Hematopoietic stem cells(HSCs)have been considered to progressively lose their self-renewal and differentiation potentials prior to the commitment to each blood lineage.However,recent studies have suggested that megak...Hematopoietic stem cells(HSCs)have been considered to progressively lose their self-renewal and differentiation potentials prior to the commitment to each blood lineage.However,recent studies have suggested that megakaryocyte progenitors(MkPs)are generated at the level of HSCs.In this study,we newly identified early megakaryocyte lineage-committed progenitors(MgPs)mainly in CD201-CD48-cells and CD48+cells separated from the CD150+CD34-Kit+Sca-1+Lin-HSC population of the bone marrow in adult mice.Single-cell colony assay and single-cell transplantation showed that MgPs,unlike platelet-biased HSCs,had little repopulating potential in vivo,but formed larger megakaryocyte colonies in vitro(on average 8 megakaryocytes per colony)than did previously reported MkPs.Single-cell RNA sequencing supported that HSCs give rise to MkPs through MgPs along a Mk differentiation pathway.Single-cell reverse transcription polymerase chain reaction(RT-PCR)analysis showed that MgPs expressed Mk-related genes,but were transcriptionally heterogenous.Clonal culture of HSCs suggested that MgPs are not direct progeny of HSCs.We propose a differentiation model in which HSCs give rise to MgPs which then give rise to MkPs,supporting a classic model in which Mk-lineage commitment takes place at a late stage of differentiation.展开更多
Emerging evidence suggests that priming intestinal stem cells(ISCs)towards secretory progenitor cells is beneficial for maintaining gut homeostasis against inflammatory bowel disease(IBD).However,the mechanism driving...Emerging evidence suggests that priming intestinal stem cells(ISCs)towards secretory progenitor cells is beneficial for maintaining gut homeostasis against inflammatory bowel disease(IBD).However,the mechanism driving such biased lineage commitment remains elusive.Here we show that MG53,also named as TRIM72,prompts ISCs to secretory lineages via upregulating peroxisome proliferator-activated receptorα(PPARα),thus maintaining intestinal epithelium integrity against noxious insults.Using genetic mouse models,we found that MG53 deficiency leads to exacerbated intestinal damage caused by various injuries in mice,whereas MG53 overexpression in ISCs is sufficient to ameliorate such damage.Mechanistically,MG53 promoted asymmetric division of ISCs to generate more progenitor cells of secretory lineages via activating PPARαsignaling.Specifically,MG53 overexpression induced PPARαexpression at transcriptional level and concomitantly increased PPARαactivity by elevating the contents of a panel of unsaturated fatty acids in the intestine that serve as potent endogenous agonists of PPARα.Furthermore,genetic ablation or pharmacological inhibition of PPARαabolished the protective effects of MG53.These findings reveal a crucial role of MG53-PPARαaxis in driving the secretory lineage commitment of ISCs,especially during injury response,highlighting the important therapeutic potential of targeting MG53-PPARαsignaling for IBD treatment and marking PPARαagonists as novel therapies for IBD caused by various etiologies.展开更多
Many biological structures such as nerves,blood and lymphatic vessels,and muscle fibres exhibit longitudinal ge-ometries with distinct cell types extending along both the length and width of internal linear axes.Model...Many biological structures such as nerves,blood and lymphatic vessels,and muscle fibres exhibit longitudinal ge-ometries with distinct cell types extending along both the length and width of internal linear axes.Modelling these three-dimensional structures in vitro is challenging:the best-defined stem-cell differentiation systems are mono-layer cultures or organoids using pluripotent stem cells.Pluripotent stem cells can differentiate into functionally mature cells depending on the signals received,holding great promise for regenerative medicine.However,the integration of in vitro differentiated cell types into diseased tissue remains a challenge.Engineered scaffolds can bridge this gap if the appropriate signalling systems are incorporated into the scaffold.Here,we have taken a biomimicry approach to generate longitudinal structures in vitro.In this approach,mouse embryonic stem cells are directed to differentiate to specific cell types on the surface of polycaprolactone(PCL)fibres treated by plasma-immersion ion implantation and to which with lineage-specifying molecules have been covalently im-mobilised.We demonstrate the simplicity and utility of our method for efficiently generating high yields of the following cell types from these pluripotent stem cells:neurons,vascular endothelial cells,osteoclasts,adipocytes,and cells of the erythroid,myeloid,and lymphoid lineages.Strategically arranged plasma-treated scaffolds with differentiated cell types could ultimately serve as a means for the repair or treatment of diseased or damaged tissue.展开更多
Lineage commitment of thymocytes can be distinguished and modulated by key factors of transcriptional networks,such as the antagonistic expression and function of Th-POK and Runx3 in the CD4 and CD8 lineages1 and Foxp...Lineage commitment of thymocytes can be distinguished and modulated by key factors of transcriptional networks,such as the antagonistic expression and function of Th-POK and Runx3 in the CD4 and CD8 lineages1 and Foxp32 and PLZF3 in CD4^(+)regulatory T(Treg)cells and natural killer T(NKT)cells,respectively.展开更多
基金supported by grants from the National Key Research and Development Program of China(2022YFA1103500,2021YFA1100900)Science,Technology&Innovation Project of Xiongan New Area(2022XAGG0142)+3 种基金the National Natural Science Foundation of China(82170118,82370116,82250710178,82222004,82070112)Haihe Laboratory of Cell Ecosystem Innovation Fund(22HHXBSS00038)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2021-I2M-1-073),Distinguished Young Scholars of Tianjin(23JCJQJC00220)the CAMS Fundamental Research Funds for Central Research Institutes(2022-RC180-06).
文摘Hematopoietic stem cells(HSCs)have been considered to progressively lose their self-renewal and differentiation potentials prior to the commitment to each blood lineage.However,recent studies have suggested that megakaryocyte progenitors(MkPs)are generated at the level of HSCs.In this study,we newly identified early megakaryocyte lineage-committed progenitors(MgPs)mainly in CD201-CD48-cells and CD48+cells separated from the CD150+CD34-Kit+Sca-1+Lin-HSC population of the bone marrow in adult mice.Single-cell colony assay and single-cell transplantation showed that MgPs,unlike platelet-biased HSCs,had little repopulating potential in vivo,but formed larger megakaryocyte colonies in vitro(on average 8 megakaryocytes per colony)than did previously reported MkPs.Single-cell RNA sequencing supported that HSCs give rise to MkPs through MgPs along a Mk differentiation pathway.Single-cell reverse transcription polymerase chain reaction(RT-PCR)analysis showed that MgPs expressed Mk-related genes,but were transcriptionally heterogenous.Clonal culture of HSCs suggested that MgPs are not direct progeny of HSCs.We propose a differentiation model in which HSCs give rise to MgPs which then give rise to MkPs,supporting a classic model in which Mk-lineage commitment takes place at a late stage of differentiation.
基金funded by National Key R&D Program of China(2022YFA1303003,2018YFA0800701,2018YFA0507603,and 2018YFA0800501)National Natural Science Foundation of China(81770376,81630008,81790621,31521062,31671177,and 81370234).
文摘Emerging evidence suggests that priming intestinal stem cells(ISCs)towards secretory progenitor cells is beneficial for maintaining gut homeostasis against inflammatory bowel disease(IBD).However,the mechanism driving such biased lineage commitment remains elusive.Here we show that MG53,also named as TRIM72,prompts ISCs to secretory lineages via upregulating peroxisome proliferator-activated receptorα(PPARα),thus maintaining intestinal epithelium integrity against noxious insults.Using genetic mouse models,we found that MG53 deficiency leads to exacerbated intestinal damage caused by various injuries in mice,whereas MG53 overexpression in ISCs is sufficient to ameliorate such damage.Mechanistically,MG53 promoted asymmetric division of ISCs to generate more progenitor cells of secretory lineages via activating PPARαsignaling.Specifically,MG53 overexpression induced PPARαexpression at transcriptional level and concomitantly increased PPARαactivity by elevating the contents of a panel of unsaturated fatty acids in the intestine that serve as potent endogenous agonists of PPARα.Furthermore,genetic ablation or pharmacological inhibition of PPARαabolished the protective effects of MG53.These findings reveal a crucial role of MG53-PPARαaxis in driving the secretory lineage commitment of ISCs,especially during injury response,highlighting the important therapeutic potential of targeting MG53-PPARαsignaling for IBD treatment and marking PPARαagonists as novel therapies for IBD caused by various etiologies.
基金supported by the Australian Research Council Laureate and Discovery fundings[FL190100216,DP190103507 and DE210100662]the University of Sydney School of Physics“Grand Challenge”program.
文摘Many biological structures such as nerves,blood and lymphatic vessels,and muscle fibres exhibit longitudinal ge-ometries with distinct cell types extending along both the length and width of internal linear axes.Modelling these three-dimensional structures in vitro is challenging:the best-defined stem-cell differentiation systems are mono-layer cultures or organoids using pluripotent stem cells.Pluripotent stem cells can differentiate into functionally mature cells depending on the signals received,holding great promise for regenerative medicine.However,the integration of in vitro differentiated cell types into diseased tissue remains a challenge.Engineered scaffolds can bridge this gap if the appropriate signalling systems are incorporated into the scaffold.Here,we have taken a biomimicry approach to generate longitudinal structures in vitro.In this approach,mouse embryonic stem cells are directed to differentiate to specific cell types on the surface of polycaprolactone(PCL)fibres treated by plasma-immersion ion implantation and to which with lineage-specifying molecules have been covalently im-mobilised.We demonstrate the simplicity and utility of our method for efficiently generating high yields of the following cell types from these pluripotent stem cells:neurons,vascular endothelial cells,osteoclasts,adipocytes,and cells of the erythroid,myeloid,and lymphoid lineages.Strategically arranged plasma-treated scaffolds with differentiated cell types could ultimately serve as a means for the repair or treatment of diseased or damaged tissue.
文摘Lineage commitment of thymocytes can be distinguished and modulated by key factors of transcriptional networks,such as the antagonistic expression and function of Th-POK and Runx3 in the CD4 and CD8 lineages1 and Foxp32 and PLZF3 in CD4^(+)regulatory T(Treg)cells and natural killer T(NKT)cells,respectively.
