyte dedifferentiation has severely compromised the clinical outcomes of cell-based cartilage regeneration.Loss-of-function chang...Articular cartilage damage is a universal health problem.Despite recent progress,chondrocyte dedifferentiation has severely compromised the clinical outcomes of cell-based cartilage regeneration.Loss-of-function changes are frequently observed in chondrocyte expansion and other pathological conditions,but the characteristics and intermediate molecular mechanisms remain unclear.In this study,we demonstrate a time-lapse atlas of chondrocyte dedifferentiation to provide molecular details and informative biomarkers associated with clinical chondrocyte evaluation.We performed various assays,such as single-cell RNA sequencing(scRNA-seq),live-cell metabolic assays,and assays for transposase-accessible chromatin with high-throughput sequencing(ATAC-seq),to develop a biphasic dedifferentiation model consisting of early and late dedifferentiation stages.Early-stage chondrocytes exhibited a glycolytic phenotype with increased expression of genes involved in metabolism and antioxidation,whereas late-stage chondrocytes exhibited ultrastructural changes involving mitochondrial damage and stress-associated chromatin remodeling.Using the chemical inhibitor BTB06584,we revealed that early and late dedifferentiated chondrocytes possessed distinct recovery potentials from functional phenotype loss.Notably,this two-stage transition was also validated in human chondrocytes.An image-based approach was established for clinical use to efficiently predict chondrocyte plasticity using stage-specific biomarkers.Overall,this study lays a foundation to improve the quality of chondrocytes in clinical use and provides deep insights into chondrocyte dedifferentiation.展开更多
Although human-induced pluripotent stem cell-derived cardiomyocytes(hi PSC-CMs) have been used for disease modeling and drug discovery, clinically relevant three-dimensional(3D) functional myocardial microtissues are ...Although human-induced pluripotent stem cell-derived cardiomyocytes(hi PSC-CMs) have been used for disease modeling and drug discovery, clinically relevant three-dimensional(3D) functional myocardial microtissues are lacking. Here, we developed a novel ring-shaped cardiac microtissue comprised of chamber-specific tissues to achieve a geometrically non-orientable ventricular myocardial band, similar to a M?bius loop. The ring-shaped cardiac tissue was constructed of hi PSC-CMs and human cardiac fibroblasts(h CFs) through a facile cellular self-assembly approach. It exhibited basic anatomical structure,positive cardiac troponin T(c Tn T) immunostaining, regular calcium transients, and cardiac-like mechanical strength. The cardiac rings can be self-assembled and scaled up into various sizes with outstanding stability, suggesting their potential for precise therapy, pathophysiological investigation, and large-scale drug screening.展开更多
Autologous mosaicplasty is a common approach used to treat osteochondral defects in clinical practice.Gap integration between host and transplanted plugs requires bone tissue reservation and hyaline cartilage regenera...Autologous mosaicplasty is a common approach used to treat osteochondral defects in clinical practice.Gap integration between host and transplanted plugs requires bone tissue reservation and hyaline cartilage regeneration without uneven surface,graft necrosis and sclerosis.However,poor gap integration is a serious concern,which eventually leads to deterioration of joint function.To deal with such complications,this study has developed a strategy to effectively enhance integration of the gap region following mosaicplasty by applying injectable bioactive supramolecular nanofiber-enabled gelatin methacryloyl(GelMA)hydrogel(BSN-GelMA).A rabbit osteochondral defect model demonstrated that BSN-GelMA achieved seamless osteochondral healing in the gap region between plugs of osteochondral defects following mosaicplasty,as early as six weeks.Moreover,the International Cartilage Repair Society score,histology score,glycosaminoglycan content,subchondral bone volume,and collagen II expression were observed to be the highest in the gap region of BSN-GelMA treated group.This improved outcome was due to bio-interactive materials,which acted as tissue fillers to bridge the gap,prevent cartilage degeneration,and promote graft survival and migration of bone marrow mesenchymal stem cells by releasing bioactive supramolecular nanofibers from the GelMA hydrogel.This study provides a powerful and applicable approach to improve gap integration after autologous mosaicplasty.It is also a promising off-the-shelf bioactive material for cell-free in situ tissue regeneration.展开更多
Dear Editor,Age-dependent adipose tissue malfunction raises the risk of diseases like diabetes,cardiovascular disease,and even cancer by contributing to metabolic decline,heterotopic fat storage,and chronic systemic i...Dear Editor,Age-dependent adipose tissue malfunction raises the risk of diseases like diabetes,cardiovascular disease,and even cancer by contributing to metabolic decline,heterotopic fat storage,and chronic systemic inflammation.1 Understanding adipose tissue aging requires in-depth knowledge of the cellular and molecular properties of various adipose tissue cell types.Although the heterogeneity of the cell population during mouse aging has been studied,2 little is known about the cellular and molecular basis of human adipose tissues aging.展开更多
The improvements and validation of several parameterization schemes in the second version of the Beijing Climate Center Atmosphere–Vegetation Interaction Model(BCC_AVIM2.0) are introduced in this study. The main upda...The improvements and validation of several parameterization schemes in the second version of the Beijing Climate Center Atmosphere–Vegetation Interaction Model(BCC_AVIM2.0) are introduced in this study. The main updates include a replacement of the water-only lake module by the common land model lake module(Co LM-lake) with a more realistic snow–ice–water–soil framework, a parameterization scheme for rice paddies added in the vegetation module, renewed parameterizations of snow cover fraction and snow surface albedo to accommodate the varied snow aging effect during different stages of a snow season, a revised parameterization to calculate the threshold temperature to initiate freeze(thaw) of soil water(ice) rather than being fixed at 0°C in BCC_AVIM1.0, a prognostic phenology scheme for vegetation growth instead of empirically prescribed dates for leaf onset/fall, and a renewed scheme to depict solar radiation transfer through the vegetation canopy. The above updates have been implemented in BCC_AVIM2.0 to serve as the land component of the BCC Climate System Model(BCC_CSM). Preliminary results of BCC_AVIM in the ongoing Land Surface, Snow, and Soil Moisture Model Intercomparison Project(LS3 MIP) of the Coupled Model Intercomparison Project Phase 6(CMIP6) show that the overall performance of BCC_AVIM2.0 is better than that of BCC_AVIM1.0 in the simulation of surface energy budgets at the seasonal timescale. Comparing the simulations of annual global land average before and after the updates in BCC_AVIM2.0 reveals that the bias of net surface radiation is reduced from-12.0 to-11.7 W m-2 and the root mean square error(RMSE) is reduced from 20.6 to 19.0 W m-2;the bias and RMSE of latent heat flux are reduced from 2.3 to-0.1 W m-2 and from 15.4 to14.3 W m-2, respectively;the bias of sensible heat flux is increased from 2.5 to 5.1 W m-2 but the RMSE is reduced from 18.4 to 17.0 W m-2.展开更多
Cartilage defects are one of the most common symptoms of osteoarthritis(OA),a degenerative disease that affects millions of people world-wide and places a significant socio-economic burden on society.Hydrogels,which a...Cartilage defects are one of the most common symptoms of osteoarthritis(OA),a degenerative disease that affects millions of people world-wide and places a significant socio-economic burden on society.Hydrogels,which are a class of biomaterials that are elastic,and display smooth surfaces while exhibiting high water content,are promising candidates for cartilage regeneration.In recent years,various kinds of hydrogels have been developed and applied for the repair of cartilage defects in vitro or in vivo,some of which are hopeful to enter clinical trials.In this review,recent research findings and developments of hydrogels for cartilage defects repair are summarized.We discuss the principle of cartilage regeneration,and outline the requirements that have to be fulfilled for the deployment of hydrogels for medical applications.We also highlight the development of advanced hydrogels with tailored properties for different kinds of cartilage defects to meet the requirements of cartilage tissue engineering and precision medicine.展开更多
基金supported by the National Key R&D Program of China(2017YFA0104900)the National Natural Science Foundation of China(31830029,81501937 and 81522029)the Fundamental Research Funds for the Central Universities(K20200099).
文摘Tendon heterotopic ossification(HO)is characterized by bone formation inside tendon tissue,which severely debilitates people in their daily life.Current therapies fail to promote functional tissue repair largely due to our limited understanding of HO pathogenesis.Here,we investigate the pathological mechanism and propose a potential treatment method for HO.Immunofluorescence assays showed that the Mohawk(MKX)expression level was decreased in human tendon HO tissue,coinciding with spontaneous HO and the upregulated expression of osteochondrogenic and angiogenic genes in the tendons of Mkx^(−/−)mice.Single-cell RNA sequencing analyses of wild-type and Mkx^(−/−)tendons identified three cell types and revealed the excessive activation of osteochondrogenic genes during the tenogenesis of Mkx^(−/−)tendon cells.Single-cell analysis revealed that the gene expression program of angiogenesis,which is strongly associated with bone formation,was activated in all cell types during HO.Moreover,inhibition of angiogenesis by the small-molecule inhibitor BIBF1120 attenuated bone formation and angiogenesis in the Achilles tendons of both Mkx mutant mice and a rat traumatic model of HO.These findings provide new insights into the cellular mechanisms of tendon HO and highlight the inhibition of angiogenesis with BIBF1120 as a potential treatment strategy for HO.
基金supported by the National Key R&D Program of China(2017YFA0104900)National Natural Science Foundation of China(T2121004,31830029,82002319)。
文摘Articular cartilage damage is a universal health problem.Despite recent progress,chondrocyte dedifferentiation has severely compromised the clinical outcomes of cell-based cartilage regeneration.Loss-of-function changes are frequently observed in chondrocyte expansion and other pathological conditions,but the characteristics and intermediate molecular mechanisms remain unclear.In this study,we demonstrate a time-lapse atlas of chondrocyte dedifferentiation to provide molecular details and informative biomarkers associated with clinical chondrocyte evaluation.We performed various assays,such as single-cell RNA sequencing(scRNA-seq),live-cell metabolic assays,and assays for transposase-accessible chromatin with high-throughput sequencing(ATAC-seq),to develop a biphasic dedifferentiation model consisting of early and late dedifferentiation stages.Early-stage chondrocytes exhibited a glycolytic phenotype with increased expression of genes involved in metabolism and antioxidation,whereas late-stage chondrocytes exhibited ultrastructural changes involving mitochondrial damage and stress-associated chromatin remodeling.Using the chemical inhibitor BTB06584,we revealed that early and late dedifferentiated chondrocytes possessed distinct recovery potentials from functional phenotype loss.Notably,this two-stage transition was also validated in human chondrocytes.An image-based approach was established for clinical use to efficiently predict chondrocyte plasticity using stage-specific biomarkers.Overall,this study lays a foundation to improve the quality of chondrocytes in clinical use and provides deep insights into chondrocyte dedifferentiation.
基金supported by the Scientific and Technology Platform and Talents Project of Changsha (No.kh1801129) (to HW)Hunan Cancer Hospital Climb Plan (No.YF2020007) (to HW)+1 种基金the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (No.LHDMZ22H020001) (To XY)the Science and Technology Program of Jinhua Science and Technology Bureau (No.2021-3-001) (To XY)。
文摘Although human-induced pluripotent stem cell-derived cardiomyocytes(hi PSC-CMs) have been used for disease modeling and drug discovery, clinically relevant three-dimensional(3D) functional myocardial microtissues are lacking. Here, we developed a novel ring-shaped cardiac microtissue comprised of chamber-specific tissues to achieve a geometrically non-orientable ventricular myocardial band, similar to a M?bius loop. The ring-shaped cardiac tissue was constructed of hi PSC-CMs and human cardiac fibroblasts(h CFs) through a facile cellular self-assembly approach. It exhibited basic anatomical structure,positive cardiac troponin T(c Tn T) immunostaining, regular calcium transients, and cardiac-like mechanical strength. The cardiac rings can be self-assembled and scaled up into various sizes with outstanding stability, suggesting their potential for precise therapy, pathophysiological investigation, and large-scale drug screening.
基金supported by the National Key Research and Development Program of China(2016YFB0700804)National Natural Science Foundation of China(NO.T2121004,31830029).
文摘Autologous mosaicplasty is a common approach used to treat osteochondral defects in clinical practice.Gap integration between host and transplanted plugs requires bone tissue reservation and hyaline cartilage regeneration without uneven surface,graft necrosis and sclerosis.However,poor gap integration is a serious concern,which eventually leads to deterioration of joint function.To deal with such complications,this study has developed a strategy to effectively enhance integration of the gap region following mosaicplasty by applying injectable bioactive supramolecular nanofiber-enabled gelatin methacryloyl(GelMA)hydrogel(BSN-GelMA).A rabbit osteochondral defect model demonstrated that BSN-GelMA achieved seamless osteochondral healing in the gap region between plugs of osteochondral defects following mosaicplasty,as early as six weeks.Moreover,the International Cartilage Repair Society score,histology score,glycosaminoglycan content,subchondral bone volume,and collagen II expression were observed to be the highest in the gap region of BSN-GelMA treated group.This improved outcome was due to bio-interactive materials,which acted as tissue fillers to bridge the gap,prevent cartilage degeneration,and promote graft survival and migration of bone marrow mesenchymal stem cells by releasing bioactive supramolecular nanofibers from the GelMA hydrogel.This study provides a powerful and applicable approach to improve gap integration after autologous mosaicplasty.It is also a promising off-the-shelf bioactive material for cell-free in situ tissue regeneration.
基金the National Natural Sciences Foundation of China(T2121004,31830029)。
文摘Dear Editor,Age-dependent adipose tissue malfunction raises the risk of diseases like diabetes,cardiovascular disease,and even cancer by contributing to metabolic decline,heterotopic fat storage,and chronic systemic inflammation.1 Understanding adipose tissue aging requires in-depth knowledge of the cellular and molecular properties of various adipose tissue cell types.Although the heterogeneity of the cell population during mouse aging has been studied,2 little is known about the cellular and molecular basis of human adipose tissues aging.
基金Supported by the National Key Research and Development Program of China(2017YFA0604300,2016YFA0602100,and2016YFA0602602)National Natural Science Foundation of China(41275075 and 91437219)
文摘The improvements and validation of several parameterization schemes in the second version of the Beijing Climate Center Atmosphere–Vegetation Interaction Model(BCC_AVIM2.0) are introduced in this study. The main updates include a replacement of the water-only lake module by the common land model lake module(Co LM-lake) with a more realistic snow–ice–water–soil framework, a parameterization scheme for rice paddies added in the vegetation module, renewed parameterizations of snow cover fraction and snow surface albedo to accommodate the varied snow aging effect during different stages of a snow season, a revised parameterization to calculate the threshold temperature to initiate freeze(thaw) of soil water(ice) rather than being fixed at 0°C in BCC_AVIM1.0, a prognostic phenology scheme for vegetation growth instead of empirically prescribed dates for leaf onset/fall, and a renewed scheme to depict solar radiation transfer through the vegetation canopy. The above updates have been implemented in BCC_AVIM2.0 to serve as the land component of the BCC Climate System Model(BCC_CSM). Preliminary results of BCC_AVIM in the ongoing Land Surface, Snow, and Soil Moisture Model Intercomparison Project(LS3 MIP) of the Coupled Model Intercomparison Project Phase 6(CMIP6) show that the overall performance of BCC_AVIM2.0 is better than that of BCC_AVIM1.0 in the simulation of surface energy budgets at the seasonal timescale. Comparing the simulations of annual global land average before and after the updates in BCC_AVIM2.0 reveals that the bias of net surface radiation is reduced from-12.0 to-11.7 W m-2 and the root mean square error(RMSE) is reduced from 20.6 to 19.0 W m-2;the bias and RMSE of latent heat flux are reduced from 2.3 to-0.1 W m-2 and from 15.4 to14.3 W m-2, respectively;the bias of sensible heat flux is increased from 2.5 to 5.1 W m-2 but the RMSE is reduced from 18.4 to 17.0 W m-2.
基金National key R&D program of China(2017YFA0104900)NSFC grants(31830029,81630065,81902187)+1 种基金the Zhejiang Provincial Natural Science Foundation of China(No.LQ19E030019,LY19C070003)China Postdoctoral Science Foundation(2019M652112,2018M642442,2019M662084).
文摘Cartilage defects are one of the most common symptoms of osteoarthritis(OA),a degenerative disease that affects millions of people world-wide and places a significant socio-economic burden on society.Hydrogels,which are a class of biomaterials that are elastic,and display smooth surfaces while exhibiting high water content,are promising candidates for cartilage regeneration.In recent years,various kinds of hydrogels have been developed and applied for the repair of cartilage defects in vitro or in vivo,some of which are hopeful to enter clinical trials.In this review,recent research findings and developments of hydrogels for cartilage defects repair are summarized.We discuss the principle of cartilage regeneration,and outline the requirements that have to be fulfilled for the deployment of hydrogels for medical applications.We also highlight the development of advanced hydrogels with tailored properties for different kinds of cartilage defects to meet the requirements of cartilage tissue engineering and precision medicine.
