Osteoarthritis(OA)is a degenerative joint disorder commonly encountered in clinical practice,and is the leading cause of disability in elderly people.Due to the poor self-healing capacity of articular cartilage and la...Osteoarthritis(OA)is a degenerative joint disorder commonly encountered in clinical practice,and is the leading cause of disability in elderly people.Due to the poor self-healing capacity of articular cartilage and lack of specific diagnostic biomarkers,OA is a challenging disease with limited treatment options.Traditional pharmacologic therapies such as acetaminophen,non-steroidal anti-inflammatory drugs,and opioids are effective in relieving pain but are incapable of reversing cartilage damage and are frequently associated with adverse events.Current research focuses on the development of new OA drugs(such as sprifermin/recombinant human fibroblast growth factor-18,tanezumab/monoclonal antibody againstβ-nerve growth factor),which aims for more effectiveness and less incidence of adverse effects than the traditional ones.Furthermore,regenerative therapies(such as autologous chondrocyte implantation(ACI),new generation of matrix-induced ACI,cell-free scaffolds,induced pluripotent stem cells(iPS cells or iPSCs),and endogenous cell homing)are also emerging as promising alternatives as they have potential to enhance cartilage repair,and ultimately restore healthy tissue.However,despite currently available therapies and research advances,there remain unmet medical needs in the treatment of OA.This review highlights current research progress on pharmacologic and regenerative therapies for OA including key advances and potential limitations.展开更多
The limited molecular classifications and disease signatures of osteoarthritis(OA)impede the development of prediagnosis and targeted therapeutics for OA patients.To classify and understand the subtypes of OA,we colle...The limited molecular classifications and disease signatures of osteoarthritis(OA)impede the development of prediagnosis and targeted therapeutics for OA patients.To classify and understand the subtypes of OA,we collected three types of tissue including cartilage,subchondral bone,and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients.By applying unsupervised clustering analysis to the cartilage transcriptome,OA patients were classified into four subtypes with distinct molecular signatures:a glycosaminoglycan metabolic disorder subtype(C1),a collagen metabolic disorder subtype(C2),an activated sensory neuron subtype(C3),and an inflammation subtype(C4).Through ligand-receptor crosstalk analysis of the three knee tissue types,we linked molecular functions with the clinical symptoms of different OA subtypes.For example,the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4,which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients.Based on the marker genes of the four OA subtypes identified in this study,we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification.The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients,which may allow for precise diagnosis and treatment of OA.展开更多
Chondrocyte differentiation is a critical process for endochondral ossification,which is responsible for long bone development and fracture repair.Considerable progress has been made in understanding the transcription...Chondrocyte differentiation is a critical process for endochondral ossification,which is responsible for long bone development and fracture repair.Considerable progress has been made in understanding the transcriptional control of chondrocyte differentiation;however,epigenetic regulation of chondrocyte differentiation remains to be further studied.NSD1 is a H3K36(histone H3 at lysine 36)methyltransferase.Here,we showed that mice with Nsd1 deficiency in Prx1+mesenchymal progenitors but not in Col2+chondrocytes showed impaired skeletal growth and fracture healing accompanied by decreased chondrogenic differentiation.Via combined RNA sequencing(RNA-seq)and chromatin immunoprecipitation sequencing(ChIP-seq)analysis,we identified sex determining region Y box 9(Sox9),the key transcription factor of chondrogenic differentiation,as a functional target gene of NSD1.Mechanistically,NSD1 regulates Sox9 expression by modulating H3K36me1 and H3K36me2 levels in the Sox9 promoter region,constituting a novel epigenetic regulatory mechanism of chondrogenesis.Moreover,we found that NSD1 can directly activate the expression of hypoxia-inducible factor 1α(HIF1α),which plays a vital role in chondrogenic differentiation through its regulation of Sox9 expression.Collectively,the results of our study reveal crucial roles of NSD1 in regulating chondrogenic differentiation,skeletal growth,and fracture repair and expand our understanding of the function of epigenetic regulation in chondrogenesis and skeletal biology.展开更多
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
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
Inflammatory bowel disease(IBD)is a chronic,immune-mediated inflammatory disease characterized by the destruction of the structure and function of the intestinal epithelial barrier.Due to the poor remission effect and...Inflammatory bowel disease(IBD)is a chronic,immune-mediated inflammatory disease characterized by the destruction of the structure and function of the intestinal epithelial barrier.Due to the poor remission effect and severe adverse events associated with current clinical medications,IBD remains an incurable disease.Here,we demonstrated a novel treatment strategy with high safety and effective inflammation remission via tissue-adhesive molecular coating.The molecular coating is composed of o-nitrobenzaldehyde(NB)-modified Gelatin(GelNB),which can strongly bond with-NH_(2)on the intestinal surface of tissue to form a thin biophysical barrier.We found that this molecular coating was able to stay on the surface of the intestine for long periods of time,effectively protecting the damaged intestinal epithelium from irritations of external intestinal metabolites and harmful flora.In addition,our results showed that this coating not only provided a beneficial environment for cell migration and proliferation to promote intestinal repair and regeneration,but also achieved a better outcome of IBD by reducing intestinal inflammation.Moreover,the in vivo experiments showed that the GelNB was better than the classic clinical medication-mesalazine.Therefore,our molecular coating showed potential as a promising strategy for the prevention and treatment of IBD.展开更多
Dynamic regulation of cell-extracellular matrix(ECM)-material interactions is crucial for various biomedical applications.In this study,a light-activated molecular switch for the modulation of cell attachment/detachme...Dynamic regulation of cell-extracellular matrix(ECM)-material interactions is crucial for various biomedical applications.In this study,a light-activated molecular switch for the modulation of cell attachment/detachment behaviors was established on monolayer graphene(Gr)/n-type Silicon substrates(Gr/Si).Initiated by light illumination at the Gr/Si interface,pre-adsorbed proteins(bovine serum albumin,ECM proteins collagen-1,and fibronectin)underwent protonation to achieve negative charge transfer to Gr films(n-doping)throughπ-πinteractions.This n-doping process stimulated the conformational switches of ECM proteins.The structural alterations in these ECM interactors significantly reduced the specificity of the cell surface receptor-ligand interaction(e.g.,integrin recognition),leading to dynamic regulation of cell adhesion and eventual cell detachment.RNA-sequencing results revealed that the detached bone marrow mesenchymal stromal cell sheets from the Gr/Si system manifested regulated immunoregulatory properties and enhanced osteogenic differentiation,implying their potential application in bone tissue regeneration.This work not only provides a fast and feasible method for controllable cells/cell sheets harvesting but also gives new insights into the understanding of cell-ECM-material communications.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 myotendinous junction(MTJ)is a complex and special anatomical area that connects muscles and tendons,and it is also the key to repairing tendons.Nevertheless,the anatomical structure and connection structure of MT...The myotendinous junction(MTJ)is a complex and special anatomical area that connects muscles and tendons,and it is also the key to repairing tendons.Nevertheless,the anatomical structure and connection structure of MTJ,the cluster and distribution of cells,and which cells are involved in repairing the tissue are still unclear.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
Nano-hydroxyapatite(nHAP)has been widely used in bone repair as an osteo-inductive and naturally-occurring material.However,the optimal applied form of nHAP and the underlying mechanisms involved remain unclear.Herein...Nano-hydroxyapatite(nHAP)has been widely used in bone repair as an osteo-inductive and naturally-occurring material.However,the optimal applied form of nHAP and the underlying mechanisms involved remain unclear.Herein,to investigate into these,a range of corresponding models were designed,including three applied forms of nHAP(Free,Coating and 3D)that belong to two states(Free or fixed).The results indicate that when fixed nHAP was applied in the 3D form,optimal osteogenesis was induced in human bone marrow stem cells(hBMSCs)with increased bone volume via integrinα7(ITGA7)-mediated upregulation of the PI3K-AKT signaling pathway,while contrary results were observed with free nHAP.Ectopic osteogenesis experiments in mice subcutaneous transplantation model further confirmed the different tendencies of ITGA7 expression and osteogenesis of hBMSCs in free and fixed states of nHAP.Our results revealed that the two states of nHAP play a different regulatory role in cell morphology and osteogenesis through the valve role of ITGA7,providing cues for better application of nanoparticles and a potential new molecular target in bone tissue engineering.展开更多
Corneal injuries will cause corneal surface diseases that may lead to blindness in millions of people worldwide.There is a tremendous need for biomaterials that can promote corneal regeneration with practical feasibil...Corneal injuries will cause corneal surface diseases that may lead to blindness in millions of people worldwide.There is a tremendous need for biomaterials that can promote corneal regeneration with practical feasibility.Here we demonstrate a strategy of a protein coating for corneal injury regeneration.We synthesize an o-nitrosobenzaldehyde group(NB)-modified gelatin(GelNB),which could adhere directly to the corneal surface with covalent bonding to form a thin molecular coating.The molecular coating could avoid rapid clearance and provide a favorable environment for cell migration,thereby effectively accelerating corneal repair and regeneration.The histological structure of the regenerated cornea is more similar to the native cornea.This molecular coating can be used conveniently as an eye drop solution,which makes it a promising strategy for corneal regeneration.展开更多
基金supported in part by NHMRCa grant from the Natural Science Foundation of China(NSFCNo. 81228013)
文摘Osteoarthritis(OA)is a degenerative joint disorder commonly encountered in clinical practice,and is the leading cause of disability in elderly people.Due to the poor self-healing capacity of articular cartilage and lack of specific diagnostic biomarkers,OA is a challenging disease with limited treatment options.Traditional pharmacologic therapies such as acetaminophen,non-steroidal anti-inflammatory drugs,and opioids are effective in relieving pain but are incapable of reversing cartilage damage and are frequently associated with adverse events.Current research focuses on the development of new OA drugs(such as sprifermin/recombinant human fibroblast growth factor-18,tanezumab/monoclonal antibody againstβ-nerve growth factor),which aims for more effectiveness and less incidence of adverse effects than the traditional ones.Furthermore,regenerative therapies(such as autologous chondrocyte implantation(ACI),new generation of matrix-induced ACI,cell-free scaffolds,induced pluripotent stem cells(iPS cells or iPSCs),and endogenous cell homing)are also emerging as promising alternatives as they have potential to enhance cartilage repair,and ultimately restore healthy tissue.However,despite currently available therapies and research advances,there remain unmet medical needs in the treatment of OA.This review highlights current research progress on pharmacologic and regenerative therapies for OA including key advances and potential limitations.
基金the National Key R&D Program of China(2017YFA0104900)the National Natural Science Foundation of China(81630065,31830029,and 81802195)the China Postdoctoral Science Foundation(2017M621913).
文摘The limited molecular classifications and disease signatures of osteoarthritis(OA)impede the development of prediagnosis and targeted therapeutics for OA patients.To classify and understand the subtypes of OA,we collected three types of tissue including cartilage,subchondral bone,and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients.By applying unsupervised clustering analysis to the cartilage transcriptome,OA patients were classified into four subtypes with distinct molecular signatures:a glycosaminoglycan metabolic disorder subtype(C1),a collagen metabolic disorder subtype(C2),an activated sensory neuron subtype(C3),and an inflammation subtype(C4).Through ligand-receptor crosstalk analysis of the three knee tissue types,we linked molecular functions with the clinical symptoms of different OA subtypes.For example,the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4,which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients.Based on the marker genes of the four OA subtypes identified in this study,we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification.The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients,which may allow for precise diagnosis and treatment of OA.
基金supported by grants from the National Natural Science Foundation of China(NSFC)[81902212,81725010,81672119,81991512]Strategic Priority Research Program of the Chinese Academy of Sciences[XDB19000000]Major Program of Development Fund for Shanghai Zhangjiang National Innovation Demonstration Zone[ZJ2018-ZD-004].
文摘Chondrocyte differentiation is a critical process for endochondral ossification,which is responsible for long bone development and fracture repair.Considerable progress has been made in understanding the transcriptional control of chondrocyte differentiation;however,epigenetic regulation of chondrocyte differentiation remains to be further studied.NSD1 is a H3K36(histone H3 at lysine 36)methyltransferase.Here,we showed that mice with Nsd1 deficiency in Prx1+mesenchymal progenitors but not in Col2+chondrocytes showed impaired skeletal growth and fracture healing accompanied by decreased chondrogenic differentiation.Via combined RNA sequencing(RNA-seq)and chromatin immunoprecipitation sequencing(ChIP-seq)analysis,we identified sex determining region Y box 9(Sox9),the key transcription factor of chondrogenic differentiation,as a functional target gene of NSD1.Mechanistically,NSD1 regulates Sox9 expression by modulating H3K36me1 and H3K36me2 levels in the Sox9 promoter region,constituting a novel epigenetic regulatory mechanism of chondrogenesis.Moreover,we found that NSD1 can directly activate the expression of hypoxia-inducible factor 1α(HIF1α),which plays a vital role in chondrogenic differentiation through its regulation of Sox9 expression.Collectively,the results of our study reveal crucial roles of NSD1 in regulating chondrogenic differentiation,skeletal growth,and fracture repair and expand our understanding of the function of epigenetic regulation in chondrogenesis and skeletal biology.
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 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.
文摘Inflammatory bowel disease(IBD)is a chronic,immune-mediated inflammatory disease characterized by the destruction of the structure and function of the intestinal epithelial barrier.Due to the poor remission effect and severe adverse events associated with current clinical medications,IBD remains an incurable disease.Here,we demonstrated a novel treatment strategy with high safety and effective inflammation remission via tissue-adhesive molecular coating.The molecular coating is composed of o-nitrobenzaldehyde(NB)-modified Gelatin(GelNB),which can strongly bond with-NH_(2)on the intestinal surface of tissue to form a thin biophysical barrier.We found that this molecular coating was able to stay on the surface of the intestine for long periods of time,effectively protecting the damaged intestinal epithelium from irritations of external intestinal metabolites and harmful flora.In addition,our results showed that this coating not only provided a beneficial environment for cell migration and proliferation to promote intestinal repair and regeneration,but also achieved a better outcome of IBD by reducing intestinal inflammation.Moreover,the in vivo experiments showed that the GelNB was better than the classic clinical medication-mesalazine.Therefore,our molecular coating showed potential as a promising strategy for the prevention and treatment of IBD.
基金The National Key R&D Program of China(2021YFC2400400),the National Science Foundation of China(52072339,21673206 and 82002271)financially supported this work。
文摘Dynamic regulation of cell-extracellular matrix(ECM)-material interactions is crucial for various biomedical applications.In this study,a light-activated molecular switch for the modulation of cell attachment/detachment behaviors was established on monolayer graphene(Gr)/n-type Silicon substrates(Gr/Si).Initiated by light illumination at the Gr/Si interface,pre-adsorbed proteins(bovine serum albumin,ECM proteins collagen-1,and fibronectin)underwent protonation to achieve negative charge transfer to Gr films(n-doping)throughπ-πinteractions.This n-doping process stimulated the conformational switches of ECM proteins.The structural alterations in these ECM interactors significantly reduced the specificity of the cell surface receptor-ligand interaction(e.g.,integrin recognition),leading to dynamic regulation of cell adhesion and eventual cell detachment.RNA-sequencing results revealed that the detached bone marrow mesenchymal stromal cell sheets from the Gr/Si system manifested regulated immunoregulatory properties and enhanced osteogenic differentiation,implying their potential application in bone tissue regeneration.This work not only provides a fast and feasible method for controllable cells/cell sheets harvesting but also gives new insights into the understanding of cell-ECM-material communications.
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This work was supported by the National Key Research and Development Program of China(2021YFA1100500)NSFC grants(T2121004,31830029,82222044,81972099,82072463,32271406,and 32271404)+1 种基金the Natural Science Foundation of Zhejiang Province of China(LR20H060001 and LZ22H060002)the Fundamental Research Funds for the Central Universities.
文摘The myotendinous junction(MTJ)is a complex and special anatomical area that connects muscles and tendons,and it is also the key to repairing tendons.Nevertheless,the anatomical structure and connection structure of MTJ,the cluster and distribution of cells,and which cells are involved in repairing the tissue are still unclear.
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.
基金the National Key R&D program of China(2018YFC1105100)the National Natural Science Foundation of China(NSFC grant NO.T2121004 and NO.31830029).
文摘Nano-hydroxyapatite(nHAP)has been widely used in bone repair as an osteo-inductive and naturally-occurring material.However,the optimal applied form of nHAP and the underlying mechanisms involved remain unclear.Herein,to investigate into these,a range of corresponding models were designed,including three applied forms of nHAP(Free,Coating and 3D)that belong to two states(Free or fixed).The results indicate that when fixed nHAP was applied in the 3D form,optimal osteogenesis was induced in human bone marrow stem cells(hBMSCs)with increased bone volume via integrinα7(ITGA7)-mediated upregulation of the PI3K-AKT signaling pathway,while contrary results were observed with free nHAP.Ectopic osteogenesis experiments in mice subcutaneous transplantation model further confirmed the different tendencies of ITGA7 expression and osteogenesis of hBMSCs in free and fixed states of nHAP.Our results revealed that the two states of nHAP play a different regulatory role in cell morphology and osteogenesis through the valve role of ITGA7,providing cues for better application of nanoparticles and a potential new molecular target in bone tissue engineering.
基金This work was supported by the National Key R&D Program of China(2017YFA0104900)National Natural Science Foundation of China(31830029,32000957,81972053).
文摘Corneal injuries will cause corneal surface diseases that may lead to blindness in millions of people worldwide.There is a tremendous need for biomaterials that can promote corneal regeneration with practical feasibility.Here we demonstrate a strategy of a protein coating for corneal injury regeneration.We synthesize an o-nitrosobenzaldehyde group(NB)-modified gelatin(GelNB),which could adhere directly to the corneal surface with covalent bonding to form a thin molecular coating.The molecular coating could avoid rapid clearance and provide a favorable environment for cell migration,thereby effectively accelerating corneal repair and regeneration.The histological structure of the regenerated cornea is more similar to the native cornea.This molecular coating can be used conveniently as an eye drop solution,which makes it a promising strategy for corneal regeneration.
