Hypertrophic scar and keloid are a major medical problem,which may lead to disfigurement,growth restriction,and permanent loss of function,causing severe physical,psychological,and economic burdens.1 When skin injury ...Hypertrophic scar and keloid are a major medical problem,which may lead to disfigurement,growth restriction,and permanent loss of function,causing severe physical,psychological,and economic burdens.1 When skin injury occurs,the wound heals through a dynamic series of physiological events,including blood clotting,granulation tissue formation,re-epithelialization,and extracellular matrix remodeling.2 However,the newly formed extracellular matrix in a scar may never achieve the flexibility or strength of the original tissue.展开更多
Skin serves as the first-order protective barrier against the environment and any significant disruptions in skin integrity must be promptly restored.Despite significant advances in therapeutic strategies,effective ma...Skin serves as the first-order protective barrier against the environment and any significant disruptions in skin integrity must be promptly restored.Despite significant advances in therapeutic strategies,effective management of large chronic skin wounds remains a clinical challenge.Dermal fibroblasts are the primary cell type responsible for remodeling the extracellular matrix(ECM)in wound healing.Here,we investigated whether ECM derived from exogenous fibroblasts,in combination with keratinocytes,promoted scarless cutaneous wound healing.To overcome the limited lifespan of primary dermal fibroblasts,we established reversibly immortalized mouse dermal fibroblasts(imDFs),which were non-tumorigenic,expressed dermal fibroblast markers,and were responsive to TGF-β1 stimulation.The decellularized ECM prepared from both imDFs and primary dermal fi-broblasts shared similar expression profiles of extracellular matrix proteins and promoted the proliferation of keratinocyte(iKera)cells.The imDFs-derived ECM solicited no local immune response.While the ECM and to a lesser extent imDFs enhanced skin wound healing with excessive fibrosis,a combination of imDFs-derived ECM and iKera cells effectively promoted the re-epithelization and scarless healing of full-thickness skin wounds.These findings strongly suggest that dermal fibroblast-derived ECM,not fibroblasts themselves,may synergize with keratinocytes in regulating scarless healing and re-epithelialization of skin wounds.Given its low immu-nogenic nature,imDFs-derived ECM should be a valuable resource of skin-specific biomaterial for wound healing and skin tissue engineering.展开更多
Non-alcoholic fatty liver disease(NAFLD)patients have multiple metabolic distur-bances,with markedly elevated levels of lactate.Lactate accumulations play pleiotropic roles in disease progression through metabolic rea...Non-alcoholic fatty liver disease(NAFLD)patients have multiple metabolic distur-bances,with markedly elevated levels of lactate.Lactate accumulations play pleiotropic roles in disease progression through metabolic rearrangements and epigenetic modifications.Mono-carboxylate transporter 4(MCT4)is highly expressed in hepatocytes and responsible for trans-porting intracellular lactate out of the cell.To explore whether elevated MCT4 levels played any role in NAFLD development,we overexpressed and silenced MCT4 in hepatocytes and per-formed a comprehensive in vitro and in vivo analysis.Our results revealed that MCT4 overex-pression down-regulated the genes for lipid synthesis while up-regulating the genes involved in lipid catabolism.Conversely,silencing MCT4 expression or inhibiting MCT4 expression led to the accumulation of intracellular lipid and glucose metabolites,resulting in hepatic steatosis.In a mouse model of NAFLD,we found that exogenous MCT4 overexpression significantly reduced lipid metabolism and alleviated hepatocellular steatosis.Mechanistically,MCT4 alle-viated hepatic steatosis by regulating a group of hub genes such as Arg2,Olr1,Cd74,Mmp8,Irf7,Spp1,and Apoe,which in turn impacted multiple pathways involved in lipid metabolism and inflammatory response,such as PPAR,HIF-1,TNF,IL-17,PI3K-AKT,Wnt,and JAK-STAT.Collectively,our results strongly suggest that MCT4 may play an important role in regulating lipid metabolism and inflammation and thus serve as a potential therapeutic target for NAFLD.展开更多
Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors,osteoinductive biofactors and biocompatible scaffold materials.Mesenchymal stem cells(MSCs)represent the most pro...Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors,osteoinductive biofactors and biocompatible scaffold materials.Mesenchymal stem cells(MSCs)represent the most promising seed cells for bone tissue engineering.As multipotent stem cells that can self-renew and differentiate into multiple lineages including bone and fat,MSCs can be isolated from numerous tissues and exhibit varied differentiation potential.To identify an optimal progenitor cell source for bone tissue engineering,we analyzed the proliferative activity and osteogenic potential of four commonly-used mouse MSC sources,including immortalized mouse embryonic fibroblasts(iMEF),immortalized mouse bone marrow stromal stem cells(imBMSC),immortalized mouse calvarial mesenchymal progenitors(iCAL),and immortalized mouse adipose-derived mesenchymal stem cells(iMAD).We found that iMAD exhibited highest osteogenic and adipogenic capabilities upon BMP9 stimulation in vitro,whereas iMAD and iCAL exhibited highest osteogenic capability in BMP9-induced ectopic osteogenesis and critical-sized calvarial defect repair.Transcriptomic analysis revealed that,while each MSC line regulated a distinct set of target genes upon BMP9 stimulation,all MSC lines underwent osteogenic differentiation by regulating osteogenesis-related signaling including Wnt,TGF-β,PI3K/AKT,MAPK,Hippo and JAK-STAT pathways.Collectively,our results demonstrate that adipose-derived MSCs represent optimal progenitor sources for cell-based bone tissue engineering.展开更多
Syrosingopine is an anti-hypertensive drug and can cause high intracellular lactate levels and end-product inhibition of lactate dehydrogenase by inhibiting the lactate transporters MCT1 and MCT4.Previous studies have...Syrosingopine is an anti-hypertensive drug and can cause high intracellular lactate levels and end-product inhibition of lactate dehydrogenase by inhibiting the lactate transporters MCT1 and MCT4.Previous studies have shown that syrosingopine plays an essential role in the process of glycolytic blockade,ATP depletion,and cell death in cancer due to high intracellular levels of lactate.展开更多
With the rapid advances in stem cell research and po-tential cell-based therapies,there is an urgent need to develop safe and reliable cell transport strategies.Except for autologous stem cell-based therapies,allogene...With the rapid advances in stem cell research and po-tential cell-based therapies,there is an urgent need to develop safe and reliable cell transport strategies.Except for autologous stem cell-based therapies,allogeneic stem cell therapies and ex vivo genetically engineered cell therapies would require safe,efficient,and reliable cell preservation and transport methods.展开更多
基金supported in part by research grants from the Natural Science Foundation of China(No.82102696 to J.F.)the Chongqing Natural Science Foundation of China(No.2024NSCQ-MSX0073 to J.F.)+1 种基金the US National Institutes of Health(No.CA226303 to T.C.H.DE030480 to R.R.R.).
文摘Hypertrophic scar and keloid are a major medical problem,which may lead to disfigurement,growth restriction,and permanent loss of function,causing severe physical,psychological,and economic burdens.1 When skin injury occurs,the wound heals through a dynamic series of physiological events,including blood clotting,granulation tissue formation,re-epithelialization,and extracellular matrix remodeling.2 However,the newly formed extracellular matrix in a scar may never achieve the flexibility or strength of the original tissue.
基金supported in part by research grants from the Natural Science Foundation of China(82102696,JF)Chongqing Nat-ural Science Foundation(2024NSCQ-MSX0073,JF)+3 种基金the National Institutes of Health(CA226303 to TCH,and DE030480 to RRR)supported in part by The University of Chicago Comprehensive Cancer Center Support Grant(P30CA014599)the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.
文摘Skin serves as the first-order protective barrier against the environment and any significant disruptions in skin integrity must be promptly restored.Despite significant advances in therapeutic strategies,effective management of large chronic skin wounds remains a clinical challenge.Dermal fibroblasts are the primary cell type responsible for remodeling the extracellular matrix(ECM)in wound healing.Here,we investigated whether ECM derived from exogenous fibroblasts,in combination with keratinocytes,promoted scarless cutaneous wound healing.To overcome the limited lifespan of primary dermal fibroblasts,we established reversibly immortalized mouse dermal fibroblasts(imDFs),which were non-tumorigenic,expressed dermal fibroblast markers,and were responsive to TGF-β1 stimulation.The decellularized ECM prepared from both imDFs and primary dermal fi-broblasts shared similar expression profiles of extracellular matrix proteins and promoted the proliferation of keratinocyte(iKera)cells.The imDFs-derived ECM solicited no local immune response.While the ECM and to a lesser extent imDFs enhanced skin wound healing with excessive fibrosis,a combination of imDFs-derived ECM and iKera cells effectively promoted the re-epithelization and scarless healing of full-thickness skin wounds.These findings strongly suggest that dermal fibroblast-derived ECM,not fibroblasts themselves,may synergize with keratinocytes in regulating scarless healing and re-epithelialization of skin wounds.Given its low immu-nogenic nature,imDFs-derived ECM should be a valuable resource of skin-specific biomaterial for wound healing and skin tissue engineering.
基金supported in part by research grants from the Natural Science Foundation of China(No.82102696 to J.F.)the Chongqing Natural Science Foundation of China(No.2024NSCQ-MSX0073 to J.F.)+3 种基金the US National Institutes of Health(No.CA226303 to T.C.H.)supported in part by The University of Chicago Cancer Center Support Grant(No.P30CA014599)the National Center for Advancing Translational Sciences of the US National Institutes of Health(No.UL1 TR000430)T.C.H.was supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.
文摘Non-alcoholic fatty liver disease(NAFLD)patients have multiple metabolic distur-bances,with markedly elevated levels of lactate.Lactate accumulations play pleiotropic roles in disease progression through metabolic rearrangements and epigenetic modifications.Mono-carboxylate transporter 4(MCT4)is highly expressed in hepatocytes and responsible for trans-porting intracellular lactate out of the cell.To explore whether elevated MCT4 levels played any role in NAFLD development,we overexpressed and silenced MCT4 in hepatocytes and per-formed a comprehensive in vitro and in vivo analysis.Our results revealed that MCT4 overex-pression down-regulated the genes for lipid synthesis while up-regulating the genes involved in lipid catabolism.Conversely,silencing MCT4 expression or inhibiting MCT4 expression led to the accumulation of intracellular lipid and glucose metabolites,resulting in hepatic steatosis.In a mouse model of NAFLD,we found that exogenous MCT4 overexpression significantly reduced lipid metabolism and alleviated hepatocellular steatosis.Mechanistically,MCT4 alle-viated hepatic steatosis by regulating a group of hub genes such as Arg2,Olr1,Cd74,Mmp8,Irf7,Spp1,and Apoe,which in turn impacted multiple pathways involved in lipid metabolism and inflammatory response,such as PPAR,HIF-1,TNF,IL-17,PI3K-AKT,Wnt,and JAK-STAT.Collectively,our results strongly suggest that MCT4 may play an important role in regulating lipid metabolism and inflammation and thus serve as a potential therapeutic target for NAFLD.
基金by research grants from the Natural Science Foundation of China(82102696 to JF)the Chongqing Bayu Young Scholar Award(JF),the 2019 Chongqing Support Program for Entrepreneurship and Innovation(No.cx2019113 to JF)+4 种基金the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298 to JF)the National Institutes of Health(CA226303 to TCH,and DE030480 to RRR)supported by the Medical Scientist Training Program of the National Institutes of Health(T32 GM007281)supported in part by The University of Chicago Cancer Center Support Grant(P30CA014599)the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1TR002389-07.
文摘Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors,osteoinductive biofactors and biocompatible scaffold materials.Mesenchymal stem cells(MSCs)represent the most promising seed cells for bone tissue engineering.As multipotent stem cells that can self-renew and differentiate into multiple lineages including bone and fat,MSCs can be isolated from numerous tissues and exhibit varied differentiation potential.To identify an optimal progenitor cell source for bone tissue engineering,we analyzed the proliferative activity and osteogenic potential of four commonly-used mouse MSC sources,including immortalized mouse embryonic fibroblasts(iMEF),immortalized mouse bone marrow stromal stem cells(imBMSC),immortalized mouse calvarial mesenchymal progenitors(iCAL),and immortalized mouse adipose-derived mesenchymal stem cells(iMAD).We found that iMAD exhibited highest osteogenic and adipogenic capabilities upon BMP9 stimulation in vitro,whereas iMAD and iCAL exhibited highest osteogenic capability in BMP9-induced ectopic osteogenesis and critical-sized calvarial defect repair.Transcriptomic analysis revealed that,while each MSC line regulated a distinct set of target genes upon BMP9 stimulation,all MSC lines underwent osteogenic differentiation by regulating osteogenesis-related signaling including Wnt,TGF-β,PI3K/AKT,MAPK,Hippo and JAK-STAT pathways.Collectively,our results demonstrate that adipose-derived MSCs represent optimal progenitor sources for cell-based bone tissue engineering.
基金supported in part by research grants from the National Natural Science Foundation of China(No.82102696 to JMF)and the National Institutes of Health(USA)(No.CA226303 to T.-C.He)supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.
文摘Syrosingopine is an anti-hypertensive drug and can cause high intracellular lactate levels and end-product inhibition of lactate dehydrogenase by inhibiting the lactate transporters MCT1 and MCT4.Previous studies have shown that syrosingopine plays an essential role in the process of glycolytic blockade,ATP depletion,and cell death in cancer due to high intracellular levels of lactate.
基金supported in part by research grants from the Natural Science Foundation of China(No.82102696 to JF)the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298 to JF)the National Institutes of Health(No.CA226303 to TCH,DE030480 to RRR).
文摘With the rapid advances in stem cell research and po-tential cell-based therapies,there is an urgent need to develop safe and reliable cell transport strategies.Except for autologous stem cell-based therapies,allogeneic stem cell therapies and ex vivo genetically engineered cell therapies would require safe,efficient,and reliable cell preservation and transport methods.
