Background Vascular hyporeactivity and leakage are key pathophysiologic features that produce multi-organ damage upon sepsis.We hypothesized that pericytes,a group of pluripotent cells that maintain vascular integrity...Background Vascular hyporeactivity and leakage are key pathophysiologic features that produce multi-organ damage upon sepsis.We hypothesized that pericytes,a group of pluripotent cells that maintain vascular integrity and tension,are protective against sepsis via regulating vascular reactivity and permeability.Methods We conducted a series of in vivo experiments using wild-type(WT),platelet-derived growth factor receptor-β(PDGFR-β)-Cre+mT/mG transgenic mice and Tie2-Cre+Cx43^(flox/flox)mice to examine the relative contribution of pericytes in sepsis,either induced by cecal ligation and puncture(CLP)or lipopolysaccharide(LPS)challenge.In a separate set of experiments with Sprague-Dawley(SD)rats,pericytes were depleted using CP-673451,a selective PDGFR-βinhibitor,at a dosage of 40 mg/(kg·d)for 7 consecutive days.Cultured pericytes,vascular endothelial cells(VECs)and vascular smooth muscle cells(VSMCs)were used for mechanistic investigations.The effects of pericytes and pericyte-derived microvesicles(PCMVs)and candidate miRNAs on vascular reactivity and barrier function were also examined.Results CLP and LPS induced severe injury/loss of pericytes,vascular hyporeactivity and leakage(P<0.05).Transplantation with exogenous pericytes protected vascular reactivity and barrier function via microvessel colonization(P<0.05).Cx43 knockout in either pericytes or VECs reduced pericyte colonization in microvessels(P<0.05).Additionally,PCMVs transferred miR-145 and miR-132 to VSMCs and VECs,respectively,exerting a protective effect on vascular reactivity and barrier function after sepsis(P<0.05).miR-145 primarily improved the contractile response of VSMCs by activating the sphingosine kinase 2(Sphk2)/sphingosine-1-phosphate receptor(S1PR)1/phosphorylation of myosin light chain 20 pathway,whereas miR-132 effectively improved the barrier function of VECs by activating the Sphk2/S1PR2/zonula occludens-1 and vascular endothelial-cadherin pathways.Conclusions Pericytes are protective against sepsis through regulating vascular reactivity and barrier function.Possible mechanisms include both direct colonization of microvasculature and secretion of PCMVs.展开更多
This study presents a rare case of delayed hemolytic transfusion reaction(DHTR)induced by anti-Ku.The patient was admitted due to recurrence of ovarian cancer.She had experienced unexplained anemia for more than 20 ye...This study presents a rare case of delayed hemolytic transfusion reaction(DHTR)induced by anti-Ku.The patient was admitted due to recurrence of ovarian cancer.She had experienced unexplained anemia for more than 20 years but had no anemia in the past 10 years.She had been pregnant four times and given birth to four babies without blood transfusions.Pretransfusion examinations showed that her blood group was A and RhD positive,and the unexpected antibody screening test was weakly reactive.She received two red blood cell transfusions and then developed unexplained anemia,with a hemoglobin decrease from 122 to 88 g/L.The unexpected antibody screening result changed to strongly positive,and she returned positive direct anti-human globulin test and major incompatible matching results.The homozygous mutation 715G>T was identified in exon 7 of the KELL gene,which is associated with a rare blood group phenotype known as K0.The patient produced anti-Ku antibodies,leading to a DHTR.Extravascular hemolysis was controlled through the administration of immunoglobulin and erythropoietin,leading to the correction of anemia.Her hemoglobin concentration was 105 g/L upon discharge from the hospital.In the management of blood transfusion for patients with rare blood types,a comprehensive analysis is required,taking into account the specificity of high-frequency antibodies produced by the patient,the types and strength of these antibodies,as well as the clinical demand for blood.When necessary,a short-term,adequate transfusion of minimally incompatible blood may be administered,along with intravenous immunoglobulin and erythropoietin to correct hemolysis and anemia.展开更多
The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis.Although it is well appreciated that the niche plays a critical role in gastric epitheli...The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis.Although it is well appreciated that the niche plays a critical role in gastric epithelium cell differentiation,the relevant molecular factors and the underlying regulatory mechanisms remain poorly understood.In this study,by combining the knowledge of the niche cells obtained from single-cell RNA sequencing and manipulation of signaling pathways,we achieved effective differentiation of various gastric epithelial cell types in mouse and human gastric organoids.These in vitro differentiated cells showed a similar gene expression profile to those in gastric tissues.Specifically,BMP4 signaling stimulates pit cell and parietal cell differentiation.Furthermore,BMP4 and EGF signaling cooperate to enhance pit cell differentiation,whereas inhibition of TGF-βand BMP4 signaling promotes chief cell differentiation.We demonstrated that Zbtb7b is a novel regulator controlling pit cell differentiation.In addition,BMP4,together with the small molecule Isoxazole 9,promotes parietal and enteroendocrine cell differentiation.Our data also revealed the different requirements of parietal and chief cell differentiation between mouse and human.Together,our findings provide a mechanistic insight into gastric epithelial cell differentiation and uncover its similarities and differences between mouse and human,laying a foundation for future investigation and potential clinical use of gastric organoids.展开更多
基金supported by the Key Projects and Innovation Group of National Natural Science Foundation of China(81830065),the Innovation Groups of NSFC(81721001),and the Young Scientists Fund(82102279).
文摘Background Vascular hyporeactivity and leakage are key pathophysiologic features that produce multi-organ damage upon sepsis.We hypothesized that pericytes,a group of pluripotent cells that maintain vascular integrity and tension,are protective against sepsis via regulating vascular reactivity and permeability.Methods We conducted a series of in vivo experiments using wild-type(WT),platelet-derived growth factor receptor-β(PDGFR-β)-Cre+mT/mG transgenic mice and Tie2-Cre+Cx43^(flox/flox)mice to examine the relative contribution of pericytes in sepsis,either induced by cecal ligation and puncture(CLP)or lipopolysaccharide(LPS)challenge.In a separate set of experiments with Sprague-Dawley(SD)rats,pericytes were depleted using CP-673451,a selective PDGFR-βinhibitor,at a dosage of 40 mg/(kg·d)for 7 consecutive days.Cultured pericytes,vascular endothelial cells(VECs)and vascular smooth muscle cells(VSMCs)were used for mechanistic investigations.The effects of pericytes and pericyte-derived microvesicles(PCMVs)and candidate miRNAs on vascular reactivity and barrier function were also examined.Results CLP and LPS induced severe injury/loss of pericytes,vascular hyporeactivity and leakage(P<0.05).Transplantation with exogenous pericytes protected vascular reactivity and barrier function via microvessel colonization(P<0.05).Cx43 knockout in either pericytes or VECs reduced pericyte colonization in microvessels(P<0.05).Additionally,PCMVs transferred miR-145 and miR-132 to VSMCs and VECs,respectively,exerting a protective effect on vascular reactivity and barrier function after sepsis(P<0.05).miR-145 primarily improved the contractile response of VSMCs by activating the sphingosine kinase 2(Sphk2)/sphingosine-1-phosphate receptor(S1PR)1/phosphorylation of myosin light chain 20 pathway,whereas miR-132 effectively improved the barrier function of VECs by activating the Sphk2/S1PR2/zonula occludens-1 and vascular endothelial-cadherin pathways.Conclusions Pericytes are protective against sepsis through regulating vascular reactivity and barrier function.Possible mechanisms include both direct colonization of microvasculature and secretion of PCMVs.
文摘This study presents a rare case of delayed hemolytic transfusion reaction(DHTR)induced by anti-Ku.The patient was admitted due to recurrence of ovarian cancer.She had experienced unexplained anemia for more than 20 years but had no anemia in the past 10 years.She had been pregnant four times and given birth to four babies without blood transfusions.Pretransfusion examinations showed that her blood group was A and RhD positive,and the unexpected antibody screening test was weakly reactive.She received two red blood cell transfusions and then developed unexplained anemia,with a hemoglobin decrease from 122 to 88 g/L.The unexpected antibody screening result changed to strongly positive,and she returned positive direct anti-human globulin test and major incompatible matching results.The homozygous mutation 715G>T was identified in exon 7 of the KELL gene,which is associated with a rare blood group phenotype known as K0.The patient produced anti-Ku antibodies,leading to a DHTR.Extravascular hemolysis was controlled through the administration of immunoglobulin and erythropoietin,leading to the correction of anemia.Her hemoglobin concentration was 105 g/L upon discharge from the hospital.In the management of blood transfusion for patients with rare blood types,a comprehensive analysis is required,taking into account the specificity of high-frequency antibodies produced by the patient,the types and strength of these antibodies,as well as the clinical demand for blood.When necessary,a short-term,adequate transfusion of minimally incompatible blood may be administered,along with intravenous immunoglobulin and erythropoietin to correct hemolysis and anemia.
基金supported by grants from the Beijing Science and Technology Plan(Z231100007223006)the Natural Science Foundation of China(92354306,31988101)+2 种基金the National Key Research and Development Program of China(2023YFA1800603)the Shenzhen Medical Research Fund(B2302022)the Natural Science Foundation of Jiangxi Province(20224 ACB209001).
文摘The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis.Although it is well appreciated that the niche plays a critical role in gastric epithelium cell differentiation,the relevant molecular factors and the underlying regulatory mechanisms remain poorly understood.In this study,by combining the knowledge of the niche cells obtained from single-cell RNA sequencing and manipulation of signaling pathways,we achieved effective differentiation of various gastric epithelial cell types in mouse and human gastric organoids.These in vitro differentiated cells showed a similar gene expression profile to those in gastric tissues.Specifically,BMP4 signaling stimulates pit cell and parietal cell differentiation.Furthermore,BMP4 and EGF signaling cooperate to enhance pit cell differentiation,whereas inhibition of TGF-βand BMP4 signaling promotes chief cell differentiation.We demonstrated that Zbtb7b is a novel regulator controlling pit cell differentiation.In addition,BMP4,together with the small molecule Isoxazole 9,promotes parietal and enteroendocrine cell differentiation.Our data also revealed the different requirements of parietal and chief cell differentiation between mouse and human.Together,our findings provide a mechanistic insight into gastric epithelial cell differentiation and uncover its similarities and differences between mouse and human,laying a foundation for future investigation and potential clinical use of gastric organoids.
