The ageing process is a systemic decline from cellular dysfunction to organ degeneration,with more predisposition to deteriorated disorders.Rejuvenation refers to giving aged cells or organisms more youthful character...The ageing process is a systemic decline from cellular dysfunction to organ degeneration,with more predisposition to deteriorated disorders.Rejuvenation refers to giving aged cells or organisms more youthful characteristics through various techniques,such as cellular reprogramming and epigenetic regulation.The great leaps in cellular rejuvenation prove that ageing is not a one-way street,and many rejuvenative interventions have emerged to delay and even reverse the ageing process.Defining the mechanism by which roadblocks and signaling inputs influence complex ageing programs is essential for understanding and developing rejuvenative strategies.Here,we discuss the intrinsic and extrinsic factors that counteract cell rejuvenation,and the targeted cells and core mechanisms involved in this process.Then,we critically summarize the latest advances in state-of-art strategies of cellular rejuvenation.Various rejuvenation methods also provide insights for treating specific ageing-related diseases,including cellular reprogramming,the removal of senescence cells(SCs)and suppression of senescence-associated secretory phenotype(SASP),metabolic manipulation,stem cells-associated therapy,dietary restriction,immune rejuvenation and heterochronic transplantation,etc.The potential applications of rejuvenation therapy also extend to cancer treatment.Finally,we analyze in detail the therapeutic opportunities and challenges of rejuvenation technology.Deciphering rejuvenation interventions will provide further insights into anti-ageing and ageing-related disease treatment in clinical settings.展开更多
Dear Editor,Sebaceous glands(SG)contribute to 90%of the skin surface lipid production and play critical roles in regulating proper skin functions including epidermal barrier maintenance,dermal immune responses,and glo...Dear Editor,Sebaceous glands(SG)contribute to 90%of the skin surface lipid production and play critical roles in regulating proper skin functions including epidermal barrier maintenance,dermal immune responses,and global body anti-microbial activities.1 Reduced sebaceous lipid has been implicated in diverse skin diseases,including scarring alopecia,inflammation,chronic itch,as well as premature aging of the skin.2 Especially,scar repair after deep burns or large-scale skin defect often leads to irreversible loss of appendages.Due to lacking SG,the regenerated tissues cannot fully recapitulate the structural and functional integrity of normal skin.Therefore,generation of expandable SG cells with developmental and lipid-producing potentials represents a promising approach for treating diseased,damaged,or aged skin with better quality of life.Recently,direct cellular reprogramming has been widely used for obtaining difficult-to-maintain human cells by cell type-specific transcription factors(TFs).展开更多
The regeneration of sweat glands(SwGs)plays a pivotal role in the functional recovery of extensive skin wounds.Recent research has illuminated the possibility of reprogramming human epidermal ker-atinocytes(HEKs)into ...The regeneration of sweat glands(SwGs)plays a pivotal role in the functional recovery of extensive skin wounds.Recent research has illuminated the possibility of reprogramming human epidermal ker-atinocytes(HEKs)into induced SwG cells through the ectopic expression of ectodysplasin A.However,the clinical application of this genetic manipulation approach is inherently limited.In this study,we pre-sent findings demonstrating that a combination of six compounds can effectively and speedily reprogram HEKs in culture into fully functional SwG cells.These chemically induced SwG-like cells(ciSGCs)closely resemble the morphology,phenotypes,and functional properties of human primary SwG ductal cells.Furthermore,ciSGCs can be stimulated to differentiate into mature SwG cell types in vitro.In a 3D culture system,they can also generate SwG organoids that exhibit structural and biological features akin to native SwGs.Upon transplantation into scalded mouse paw skin,ciSGCs significantly expedited cuta-neous wound healing and completely restored the structural and functional aspects of the SwGs.In con-clusion,the small molecule cocktail-directed SwG reprogramming offers a non-transgenic and controllable strategy for producing high-quality,clinical-grade SwG cells,showing immense potential for the treatment of burn patients.展开更多
Sebaceous glands(SGs),as holocrine-secreting appendages,lubricate the skin and play a central role in the skin barrier.Large full-thickness skin defects cause overall architecture disruption and SG loss.However,an eff...Sebaceous glands(SGs),as holocrine-secreting appendages,lubricate the skin and play a central role in the skin barrier.Large full-thickness skin defects cause overall architecture disruption and SG loss.However,an effective strategy for SG regeneration is lacking.Organoids are 3D multicellular structures that replicate key anatomical and functional characteristics of in vivo tissues and exhibit great potential in regenerative medicine.Recently,considerable progress has been made in developing reliable procedures for SG organoids and existing SG organoids recapitulate the main morphological,structural and functional features of their in vivo counterparts.Engineering approaches empower researchers to manipulate cell behaviors,the surrounding environment and cell-environment crosstalk within the culture system as needed.These techniques can be applied to the SG organoid culture system to generate functionally more competent SG organoids.This review aims to provide an overview of recent advancements in SG organoid engineering.It highlights some potential strategies for SG organoid functionalization that are promising to forge a platform for engineering vascularized,innervated,immune-interactive and lipogenic SG organoids.We anticipate that this review will not only contribute to improving our understanding of SG biology and regeneration but also facilitate the transition of the SG organoid from laboratory research to a feasible clinical application.展开更多
Background:Promoting rapid wound healing with functional recovery of all skin appendages is the main goal of regenerative medicine.So far current methodologies,including the commonly used back excisional wound model(B...Background:Promoting rapid wound healing with functional recovery of all skin appendages is the main goal of regenerative medicine.So far current methodologies,including the commonly used back excisional wound model(BEWM)and paw skin scald wound model,are focused on assessing the regeneration of either hair follicles(HFs)or sweat glands(SwGs).How to achieve de novo appendage regeneration by synchronized evaluation of HFs,SwGs and sebaceous glands(SeGs)is still challenging.Here,we developed a volar skin excisional wound model(VEWM)that is suitable for examining cutaneous wound healing with multiple-appendage restoration,as well as innervation,providing a new research paradigm for the perfect regeneration of skin wounds.Methods:Macroscopic observation,iodine-starch test,morphological staining and qRT-PCR anal-ysis were used to detect the existence of HFs,SwGs,SeGs and distribution of nerve fibres in the volar skin.Wound healing process monitoring,HE/Masson staining,fractal analysis and behavioral response assessment were performed to verify that VEWM could mimic the pathological process and outcomes of human scar formation and sensory function impairment.Results:HFs are limited to the inter-footpads.SwGs are densely distributed in the footpads,scattered in the IFPs.The volar skin is richly innervated.The wound area of the VEWM at 1,3,7 and 10 days after the operation is respectively 89.17%±2.52%,71.72%±3.79%,55.09%±4.94%and 35.74%±4.05%,and the final scar area accounts for 47.80%±6.22%of the initial wound.While the wound area of BEWM at 1,3,7 and 10 days after the operation are respectively 61.94%±5.34%,51.26%±4.89%,12.63%±2.86%and 6.14%±2.84%,and the final scar area accounts for 4.33%±2.67%of the initial wound.Fractal analysis of the post-traumatic repair site for VEWM vs human was performed:lacunarity values,0.040±0.012 vs 0.038±0.014;fractal dimen-sion values,1.870±0.237 vs 1.903±0.163.Sensory nerve function of normal skin vs post-traumatic repair site was assessed:mechanical threshold,1.05±0.52 vs 4.90 g±0.80;response rate to pin-prick,100%vs 71.67%±19.92%,and temperature threshold,50.34◦C±3.11◦C vs 52.13◦C±3.54◦C.Conclusions:VEWM closely reflects the pathological features of human wound healing and can be applied for skin multiple-appendages regeneration and innervation evaluation.展开更多
An innovative composite deck system has recently been proposed for improved structural performance.To study the fatigue behavior of a steel-concrete composite bridge deck,we took a newly-constructed rail-cum-road stee...An innovative composite deck system has recently been proposed for improved structural performance.To study the fatigue behavior of a steel-concrete composite bridge deck,we took a newly-constructed rail-cum-road steel truss bridge as a case study.The transverse stress history of the bridge deck near the main truss under the action of a standard fatigue vehicle was calculated using finite element analysis.Due to the fact that fatigue provision remains unavailable in the governing code of highway concrete bridges in China,a preliminary fatigue evaluation was conducted according to the fib Model Code.The results indicate that flexural failure of the bridge deck in the transverse negative bending moment region is the controlling fatigue failure mode.The fatigue life associated with the fatigue fracture of steel reinforcement is 56 years.However,while the top surface of the bridge deck concrete near the truss cracks after just six years,the bridge deck performs with fatigue cracks during most of its design service life.Although fatigue capacity is acceptable under design situations,overloading or understrength may increase its risk of failure.The method presented in this work can be applied to similar bridges for preliminary fatigue assessment.展开更多
基金the National Natural Science Foundation of China(81871569,81830064,81721092,61803250)the National Key Research and Development Plan(2018YFC1105704,2017YFC1103304,2016YFA0101000,2016YFA0101002)+3 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-059)the Military Key Basic Research of Foundational Strengthening Program(2020-JCJQ-ZD-256-021)the Military Medical Research and Development Projects(AWS17J005,2019-126)the Specific Research Fund of The Innovation Platform for Academicians of Hainan Province.
文摘The ageing process is a systemic decline from cellular dysfunction to organ degeneration,with more predisposition to deteriorated disorders.Rejuvenation refers to giving aged cells or organisms more youthful characteristics through various techniques,such as cellular reprogramming and epigenetic regulation.The great leaps in cellular rejuvenation prove that ageing is not a one-way street,and many rejuvenative interventions have emerged to delay and even reverse the ageing process.Defining the mechanism by which roadblocks and signaling inputs influence complex ageing programs is essential for understanding and developing rejuvenative strategies.Here,we discuss the intrinsic and extrinsic factors that counteract cell rejuvenation,and the targeted cells and core mechanisms involved in this process.Then,we critically summarize the latest advances in state-of-art strategies of cellular rejuvenation.Various rejuvenation methods also provide insights for treating specific ageing-related diseases,including cellular reprogramming,the removal of senescence cells(SCs)and suppression of senescence-associated secretory phenotype(SASP),metabolic manipulation,stem cells-associated therapy,dietary restriction,immune rejuvenation and heterochronic transplantation,etc.The potential applications of rejuvenation therapy also extend to cancer treatment.Finally,we analyze in detail the therapeutic opportunities and challenges of rejuvenation technology.Deciphering rejuvenation interventions will provide further insights into anti-ageing and ageing-related disease treatment in clinical settings.
基金This work was supported in part by the National Natural Science Foundation of China(92268206,81830064)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-059)+2 种基金the Military Medical Research Projects(145AKJ260015000X,2022-JCJQ-ZB-09600,2020-JCJQ-ZD-256-021)the Military Medical Research and Development Projects(AWS17J005,2019-126)the Specific Research Fund of The Innovation Platform for Academicians of Hainan Province(YSPTZX202317).
文摘Dear Editor,Sebaceous glands(SG)contribute to 90%of the skin surface lipid production and play critical roles in regulating proper skin functions including epidermal barrier maintenance,dermal immune responses,and global body anti-microbial activities.1 Reduced sebaceous lipid has been implicated in diverse skin diseases,including scarring alopecia,inflammation,chronic itch,as well as premature aging of the skin.2 Especially,scar repair after deep burns or large-scale skin defect often leads to irreversible loss of appendages.Due to lacking SG,the regenerated tissues cannot fully recapitulate the structural and functional integrity of normal skin.Therefore,generation of expandable SG cells with developmental and lipid-producing potentials represents a promising approach for treating diseased,damaged,or aged skin with better quality of life.Recently,direct cellular reprogramming has been widely used for obtaining difficult-to-maintain human cells by cell type-specific transcription factors(TFs).
基金supported by the National Nature Science Foundation of China(92268206)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-059)+3 种基金the Military Medical Research Projects(2023-JSKY-SSQG-006)the Independent Research Project of State Key Laboratory of Trauma and Chemical Poisoning,the National Key Research and Development Program of China(2023YFC3011900)the Specific Research Fund of The Innovation Platform for Academicians of Hainan Province(YSPTZX202317)the Open Project of the State Key Laboratory of Trauma,Burn and Combined Injury,Third Military Medical University(SKLKF202301).
文摘The regeneration of sweat glands(SwGs)plays a pivotal role in the functional recovery of extensive skin wounds.Recent research has illuminated the possibility of reprogramming human epidermal ker-atinocytes(HEKs)into induced SwG cells through the ectopic expression of ectodysplasin A.However,the clinical application of this genetic manipulation approach is inherently limited.In this study,we pre-sent findings demonstrating that a combination of six compounds can effectively and speedily reprogram HEKs in culture into fully functional SwG cells.These chemically induced SwG-like cells(ciSGCs)closely resemble the morphology,phenotypes,and functional properties of human primary SwG ductal cells.Furthermore,ciSGCs can be stimulated to differentiate into mature SwG cell types in vitro.In a 3D culture system,they can also generate SwG organoids that exhibit structural and biological features akin to native SwGs.Upon transplantation into scalded mouse paw skin,ciSGCs significantly expedited cuta-neous wound healing and completely restored the structural and functional aspects of the SwGs.In con-clusion,the small molecule cocktail-directed SwG reprogramming offers a non-transgenic and controllable strategy for producing high-quality,clinical-grade SwG cells,showing immense potential for the treatment of burn patients.
基金supported in part by the National Natural Science Foundation of China(92268206,81830064)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-059)+2 种基金the Military Medical Research Projects(145AKJ260015000X,2022-JCJQ-ZB-09600,2020-JCJQ-ZD-256-021)the Military Medical Research and Development Projects(AWS17J005,2019-126)the Specific Research Fund of The Innovation Platform for Academicians of Hainan Province(YSPTZX202317).
文摘Sebaceous glands(SGs),as holocrine-secreting appendages,lubricate the skin and play a central role in the skin barrier.Large full-thickness skin defects cause overall architecture disruption and SG loss.However,an effective strategy for SG regeneration is lacking.Organoids are 3D multicellular structures that replicate key anatomical and functional characteristics of in vivo tissues and exhibit great potential in regenerative medicine.Recently,considerable progress has been made in developing reliable procedures for SG organoids and existing SG organoids recapitulate the main morphological,structural and functional features of their in vivo counterparts.Engineering approaches empower researchers to manipulate cell behaviors,the surrounding environment and cell-environment crosstalk within the culture system as needed.These techniques can be applied to the SG organoid culture system to generate functionally more competent SG organoids.This review aims to provide an overview of recent advancements in SG organoid engineering.It highlights some potential strategies for SG organoid functionalization that are promising to forge a platform for engineering vascularized,innervated,immune-interactive and lipogenic SG organoids.We anticipate that this review will not only contribute to improving our understanding of SG biology and regeneration but also facilitate the transition of the SG organoid from laboratory research to a feasible clinical application.
基金supported in part by the National Nature Science Foundation of China[92268206,81830064]the CAMS Innovation Fund for Medical Sciences[CIFMS,2019-I2M-5-059]+2 种基金the Military Medical Research Projects[145AKJ260015000X,2022-JCJQ-ZB-09600,2020-JCJQZD-256-021]the Military Medical Research and Development Projects[AWS17J005,2019-126]the Specific Research Fund of The Innovation Platform for Academicians of Hainan Province[YSPTZX202317].
文摘Background:Promoting rapid wound healing with functional recovery of all skin appendages is the main goal of regenerative medicine.So far current methodologies,including the commonly used back excisional wound model(BEWM)and paw skin scald wound model,are focused on assessing the regeneration of either hair follicles(HFs)or sweat glands(SwGs).How to achieve de novo appendage regeneration by synchronized evaluation of HFs,SwGs and sebaceous glands(SeGs)is still challenging.Here,we developed a volar skin excisional wound model(VEWM)that is suitable for examining cutaneous wound healing with multiple-appendage restoration,as well as innervation,providing a new research paradigm for the perfect regeneration of skin wounds.Methods:Macroscopic observation,iodine-starch test,morphological staining and qRT-PCR anal-ysis were used to detect the existence of HFs,SwGs,SeGs and distribution of nerve fibres in the volar skin.Wound healing process monitoring,HE/Masson staining,fractal analysis and behavioral response assessment were performed to verify that VEWM could mimic the pathological process and outcomes of human scar formation and sensory function impairment.Results:HFs are limited to the inter-footpads.SwGs are densely distributed in the footpads,scattered in the IFPs.The volar skin is richly innervated.The wound area of the VEWM at 1,3,7 and 10 days after the operation is respectively 89.17%±2.52%,71.72%±3.79%,55.09%±4.94%and 35.74%±4.05%,and the final scar area accounts for 47.80%±6.22%of the initial wound.While the wound area of BEWM at 1,3,7 and 10 days after the operation are respectively 61.94%±5.34%,51.26%±4.89%,12.63%±2.86%and 6.14%±2.84%,and the final scar area accounts for 4.33%±2.67%of the initial wound.Fractal analysis of the post-traumatic repair site for VEWM vs human was performed:lacunarity values,0.040±0.012 vs 0.038±0.014;fractal dimen-sion values,1.870±0.237 vs 1.903±0.163.Sensory nerve function of normal skin vs post-traumatic repair site was assessed:mechanical threshold,1.05±0.52 vs 4.90 g±0.80;response rate to pin-prick,100%vs 71.67%±19.92%,and temperature threshold,50.34◦C±3.11◦C vs 52.13◦C±3.54◦C.Conclusions:VEWM closely reflects the pathological features of human wound healing and can be applied for skin multiple-appendages regeneration and innervation evaluation.
基金This research was funded by the National Natural Science Foundation of China(Grant No.51008006)the China Railway No.18 Engineering Group(No.40004015201911).
文摘An innovative composite deck system has recently been proposed for improved structural performance.To study the fatigue behavior of a steel-concrete composite bridge deck,we took a newly-constructed rail-cum-road steel truss bridge as a case study.The transverse stress history of the bridge deck near the main truss under the action of a standard fatigue vehicle was calculated using finite element analysis.Due to the fact that fatigue provision remains unavailable in the governing code of highway concrete bridges in China,a preliminary fatigue evaluation was conducted according to the fib Model Code.The results indicate that flexural failure of the bridge deck in the transverse negative bending moment region is the controlling fatigue failure mode.The fatigue life associated with the fatigue fracture of steel reinforcement is 56 years.However,while the top surface of the bridge deck concrete near the truss cracks after just six years,the bridge deck performs with fatigue cracks during most of its design service life.Although fatigue capacity is acceptable under design situations,overloading or understrength may increase its risk of failure.The method presented in this work can be applied to similar bridges for preliminary fatigue assessment.
