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
The evolutionarily conserved Wnt signaling pathway plays a central role in develop-ment and adult tissue homeostasis across species.Wnt proteins are secreted,lipid-modified signaling molecules that activate the canoni...The evolutionarily conserved Wnt signaling pathway plays a central role in develop-ment and adult tissue homeostasis across species.Wnt proteins are secreted,lipid-modified signaling molecules that activate the canonical(β-catenin dependent)and non-canonical(β-catenin independent)Wnt signaling pathways.Cellular behaviors such as proliferation,differ-entiation,maturation,and proper body-axis specification are carried out by the canonical pathway,which is the best characterized of the known Wnt signaling paths.Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues.This includes but is not limited to embryonic,hematopoietic,mesenchymal,gut,neural,and epidermal stem cells.Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties.Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders.Not surprisingly,aberrant Wnt signaling is also associated with a wide variety of diseases,including cancer.Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation,epithelial-mesenchymal transition,and metastasis.Altogether,advances in the understand-ing of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway.Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt,this review aims to summarize the cur-rent knowledge of Wnt signaling in stem cells,aberrations to the Wnt pathway associated with diseases,and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.展开更多
Recombinant adenovirus(rAdV)is a commonly used vector system for gene transfer.Efficient initial packaging and subsequent production of rAdV remains time-consuming and labor-intensive,possibly attributable to rAdv inf...Recombinant adenovirus(rAdV)is a commonly used vector system for gene transfer.Efficient initial packaging and subsequent production of rAdV remains time-consuming and labor-intensive,possibly attributable to rAdv infection-associated oxidative stress and reactive oxygen species(ROS)production.Here,we show that exogenous GAPDH expression mitigates adenovirus-induced ROS-associated apoptosis in HEK293 cells,and expedites adenovirus production.By stably overexpressing GAPDH in HEK293(293G)and 293pTP(293GP)cells,respectively,we demonstrated that rAdV-induced RoS production and cell apoptosis were significantly suppressed in 293G and 293GP cells.Transfection of 293G cells with adenoviral plasmid pAd-G2Luc yielded much higher titers of Ad-G2Luc at day 7 than that in HEK293 cells.Similarly,Ad-G2Luc was amplified more efficiently in 293G than in HEK293 cells.We further showed that transfection of 293GP cells with pAd-G2Luc produced much higher titers of Ad-G2Luc at day 5 than that of 293pTP cells.293GP cells amplified the Ad-G2Luc much more efficiently than 293pTP cells,indicating that exogenous GAPDH can further augment pTP-enhanced adenovirus production.These results demonstrate that exogenous GAPDH can effectively suppress adenovirus-induced ROS and thus accelerate adenovirus production.Therefore,the engineered 293GP cells represent a superfast rAdV production system for adenovirus-based gene transfer and gene therapy.展开更多
Wnt signaling plays a major role in regulating cell proliferation and differentiation.The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors an...Wnt signaling plays a major role in regulating cell proliferation and differentiation.The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either throughβ-catenin in the canonical pathway or through a series of other proteins in the nonca-nonical pathway.Many of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body,establishing the complex interplay between Wnt signaling and other signaling pathways.This crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ processes.Dys-regulation of this system has been implicated in many diseases affecting a wide array of organ systems,including cancer and embryological defects,and can even cause embryonic lethality.The complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic treatments.However,both stimulatory and inhibitory treatments come with potential risks that need to be addressed.This review synthesized much of the current knowl-edge on the Wnt signaling pathway,beginning with the history of Wnt signaling.It thoroughly described the different variants of Wnt signaling,including canonical,noncanonical Wnt/PCP,and the noncanonical Wnt/Ca2+pathway.Further description involved each of its components and their involvement in other cellular processes.Finally,this review explained the various other pathways and processes that crosstalk with Wnt signaling.展开更多
To the Editor:Creatine kinase(CK),also called creatine phosphokinase,is primarily located in the cytoplasm and mitochondria.It can be used to diagnose cardiac diseases such as myocardial infarction,viral myocarditis,a...To the Editor:Creatine kinase(CK),also called creatine phosphokinase,is primarily located in the cytoplasm and mitochondria.It can be used to diagnose cardiac diseases such as myocardial infarction,viral myocarditis,and pericarditis because it is a vital kinase directly related to intracellular energy operation,muscle contraction,and adenosine triphosphate(ATP)regeneration.Several studies have confirmed in recent years that serum biomarkers such as elevated CK are associated with Alzheimer’s disease(AD)and its related pathological protein.[1]Previous research indicated that systemic conditions,particularly cardiovascular and cerebrovascular diseases,are significant risk factors for cognitive impairment,and dysfunction of peripheral organs may also contribute to cognitive decline and AD.[2]However,the connection between CK and AD remains unknown.Therefore,to investigate the association between CK and cerebrospinal fluid(CSF)AD pathology biomarkers,we analyzed data from the Alzheimer’s Disease Neuroimaging Initiative(ADNI),a global multi-centered database.展开更多
Recent advances in deep sequencing technologies have revealed that,while less than 2%of the human genome is transcribed into mRNA for protein synthesis,over 80%of the genome is transcribed,leading to the production of...Recent advances in deep sequencing technologies have revealed that,while less than 2%of the human genome is transcribed into mRNA for protein synthesis,over 80%of the genome is transcribed,leading to the production of large amounts of noncoding RNAs(ncRNAs).It has been shown that ncRNAs,especially long non-coding RNAs(lncRNAs),may play crucial regulatory roles in gene expression.As one of the first isolated and reported lncRNAs,H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis,development,tumorigenesis,osteogen-esis,and metabolism.Mechanistically,H19 mediates diverse regulatory functions by serving as competing endogenous RNAs(CeRNAs),Igf2/H19 imprinted tandem gene,modular scaffold,cooperating with H19 antisense,and acting directly with other mRNAs or lncRNAs.Here,we summarized the current understanding of H19 in embryogenesis and development,cancer development and progression,mesenchymal stem cell lineage-specific differentiation,and metabolic diseases.We discussed the potential regulatory mechanisms underlying H19’s func-tions in those processes although more in-depth studies are warranted to delineate the exact molecular,cellular,epigenetic,and genomic regulatory mechanisms underlying the physiolog-ical and pathological roles of H19.Ultimately,these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.展开更多
While progenitor cell-based cardiomyocyte regeneration holds great promise of repairing an injured heart,primary cardiomyogenic progenitors(CPs)have a limited life span in culture,hampering the use of CPs for in vitro...While progenitor cell-based cardiomyocyte regeneration holds great promise of repairing an injured heart,primary cardiomyogenic progenitors(CPs)have a limited life span in culture,hampering the use of CPs for in vitro and in vivo studies.We previously isolated primary CPs from mouse E15.5 fetal heart,and reversibly immortalized them with SV40 large T antigen(SV40 LTA),resulting in immortalized CPs(iCPs),which maintain long-term proliferation and ex-press cardiomyogenic markers and retain differentiation potential under appropriate differentiation conditions.展开更多
Although bone morphogenetic proteins(BMPs)initially showed effective induction of ectopic bone growth in muscle,it has since been determined that these proteins,as members of the TGF-b superfamily,play a diverse and c...Although bone morphogenetic proteins(BMPs)initially showed effective induction of ectopic bone growth in muscle,it has since been determined that these proteins,as members of the TGF-b superfamily,play a diverse and critical array of biological roles.These roles include regulating skeletal and bone formation,angiogenesis,and development and homeostasis of multiple organ systems.Disruptions of the members of the TGF-b/BMP superfamily result in severe skeletal and extra-skeletal irregularities,suggesting high therapeutic potential from understanding this family of BMP proteins.Although it was once one of the least characterized BMPs,BMP9 has revealed itself to have the highest osteogenic potential across numerous experiments both in vitro and in vivo,with recent studies suggesting that the exceptional potency of BMP9 may result from unique signaling pathways that differentiate it from other BMPs.The effectiveness of BMP9 in inducing bone formation was recently revealed in promising experiments that demonstrated efficacy in the repair of critical sized cranial defects as well as compatibility with bone-inducing bio-implants,revealing the great translational promise of BMP9.Furthermore,emerging evidence indicates that,besides its osteogenic activity,BMP9 exerts a broad range of biological functions,including stem cell differentiation,angiogenesis,neurogenesis,tumorigenesis,and metabolism.This review aims to summarize our current understanding of BMP9 across biology and the body.展开更多
Tooth is a complex hard tissue organ and consists of multiple cell types that are regulated by important signaling pathways such as Wnt and BMP signaling.Serious injuries and/or loss of tooth or periodontal tissues ma...Tooth is a complex hard tissue organ and consists of multiple cell types that are regulated by important signaling pathways such as Wnt and BMP signaling.Serious injuries and/or loss of tooth or periodontal tissues may significantly impact aesthetic appearance,essential oral functions and the quality of life.Regenerative dentistry holds great promise in treating oral/dental disorders.The past decade has witnessed a rapid expansion of our understanding of the biological features of dental stem cells,along with the signaling mechanisms governing stem cell self-renewal and differentiation.In this review,we first summarize the biological characteristics of seven types of dental stem cells,including dental pulp stem cells,stem cells from apical papilla,stem cells from human exfoliated deciduous teeth,dental follicle precursor cells,periodontal ligament stem cells,alveolar bone-derived mesenchymal stem cells(MSCs),and MSCs from gingiva.We then focus on how these stem cells are regulated by bone morphogenetic protein(BMP)and/or Wnt signaling by examining the interplays between these pathways.Lastly,we analyze the current status of dental tissue engineering strategies that utilize oral/dental stem cells by harnessing the interplays between BMP and Wnt pathways.We also highlight the challenges that must be addressed before the dental stem cells may reach any clinical applications.Thus,we can expect to witness significant progresses to be made in regenerative dentistry in the coming decade.展开更多
Bone morphogenetic protein 9(BMP9)(or GDF2)was originally identified from fetal mouse liver cDNA libraries.Emerging evidence indicates BMP9 exerts diverse and pleiotropic functions during postnatal development and in ...Bone morphogenetic protein 9(BMP9)(or GDF2)was originally identified from fetal mouse liver cDNA libraries.Emerging evidence indicates BMP9 exerts diverse and pleiotropic functions during postnatal development and in maintaining tissue homeostasis.However,the expression landscape of BMP9 signaling during development and/or in adult tissues remains to be analyzed.Here,we conducted a comprehensive analysis of the expression landscape of BMP9 and its signaling mediators in postnatal mice.By analyzing mouse ENCODE transcriptome datasets we found Bmp9 was highly expressed in the liver and detectable in embryonic brain,adult lungs and adult placenta.We next conducted a comprehensive qPCR analysis of RNAs isolated from major mouse tissues/organs at various ages.We found that Bmp9 was highly expressed in the liver and lung tissues of young adult mice,but decreased in older mice.Interestingly,Bmp9 was only expressed at low to modest levels in developing bones.BMP9-associated TGFβ/BMPR type I receptor Alk1 was highly expressed in the adult lungs.Furthermore,the feedback inhibitor Smads Smad6 and Smad7 were widely expressed in mouse postnatal tissues.However,the BMP signaling antagonist noggin was highly expressed in fat and heart in the older age groups,as well as in kidney,liver and lungs in a biphasic fashion.Thus,our findings indicate that the circulating BMP9 produced in liver and lungs may account for its pleiotropic effects on postnatal tissues/organs although possible roles of BMP9 signaling in liver and lungs remain to be fully understood.展开更多
The treatment of cancer mainly involves surgical excision supplemented by radiotherapy and chemotherapy.Chemotherapy drugs act by interfering with tumor growth and inducing the death of cancer cells.Anti-tumor drugs w...The treatment of cancer mainly involves surgical excision supplemented by radiotherapy and chemotherapy.Chemotherapy drugs act by interfering with tumor growth and inducing the death of cancer cells.Anti-tumor drugs were developed to induce apoptosis,but some patient’s show apoptosis escape and chemotherapy resistance.Therefore,other forms of cell death that can overcome the resistance of tumor cells are important in the context of cancer treatment.Ferroptosis is a newly discovered iron-dependent,non-apoptotic type of cell death that is highly negatively correlated with cancer development.Ferroptosis is mainly caused by the abnormal increase in iron-dependent lipid reactive oxygen species and the imbalance of redox homeostasis.This review summarizes the progression and regulatory mechanism of ferroptosis in cancer and discusses its possible clinical applications in cancer diagnosis and treatment.展开更多
A thin layer of poly(vinyl alcohol)(PVA) was coated on the surface of silicon carbide whiskers(SCWs)and crosslinked by glutaraldehyde, and then these modified whiskers(mSCWs) were incorporated into high density polyet...A thin layer of poly(vinyl alcohol)(PVA) was coated on the surface of silicon carbide whiskers(SCWs)and crosslinked by glutaraldehyde, and then these modified whiskers(mSCWs) were incorporated into high density polyethylene(HDPE) to prepare HDPE/mSCW composites with a high thermal conductivity.The thermal conductivity, mechanical properties, heat resistance, thermal stability and morphology of HDPE/mSCW and HDPE/SCW composites were characterized and compared. The results reveal that the thermal conductivity of both HDPE/SCW and HDPE/mSCW composites increases with the increase of filler loading, and reaches a maximum of 1.48 and 1.69 W/(m K) at 40 wt% filler loading, which is 251.20% and 300.75% higher than that of HDPE, respectively. Significantly, HDPE/mSCW composites have a higher thermal conductivity than their HDPE/SCW counterparts with the same filler loading. In addition, the heat resistance, Young’s modulus and yield strength of both HDPE/SCW and HDPE/mSCW composites are also improved compared with that of HDPE. mSCW can be homogenously dispersed in the HDPE matrix, which contributes to the formation of thermally conductive networks by the inter-connection of mSCWs.展开更多
As multipotent progenitor cells,mesenchymal stem cells(MSCs)can renew themselves and give rise to multiple lineages including osteoblastic,chondrogenic and adipogenic lineages.It’s previously shown that BMP9 is the m...As multipotent progenitor cells,mesenchymal stem cells(MSCs)can renew themselves and give rise to multiple lineages including osteoblastic,chondrogenic and adipogenic lineages.It’s previously shown that BMP9 is the most potent BMP and induces osteogenic and adipogenic differentiation of MSCs.However,the molecular mechanism through which BMP9 regulates MSC differentiation remains poorly understood.Emerging evidence indicates that noncoding RNAs,especially microRNAs,may play important roles in regulating MSC differentiation and bone formation.As highly conserved RNA binding proteins,Argonaute(AGO)proteins are essential components of the multi-protein RNA-induced silencing complexes(RISCs),which are critical for small RNA biogenesis.Here,we investigate possible roles of AGO proteins in BMP9-induced lineage-specific differentiation of MSCs.We first found that BMP9 upregulated the expression of Ago1,Ago2 and Ago3 in MSCs.By engineering multiplex siRNA vectors that express multiple siRNAs targeting individual Ago genes or all four Ago genes,we found that silencing individual Ago expression led to a decrease in BMP9-induced early osteogenic marker alkaline phosphatase(ALP)activity in MSCs.Furthermore,we demonstrated that simultaneously silencing all four Ago genes significantly diminished BMP9-induced osteogenic and adipogenic differentiation of MSCs and matrix mineralization,and ectopic bone formation.Collectively,our findings strongly indicate that AGO proteins and associated small RNA biogenesis pathway play an essential role in mediating BMP9-induced osteogenic differentiation of MSCs.展开更多
Skin injury is repaired through a multi-phase wound healing process of tissue granulation and re-epithelialization.Any failure in the healing process may lead to chronic non-healing wounds or abnormal scar formation.A...Skin injury is repaired through a multi-phase wound healing process of tissue granulation and re-epithelialization.Any failure in the healing process may lead to chronic non-healing wounds or abnormal scar formation.Although significant progress has been made in developing novel scaffolds and/or cell-based therapeutic strategies to promote wound healing,effective management of large chronic skin wounds remains a clinical challenge.Keratinocytes are critical to re-epithelialization and wound healing.Here,we investigated whether exogenous keratinocytes,in combination with a citrate-based scaffold,enhanced skin wound healing.We first established reversibly immortalized mouse keratinocytes(iKera),and confirmed that the iKera cells expressed keratinocyte markers,and were responsive to UVB treatment,and were non-tumorigenic.In a proof-of-principle experiment,we demonstrated that iKera cells embedded in citrate-based scaffold PPCN provided more effective re-epithelialization and cutaneous wound healing than that of either PPCN or iKera cells alone,in a mouse skin wound model.Thus,these results demonstrate that iKera cells may serve as a valuable skin epithelial source when,combining with appropriate biocompatible scaffolds,to investigate cutaneous wound healing and skin regeneration.展开更多
Liver is an important organ for regulating glucose and lipid metabolism.Recent studies have shown that bone morphogenetic proteins(BMPs)may play important roles in regu-lating glucose and lipid metabolism.Inour previo...Liver is an important organ for regulating glucose and lipid metabolism.Recent studies have shown that bone morphogenetic proteins(BMPs)may play important roles in regu-lating glucose and lipid metabolism.Inour previous studies,we demonstrated that BMP4 signif-icantly inhibits hepatic steatosis and lowers serum triglycerides,playing a protective role against the progression of non-alcoholic fatty liver disease(NAFLD).However,the direct impact of BMP4 on hepatic glucose metabolism is poorly understood.Here,we investigated the regulatory roles of BMP4 in hepatic glucose metabolism.Through a comprehensive analysis of the 14 types of BMPs,we found that BMP4 was one of the most potent BMPs in promoting hepatic glycogen accumulation,reducing the level of glucose in hepatocytes and effecting the expression of genes related to glucose metabolism.Mechanistically,we demonstrated that BMP4 reduced the hepatic glucose lewels through the activation of mTORC2 signaling pathway in vitro and in wivo.Collectively,our findings strongly suggest that BMP4 may play an essential role in regulating hepatic glucose metabolism.This knowledge should aid us to understand the molecular pathogenesis of NAFLD,and may lead to the development of novel therapeutics by exploiting the inhibitory effects of BMPs on hepatic glucose and lipid metabolism.展开更多
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.
基金supported in part by research grants from the National Institutes of Health(No.CA226303 to TCH and No.DE030480 to RRR)JF was supported in part by research grants from the Natural Science Foundation of China(No.82102696)+4 种基金the 2019 Science and Technology Research Plan Project of Chongqing Education Commission(China)(No.KJQN201900410)the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298,Chongqing,China)WW was supported by the Medical Scientist Training Program of the National Institutes of Health(No.T32 GM007281)This project was also supported in part by The University of Chicago Cancer Center Support Grant(No.P30CA014599)the National Center for Advancing Translational Sciences(NCATS)of the National Institutes of Health(No.5UL1TR002389).
文摘The evolutionarily conserved Wnt signaling pathway plays a central role in develop-ment and adult tissue homeostasis across species.Wnt proteins are secreted,lipid-modified signaling molecules that activate the canonical(β-catenin dependent)and non-canonical(β-catenin independent)Wnt signaling pathways.Cellular behaviors such as proliferation,differ-entiation,maturation,and proper body-axis specification are carried out by the canonical pathway,which is the best characterized of the known Wnt signaling paths.Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues.This includes but is not limited to embryonic,hematopoietic,mesenchymal,gut,neural,and epidermal stem cells.Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties.Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders.Not surprisingly,aberrant Wnt signaling is also associated with a wide variety of diseases,including cancer.Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation,epithelial-mesenchymal transition,and metastasis.Altogether,advances in the understand-ing of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway.Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt,this review aims to summarize the cur-rent knowledge of Wnt signaling in stem cells,aberrations to the Wnt pathway associated with diseases,and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.
基金supported in part by research grants from the Natural Science Foundation of China (No.82000744 to ZT,and 82102696 to J.F.)the Chongqing Bayu Young Scholar Award (China) (to J.F.)+5 种基金the 2019 Funding for Postdoctoral Research (Chongqing Human Resources and Social Security Bureau of China) (No.298 to J.F.)the National Institutes of Health (No.CA226303 to T.C.H.,DE030480 to R.R.R.)supported by the Medical Scientist Training Program of the National Institutes of Health (USA) (No.T32 GM007281)supported in part by The University of Chicago Cancer Center Support Grant (No.P30CA014599)the National Center for Advancing Translational Sciences of the National Institutes of Health through grant number 2UL1TR002389-06 that funds the Institute for Translational Medicine (ITM)supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.
文摘Recombinant adenovirus(rAdV)is a commonly used vector system for gene transfer.Efficient initial packaging and subsequent production of rAdV remains time-consuming and labor-intensive,possibly attributable to rAdv infection-associated oxidative stress and reactive oxygen species(ROS)production.Here,we show that exogenous GAPDH expression mitigates adenovirus-induced ROS-associated apoptosis in HEK293 cells,and expedites adenovirus production.By stably overexpressing GAPDH in HEK293(293G)and 293pTP(293GP)cells,respectively,we demonstrated that rAdV-induced RoS production and cell apoptosis were significantly suppressed in 293G and 293GP cells.Transfection of 293G cells with adenoviral plasmid pAd-G2Luc yielded much higher titers of Ad-G2Luc at day 7 than that in HEK293 cells.Similarly,Ad-G2Luc was amplified more efficiently in 293G than in HEK293 cells.We further showed that transfection of 293GP cells with pAd-G2Luc produced much higher titers of Ad-G2Luc at day 5 than that of 293pTP cells.293GP cells amplified the Ad-G2Luc much more efficiently than 293pTP cells,indicating that exogenous GAPDH can further augment pTP-enhanced adenovirus production.These results demonstrate that exogenous GAPDH can effectively suppress adenovirus-induced ROS and thus accelerate adenovirus production.Therefore,the engineered 293GP cells represent a superfast rAdV production system for adenovirus-based gene transfer and gene therapy.
基金supported in part by research grants from the National Institutes of Health(No.CA226303 to TCH and No.DE030480 to RRR)the American Shoulder and Elbow Surgeons PJI Research Grant(LLS).JF was supported in part by research grants from the Natural Science Foundation of China(No.82102696)+4 种基金the 2019 Science and Technology Research Plan Project of Chongqing Education Commission(China)(No.KJQN201900410)the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298)WW was supported by the Medical Scientist Training Program of the National Institutes of Health(No.T32 GM007281)This project was also supported in partby The University of Chicago Cancer Center Support Grant(No.P30CA014599)the National Center for Advancing Translational Sciences(NCATS)of the National Institutes of Health through Grant Number 5UL1TR002389.
文摘Wnt signaling plays a major role in regulating cell proliferation and differentiation.The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either throughβ-catenin in the canonical pathway or through a series of other proteins in the nonca-nonical pathway.Many of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body,establishing the complex interplay between Wnt signaling and other signaling pathways.This crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ processes.Dys-regulation of this system has been implicated in many diseases affecting a wide array of organ systems,including cancer and embryological defects,and can even cause embryonic lethality.The complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic treatments.However,both stimulatory and inhibitory treatments come with potential risks that need to be addressed.This review synthesized much of the current knowl-edge on the Wnt signaling pathway,beginning with the history of Wnt signaling.It thoroughly described the different variants of Wnt signaling,including canonical,noncanonical Wnt/PCP,and the noncanonical Wnt/Ca2+pathway.Further description involved each of its components and their involvement in other cellular processes.Finally,this review explained the various other pathways and processes that crosstalk with Wnt signaling.
基金supported by the Clinical Trial Ability Improvement Project of the Cardiovascular Professional Group of the First Affiliated Hospital of Soochow University(No.201900180019)
文摘To the Editor:Creatine kinase(CK),also called creatine phosphokinase,is primarily located in the cytoplasm and mitochondria.It can be used to diagnose cardiac diseases such as myocardial infarction,viral myocarditis,and pericarditis because it is a vital kinase directly related to intracellular energy operation,muscle contraction,and adenosine triphosphate(ATP)regeneration.Several studies have confirmed in recent years that serum biomarkers such as elevated CK are associated with Alzheimer’s disease(AD)and its related pathological protein.[1]Previous research indicated that systemic conditions,particularly cardiovascular and cerebrovascular diseases,are significant risk factors for cognitive impairment,and dysfunction of peripheral organs may also contribute to cognitive decline and AD.[2]However,the connection between CK and AD remains unknown.Therefore,to investigate the association between CK and cerebrospinal fluid(CSF)AD pathology biomarkers,we analyzed data from the Alzheimer’s Disease Neuroimaging Initiative(ADNI),a global multi-centered database.
基金supported by the National Natural Science Foundation of China(NSFC)(No.82002312,81972069)supported in part by research grants from the National Institutes of Health,USA(No.CA226303 to TCH,No.DE030480 to RRR)+10 种基金supported by the Science and Technology Research Program of Chongqing Education Commission,China(No.KJQN202100431,KJZD-M202100401)the Top Talent Award from The First Affiliated Hospital of Chongqing Medical University,China(No.BJRC2021-04)Cultivation Program of Postdoctoral Research of The First Affiliated Hospital of Chongqing Medical University,China(No.CYYY-BSHPYXM-202202)supported by a post-doctoral fellowship from Chongqing Medical University and rewarded by China Postdoctoral Science Foundation(No.2022M720605)supported in part by research grants from the 2019 Science and Technology Project of Chongqing Education Commission,China(No.KJQN201900410)the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298)the Natural Science Foundation of China(No.82102696)supported by the Medical Scientist Training Program of the National Institutes of Health,USA(No.T32 GM007281)supported in part by The University of Chicago Cancer Center Support Grant,USA(No.P30CA014599)the National Center for Advancing Translational Sciences(NCATS)of the National Institutes of Health,USA(No.5UL1TR002389)supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopedics Alumni Fund.
文摘Recent advances in deep sequencing technologies have revealed that,while less than 2%of the human genome is transcribed into mRNA for protein synthesis,over 80%of the genome is transcribed,leading to the production of large amounts of noncoding RNAs(ncRNAs).It has been shown that ncRNAs,especially long non-coding RNAs(lncRNAs),may play crucial regulatory roles in gene expression.As one of the first isolated and reported lncRNAs,H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis,development,tumorigenesis,osteogen-esis,and metabolism.Mechanistically,H19 mediates diverse regulatory functions by serving as competing endogenous RNAs(CeRNAs),Igf2/H19 imprinted tandem gene,modular scaffold,cooperating with H19 antisense,and acting directly with other mRNAs or lncRNAs.Here,we summarized the current understanding of H19 in embryogenesis and development,cancer development and progression,mesenchymal stem cell lineage-specific differentiation,and metabolic diseases.We discussed the potential regulatory mechanisms underlying H19’s func-tions in those processes although more in-depth studies are warranted to delineate the exact molecular,cellular,epigenetic,and genomic regulatory mechanisms underlying the physiolog-ical and pathological roles of H19.Ultimately,these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.
基金supported in part by research grants from the National Institutes of Health(No.CA226303 to T.C.H.,No.DE030480 to R.R.R.).supported in part by research grants from the 2019 Science and Technology Research Plan Project of the Chongqing Education Commission(China)(No.KJQN201900410)+2 种基金the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298)the Natural Science Foundation of China(No.82102696)supported by the Medical Scientist Training Program of the National Institutes of Health(No.T32 GM007281).
文摘While progenitor cell-based cardiomyocyte regeneration holds great promise of repairing an injured heart,primary cardiomyogenic progenitors(CPs)have a limited life span in culture,hampering the use of CPs for in vitro and in vivo studies.We previously isolated primary CPs from mouse E15.5 fetal heart,and reversibly immortalized them with SV40 large T antigen(SV40 LTA),resulting in immortalized CPs(iCPs),which maintain long-term proliferation and ex-press cardiomyogenic markers and retain differentiation potential under appropriate differentiation conditions.
基金The reported work was supported in part by research grants from the National Institutes of Health(CA226303,DE020140 to TCH and RRR)the U.S.Department of Defense(OR130096 to JMW)+5 种基金the Scoliosis Research Society(TCH and MJL)the Scoliosis Research Society(TCH and MJL)the National Key Research and Development Program of China(2016YFC1000803 and 2011CB707906).This project was also supported in part by The University of Chicago Cancer Center Support Grant(P30CA014599)and the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430.SM and MP were supported by the Summer Research Program of The University of Chicago Pritzker School of Medicine.TCH was also supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedic Alumni Fund.Funding sources were not involved in the study designin the collection,analysis and interpretation of datain the writing of the reportand in the decision to submit the paper for publication.
文摘Although bone morphogenetic proteins(BMPs)initially showed effective induction of ectopic bone growth in muscle,it has since been determined that these proteins,as members of the TGF-b superfamily,play a diverse and critical array of biological roles.These roles include regulating skeletal and bone formation,angiogenesis,and development and homeostasis of multiple organ systems.Disruptions of the members of the TGF-b/BMP superfamily result in severe skeletal and extra-skeletal irregularities,suggesting high therapeutic potential from understanding this family of BMP proteins.Although it was once one of the least characterized BMPs,BMP9 has revealed itself to have the highest osteogenic potential across numerous experiments both in vitro and in vivo,with recent studies suggesting that the exceptional potency of BMP9 may result from unique signaling pathways that differentiate it from other BMPs.The effectiveness of BMP9 in inducing bone formation was recently revealed in promising experiments that demonstrated efficacy in the repair of critical sized cranial defects as well as compatibility with bone-inducing bio-implants,revealing the great translational promise of BMP9.Furthermore,emerging evidence indicates that,besides its osteogenic activity,BMP9 exerts a broad range of biological functions,including stem cell differentiation,angiogenesis,neurogenesis,tumorigenesis,and metabolism.This review aims to summarize our current understanding of BMP9 across biology and the body.
基金The authors apologize to those investigators whose original work was not cited due to space constraints.The authors’research was supported in part by research grants from the National Institutes of Health(AT004418&AR054381 to TCH&HHL)Scoliosis Research Society(MJL&TCH),the 973 Program of Ministry of Science and Technology(MOST)of China(#2011CB707900 to TCH),the National Natural Science Foundation of China(#81400493 to FZ)+2 种基金Chongqing Municipal Commissions on Education(#KJ130303 to JW)Chongqing Municipal Commissions on Science&Technology(#cstc2013jcyjA0093 to JW)Chongqing Municipal Commissions Yubei District Science&Technology(#2014 Society of Human Resource Unit 14 to JW).MKM was a recipient of Howard Hughes Medical Institute Medical Research Fellowship.
文摘Tooth is a complex hard tissue organ and consists of multiple cell types that are regulated by important signaling pathways such as Wnt and BMP signaling.Serious injuries and/or loss of tooth or periodontal tissues may significantly impact aesthetic appearance,essential oral functions and the quality of life.Regenerative dentistry holds great promise in treating oral/dental disorders.The past decade has witnessed a rapid expansion of our understanding of the biological features of dental stem cells,along with the signaling mechanisms governing stem cell self-renewal and differentiation.In this review,we first summarize the biological characteristics of seven types of dental stem cells,including dental pulp stem cells,stem cells from apical papilla,stem cells from human exfoliated deciduous teeth,dental follicle precursor cells,periodontal ligament stem cells,alveolar bone-derived mesenchymal stem cells(MSCs),and MSCs from gingiva.We then focus on how these stem cells are regulated by bone morphogenetic protein(BMP)and/or Wnt signaling by examining the interplays between these pathways.Lastly,we analyze the current status of dental tissue engineering strategies that utilize oral/dental stem cells by harnessing the interplays between BMP and Wnt pathways.We also highlight the challenges that must be addressed before the dental stem cells may reach any clinical applications.Thus,we can expect to witness significant progresses to be made in regenerative dentistry in the coming decade.
基金The reported work was supported in part by research grants from the National Institutes of Health(CA226303 to TCH)the U.S.Department of Defense(OR130096 to JMW)+3 种基金the Scoliosis Research Society(TCH and MJL)This project was also 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 UL1 TR000430.TCH was also supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.Funding sources were not involved in the study design,in the collection,analysis and interpretation of datain the writing of the report,and in the decision to submit the paper for publication。
文摘Bone morphogenetic protein 9(BMP9)(or GDF2)was originally identified from fetal mouse liver cDNA libraries.Emerging evidence indicates BMP9 exerts diverse and pleiotropic functions during postnatal development and in maintaining tissue homeostasis.However,the expression landscape of BMP9 signaling during development and/or in adult tissues remains to be analyzed.Here,we conducted a comprehensive analysis of the expression landscape of BMP9 and its signaling mediators in postnatal mice.By analyzing mouse ENCODE transcriptome datasets we found Bmp9 was highly expressed in the liver and detectable in embryonic brain,adult lungs and adult placenta.We next conducted a comprehensive qPCR analysis of RNAs isolated from major mouse tissues/organs at various ages.We found that Bmp9 was highly expressed in the liver and lung tissues of young adult mice,but decreased in older mice.Interestingly,Bmp9 was only expressed at low to modest levels in developing bones.BMP9-associated TGFβ/BMPR type I receptor Alk1 was highly expressed in the adult lungs.Furthermore,the feedback inhibitor Smads Smad6 and Smad7 were widely expressed in mouse postnatal tissues.However,the BMP signaling antagonist noggin was highly expressed in fat and heart in the older age groups,as well as in kidney,liver and lungs in a biphasic fashion.Thus,our findings indicate that the circulating BMP9 produced in liver and lungs may account for its pleiotropic effects on postnatal tissues/organs although possible roles of BMP9 signaling in liver and lungs remain to be fully understood.
基金This study was supported by The National Natural Science Foundation of China(No.81904231,82072978,82072979)the China Postdoctoral Science Foundation(No.2020M672369)+1 种基金the Natural Science Foundation of Hubei Province(No.2020CFB861)the Postdoctoral Innovation Practice Post in Hubei Province(No.34).
文摘The treatment of cancer mainly involves surgical excision supplemented by radiotherapy and chemotherapy.Chemotherapy drugs act by interfering with tumor growth and inducing the death of cancer cells.Anti-tumor drugs were developed to induce apoptosis,but some patient’s show apoptosis escape and chemotherapy resistance.Therefore,other forms of cell death that can overcome the resistance of tumor cells are important in the context of cancer treatment.Ferroptosis is a newly discovered iron-dependent,non-apoptotic type of cell death that is highly negatively correlated with cancer development.Ferroptosis is mainly caused by the abnormal increase in iron-dependent lipid reactive oxygen species and the imbalance of redox homeostasis.This review summarizes the progression and regulatory mechanism of ferroptosis in cancer and discusses its possible clinical applications in cancer diagnosis and treatment.
基金financially sponsored by the National Natural Science Foundation of China(No.U1507123)the Foundation of Qinghai Science and Technology Department(No.2017-HZ-803)+1 种基金the Thousand Talents Program of Qinghai ProvinceKunlun Scholar Award Program of Qinghai Province
文摘A thin layer of poly(vinyl alcohol)(PVA) was coated on the surface of silicon carbide whiskers(SCWs)and crosslinked by glutaraldehyde, and then these modified whiskers(mSCWs) were incorporated into high density polyethylene(HDPE) to prepare HDPE/mSCW composites with a high thermal conductivity.The thermal conductivity, mechanical properties, heat resistance, thermal stability and morphology of HDPE/mSCW and HDPE/SCW composites were characterized and compared. The results reveal that the thermal conductivity of both HDPE/SCW and HDPE/mSCW composites increases with the increase of filler loading, and reaches a maximum of 1.48 and 1.69 W/(m K) at 40 wt% filler loading, which is 251.20% and 300.75% higher than that of HDPE, respectively. Significantly, HDPE/mSCW composites have a higher thermal conductivity than their HDPE/SCW counterparts with the same filler loading. In addition, the heat resistance, Young’s modulus and yield strength of both HDPE/SCW and HDPE/mSCW composites are also improved compared with that of HDPE. mSCW can be homogenously dispersed in the HDPE matrix, which contributes to the formation of thermally conductive networks by the inter-connection of mSCWs.
基金The reported work was supported in part by research grants from the National Institutes of Health(CA226303 to TCH,and AR072731 to JY)the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust(RRR),and the Scoliosis Research Society(TCH and MJL)+2 种基金WW was supported by the Medical Scientist Training Program of the National Institutes of Health(T32 GM007281)This project was also supported in part by The University of Chicago Cancer Center Support Grant(P30CA014599)the National Center for Advancing Translational Sciences(NCATS)of the National Institutes of Health(NIH)through Grant Number 5UL1TR002389-02 that funds the Institute for Translational Medicine(ITM).TCH was supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.
文摘As multipotent progenitor cells,mesenchymal stem cells(MSCs)can renew themselves and give rise to multiple lineages including osteoblastic,chondrogenic and adipogenic lineages.It’s previously shown that BMP9 is the most potent BMP and induces osteogenic and adipogenic differentiation of MSCs.However,the molecular mechanism through which BMP9 regulates MSC differentiation remains poorly understood.Emerging evidence indicates that noncoding RNAs,especially microRNAs,may play important roles in regulating MSC differentiation and bone formation.As highly conserved RNA binding proteins,Argonaute(AGO)proteins are essential components of the multi-protein RNA-induced silencing complexes(RISCs),which are critical for small RNA biogenesis.Here,we investigate possible roles of AGO proteins in BMP9-induced lineage-specific differentiation of MSCs.We first found that BMP9 upregulated the expression of Ago1,Ago2 and Ago3 in MSCs.By engineering multiplex siRNA vectors that express multiple siRNAs targeting individual Ago genes or all four Ago genes,we found that silencing individual Ago expression led to a decrease in BMP9-induced early osteogenic marker alkaline phosphatase(ALP)activity in MSCs.Furthermore,we demonstrated that simultaneously silencing all four Ago genes significantly diminished BMP9-induced osteogenic and adipogenic differentiation of MSCs and matrix mineralization,and ectopic bone formation.Collectively,our findings strongly indicate that AGO proteins and associated small RNA biogenesis pathway play an essential role in mediating BMP9-induced osteogenic differentiation of MSCs.
基金The reported study was supported in part by research grants from the 2019 Chongqing Support Program for Entrepreneurship and Innovation(No.cx2019113)(JF)the 2019 Science and Technology Research Plan Project of Chongqing Education Commission(KJQN201900410)(JF)+9 种基金the 2019 Youth Innovative Talent Training Program of Chongqing Education Commission(No.CY200409)(JF)the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298)(JF)and the National Key Research and Development Program of China(2016YFC1000803)RRR,TCH and GAA were partially funded by the National Institutes of Health(DE030480)WW was supported by the Medical Scientist Training Program of the National Institutes of Health(T32 GM007281)This project was also 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 UL1 TR000430TCH was also supported by the Mabel Green Myers Research Endowment Fund,The University of Chicago Orthopaedics Alumni Fund,and The University of Chicago SHOCK Fund.Funding sources were not involved in the study designin the collection,analysis and/or interpretation of datain the writing of the reportor in the decision to submit the paper for publication.
文摘Skin injury is repaired through a multi-phase wound healing process of tissue granulation and re-epithelialization.Any failure in the healing process may lead to chronic non-healing wounds or abnormal scar formation.Although significant progress has been made in developing novel scaffolds and/or cell-based therapeutic strategies to promote wound healing,effective management of large chronic skin wounds remains a clinical challenge.Keratinocytes are critical to re-epithelialization and wound healing.Here,we investigated whether exogenous keratinocytes,in combination with a citrate-based scaffold,enhanced skin wound healing.We first established reversibly immortalized mouse keratinocytes(iKera),and confirmed that the iKera cells expressed keratinocyte markers,and were responsive to UVB treatment,and were non-tumorigenic.In a proof-of-principle experiment,we demonstrated that iKera cells embedded in citrate-based scaffold PPCN provided more effective re-epithelialization and cutaneous wound healing than that of either PPCN or iKera cells alone,in a mouse skin wound model.Thus,these results demonstrate that iKera cells may serve as a valuable skin epithelial source when,combining with appropriate biocompatible scaffolds,to investigate cutaneous wound healing and skin regeneration.
基金The reported study was supported in part by research grants from the 2017 Chongqing Postdoctoral Innovation Talent Support Program(Chongqing Human Resources and Social Security Bureau No.356)(JMF)the 64th China Postdoctoral Science Fund(No.2018M643426)(JMF)+4 种基金the 2019 Chongqing Support Program for Entrepreneurship and Innovation(Chongqing Human Resources and Social Security Bureau No.288)(JMF)the 2019 Science and Technology Research Plan Project of Chongqing Education Commission(KJQN201900410)(JMF)the 2019 Youth Innovative Talent Training Program of Chongqing Education Commission(CY200409)(JMF)the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298)(JMF)the National Key Research and Development Program of China(2016YFC1000803 and 2011CB707906).
文摘Liver is an important organ for regulating glucose and lipid metabolism.Recent studies have shown that bone morphogenetic proteins(BMPs)may play important roles in regu-lating glucose and lipid metabolism.Inour previous studies,we demonstrated that BMP4 signif-icantly inhibits hepatic steatosis and lowers serum triglycerides,playing a protective role against the progression of non-alcoholic fatty liver disease(NAFLD).However,the direct impact of BMP4 on hepatic glucose metabolism is poorly understood.Here,we investigated the regulatory roles of BMP4 in hepatic glucose metabolism.Through a comprehensive analysis of the 14 types of BMPs,we found that BMP4 was one of the most potent BMPs in promoting hepatic glycogen accumulation,reducing the level of glucose in hepatocytes and effecting the expression of genes related to glucose metabolism.Mechanistically,we demonstrated that BMP4 reduced the hepatic glucose lewels through the activation of mTORC2 signaling pathway in vitro and in wivo.Collectively,our findings strongly suggest that BMP4 may play an essential role in regulating hepatic glucose metabolism.This knowledge should aid us to understand the molecular pathogenesis of NAFLD,and may lead to the development of novel therapeutics by exploiting the inhibitory effects of BMPs on hepatic glucose and lipid metabolism.