STEM CELLS最新文献

{"title":"Inflammatory Periodontal Ligament Stem Cells Drive M1 Macrophage Polarization via Exosomal miR-143-3p-Mediated Regulation of PI3K/AKT/NF-κB Signaling.","authors":"Yazheng Wang,&nbsp;Xige Zhang,&nbsp;Jinjin Wang,&nbsp;Yang Zhang,&nbsp;Qingyuan Ye,&nbsp;Yang Wang,&nbsp;Dongdong Fei,&nbsp;Qintao Wang","doi":"10.1093/stmcls/sxac087","DOIUrl":"https://doi.org/10.1093/stmcls/sxac087","url":null,"abstract":"<p><p>Macrophage polarization plays an important role in the progression of inflammation. Exosomes derived from stem cells are promising candidates for macrophage immunoregulation. However, how exosomes derived from periodontal ligament stem cells (PDLSCs) in an inflammatory environment influence macrophage polarization has yet to be fully elucidated. In this study, inflammatory PDLSCs were found to downregulate M2 macrophage polarization at the mRNA and protein levels in a Transwell coculture system of PDLSCs and THP-1-derived M0 macrophages. Furthermore, inflammatory PDLSC-derived exosomes shifted macrophages toward the M1 phenotype. The inhibition of inflammatory PDLSC-derived exosomes by GW4869 weakened inflammatory PDLSC-mediated M1 macrophage polarization. A miRNA microarray was used to determine the differential miRNAs shuttled by healthy and inflammatory PDLSC-derived exosomes. Compared with healthy exosomes, miR-143-3p was enriched in inflammatory PDLSC-derived exosomes, which targeted and inhibited the expression of PI3Kγ and promoted M1 macrophage polarization by suppressing PI3K/AKT signaling and activating NF-κB signaling, while an agonist of the PI3K pathway reversed this effect. Moreover, exosome-shuttled miR-143-3p from PDLSCs drove M1 macrophage polarization and aggravated periodontal inflammation in a mouse periodontitis model. In conclusion, these results demonstrate that inflammatory PDLSCs facilitate M1 macrophage polarization through the exosomal miR-143-3p-mediated regulation of PI3K/AKT/NF-κB signaling, providing a potential new target for periodontitis treatment.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 2","pages":"184-199"},"PeriodicalIF":5.2,"publicationDate":"2023-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9189311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone Marrow Mesenchymal Stem Cells-Derived miR-21-5p Protects Grafted Islets Against Apoptosis by Targeting PDCD4.","authors":"Jingwen Wang,&nbsp;Jiale Wang,&nbsp;Ying Wang,&nbsp;Ruiyang Ma,&nbsp;Shucong Zhang,&nbsp;Jin Zheng,&nbsp;Wujun Xue,&nbsp;Xiaoming Ding","doi":"10.1093/stmcls/sxac085","DOIUrl":"https://doi.org/10.1093/stmcls/sxac085","url":null,"abstract":"<p><p>The apoptosis of grafted islets is an urgent problem due to the high rate of islet loss soon after transplantation. MicroRNA-21-5p (miR-21-5p) is an essential mediator of bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exo) during anti-apoptosis, but its effect and the underlying molecular mechanism in islet transplantation remain partially understood. Here, we found that miR-21-5p could be delivered to islet cells via BMSCs-Exo. Subsequently, we demonstrated that miR-21-5p overexpression reduced apoptosis in islets and INS-1 cells, whereas miR-21-5p inhibition enhanced apoptosis. A mechanistic analysis involving RNA sequencing and bioinformatic analysis was performed to determine the interaction between miR-21-5p and its target gene programmed cell death 4 (PDCD4), which was further verified by a dual luciferase assay. In vivo, the grafted islets overexpressing miR-21-5p showed a higher survival rate, better insulin secretion function, and a lower apoptosis rate. In conclusion, these results demonstrated that miR‑21‑5p from BMSCs-Exo protects against the apoptosis of grafted islets by inhibiting PDCD4 expression. Hence, miR-21-5p can be used as a cell-free therapeutic agent to minimize β-cell apoptosis at the early stage of islet transplantation.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 2","pages":"169-183"},"PeriodicalIF":5.2,"publicationDate":"2023-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/38/bb/sxac085.PMC9982070.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9182252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Heterogeneous Cellular States of Glioblastoma Stem Cells Revealed by Single Cell Analysis.","authors":"Haoteng Yan,&nbsp;Jiali Zhu,&nbsp;Yanyan Ping,&nbsp;Min Yan,&nbsp;Gaoming Liao,&nbsp;Huating Yuan,&nbsp;Yao Zhou,&nbsp;Fengyu Xiang,&nbsp;Bo Pang,&nbsp;Jinyuan Xu,&nbsp;Lin Pang","doi":"10.1093/stmcls/sxac088","DOIUrl":"https://doi.org/10.1093/stmcls/sxac088","url":null,"abstract":"<p><p>Glioblastoma stem cells (GSCs) contributed to the progression, treatment resistance, and relapse of glioblastoma (GBM). However, current researches on GSCs were performed usually outside the human tumor microenvironment, ignoring the importance of the cellular states of primary GSCs. In this study, we leveraged single-cell transcriptome sequencing data of 6 independent GBM cohorts from public databases, and combined lineage and stemness features to identify primary GSCs. We dissected the cell states of GSCs and correlated them with the clinical outcomes of patients. As a result, we constructed a cellular hierarchy where GSCs resided at the center. In addition, we identified and characterized 2 different and recurrent GSCs subpopulations: proliferative GSCs (pGSCs) and quiescent GSCs (qGSCs). The pGSCs showed high cell cycle activity, indicating rapid cell division, while qGSCs showed a quiescent state. Then we traced the processes of tumor development by pseudo-time analysis and tumor phylogeny, and found that GSCs accumulated throughout the whole tumor development period. During the process, pGSCs mainly contributed to the early stage and qGSCs were enriched in the later stage. Finally, we constructed an 8-gene prognostic signature reflecting pGSCs activity and found that patients whose tumors were enriched for the pGSC signature had poor clinical outcomes. Our study highlights the primary GSCs heterogeneity and its correlation to tumor development and clinical outcomes, providing the potential targets for GBM treatment.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 2","pages":"111-125"},"PeriodicalIF":5.2,"publicationDate":"2023-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9184492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ETV2 Upregulation Marks the Specification of Early Cardiomyocytes and Endothelial Cells During Co-differentiation.","authors":"Xu Cao,&nbsp;Maria Mircea,&nbsp;Gopala Krishna Yakala,&nbsp;Francijna E van den Hil,&nbsp;Marcella Brescia,&nbsp;Hailiang Mei,&nbsp;Christine L Mummery,&nbsp;Stefan Semrau,&nbsp;Valeria V Orlova","doi":"10.1093/stmcls/sxac086","DOIUrl":"https://doi.org/10.1093/stmcls/sxac086","url":null,"abstract":"<p><p>The ability to differentiate human-induced pluripotent stem cells (hiPSCs) efficiently into defined cardiac lineages, such as cardiomyocytes and cardiac endothelial cells, is crucial to study human heart development and model cardiovascular diseases in vitro. The mechanisms underlying the specification of these cell types during human development are not well understood which limits fine-tuning and broader application of cardiac model systems. Here, we used the expression of ETV2, a master regulator of hematoendothelial specification in mice, to identify functionally distinct subpopulations during the co-differentiation of endothelial cells and cardiomyocytes from hiPSCs. Targeted analysis of single-cell RNA-sequencing data revealed differential ETV2 dynamics in the 2 lineages. A newly created fluorescent reporter line allowed us to identify early lineage-predisposed states and show that a transient ETV2-high-state initiates the specification of endothelial cells. We further demonstrated, unexpectedly, that functional cardiomyocytes can originate from progenitors expressing ETV2 at a low level. Our study thus sheds light on the in vitro differentiation dynamics of 2 important cardiac lineages.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 2","pages":"140-152"},"PeriodicalIF":5.2,"publicationDate":"2023-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9982073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9177691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Reply: Revisiting Claims of the Continued Absence of Functional Germline Stem Cells in Adult Ovaries.","authors":"Masahito Yoshihara,&nbsp;Magdalena Wagner,&nbsp;Anastasios Damdimopoulos,&nbsp;Cheng Zhao,&nbsp;Sophie Petropoulos,&nbsp;Shintaro Katayama,&nbsp;Juha Kere,&nbsp;Fredrik Lanner,&nbsp;Pauliina Damdimopoulou","doi":"10.1093/stmcls/sxac084","DOIUrl":"https://doi.org/10.1093/stmcls/sxac084","url":null,"abstract":"Received: 12 November 2022; Accepted: 12 November 2022. © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com. In Reply: Revisiting Claims of the Continued Absence of Functional Germline Stem Cells in Adult Ovaries","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 2","pages":"205-206"},"PeriodicalIF":5.2,"publicationDate":"2023-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1d/be/sxac084.PMC9982065.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9534083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iPSC-Derived Airway Epithelial Cells: Progress, Promise, and Challenges.","authors":"Fenggang Yu,&nbsp;Fei Liu,&nbsp;Xiaohua Liang,&nbsp;Linwei Duan,&nbsp;Qiongqiong Li,&nbsp;Ge Pan,&nbsp;Chengyao Ma,&nbsp;Minmin Liu,&nbsp;Mingyue Li,&nbsp;Peng Wang,&nbsp;Xuening Zhao","doi":"10.1093/stmcls/sxac074","DOIUrl":"https://doi.org/10.1093/stmcls/sxac074","url":null,"abstract":"<p><p>Induced pluripotent stem cells (iPSCs) generated from somatic cell sources are pluripotent and capable of indefinite expansion in vitro. They provide an unlimited source of cells that can be differentiated into lung progenitor cells for potential clinical use in pulmonary regenerative medicine. This review gives a comprehensive overview of recent progress toward the use of iPSCs to generate proximal and distal airway epithelial cells and mix lung organoids. Furthermore, their potential applications and future challenges for the field are discussed, with a focus on the technological hurdles that must be cleared before stem cell therapeutics can be used for clinical treatment.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 1","pages":"1-10"},"PeriodicalIF":5.2,"publicationDate":"2023-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9208983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Hypoxia Preconditioning on the Regenerative Capacity of Adipose Tissue Derived Mesenchymal Stem Cells in a Model of Renal Artery Stenosis.","authors":"Naba Farooqui,&nbsp;Arjunmohan Mohan,&nbsp;Busra Isik,&nbsp;Busra B Goksu,&nbsp;Roman Thaler,&nbsp;Xiang Yang Zhu,&nbsp;James D Krier,&nbsp;Ishran M Saadiq,&nbsp;Christopher M Ferguson,&nbsp;Kyra L Jordan,&nbsp;Hui Tang,&nbsp;Stephen C Textor,&nbsp;La Tonya J Hickson,&nbsp;Andre J van Wijnen,&nbsp;Alfonso Eirin,&nbsp;Lilach O Lerman,&nbsp;Sandra M Herrmann","doi":"10.1093/stmcls/sxac073","DOIUrl":"10.1093/stmcls/sxac073","url":null,"abstract":"<p><p>Atherosclerotic renal artery stenosis (ARAS) is associated with irreversible parenchymal renal disease and regenerative stem cell therapies may improve renal outcomes. Hypoxia preconditioning (HPC) may improve the regenerative functions of adipose tissue-derived mesenchymal stem cells (AMSC) by affecting DNA 5-hydroxymethylcytosine (5hmC) marks in angiogenic genes. Here, we investigated using a porcine ARAS model, whether growth of ARAS AMSCs in hypoxia (Hx) versus normoxia (Nx) would enhance renal tissue repair, and comprehensively analyze how HPC modifies DNA hydroxymethylation compared to untreated ARAS and healthy/normal pigs (n=5 each). ARAS pigs exhibited elevated serum cholesterol, serum creatinine and renal artery stenosis, with a concomitant decrease in renal blood flow (RBF) and increased blood pressure (BP) compared to healthy pigs. Renal artery injection of either autologous Nx or Hx AMSCs improved diastolic BP, reduced kidney tissue fibrosis, and inflammation (CD3+ T-cells) in ARAS pigs. In addition, renal medullary hypoxia significantly lowered with Nx but not Hx AMSC treatment. Mechanistically, levels of epigenetic 5hmC marks (which reflect gene activation) estimated using DNA immunoprecipitation technique were elevated in profibrotic and inflammatory genes in ARAS compared with normal AMSCs. HPC significantly reduced 5hmC levels in cholesterol biosynthesis and oxidative stress response pathways in ARAS AMSCs. Thus, autologous AMSCs improve key renovascular parameters and inflammation in ARAS pigs, with HPC mitigating pathological molecular effects on inflammatory and profibrotic genes which may play a role in augmenting regenerative capacity of AMSCs.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 1","pages":"50-63"},"PeriodicalIF":5.2,"publicationDate":"2023-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9887092/pdf/sxac073.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10712182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Priming Mesenchymal Stem/Stromal Cells with a Combination of a Low Dose of IFN-γ and Bortezomib Results in Potent Suppression of Pathogenic Th17 Immunity Through the IDO1-AHR Axis.","authors":"Ha Young Park,&nbsp;Chae Eun Kim,&nbsp;Soung-Min Lee,&nbsp;Joo Mi Ahn,&nbsp;Eun Hye Yoon,&nbsp;Minjoo Yoo,&nbsp;Jung-Mi Kim,&nbsp;Jiyeon Back,&nbsp;Dae Hwi Park,&nbsp;Won Hee Jang,&nbsp;Byungsuk Kwon,&nbsp;Su-Kil Seo","doi":"10.1093/stmcls/sxac075","DOIUrl":"https://doi.org/10.1093/stmcls/sxac075","url":null,"abstract":"<p><p>Preconditioning of mesenchymal stem/stromal cells (MSCs) with the inflammatory cytokine IFN-γ enhances not only their immunosuppressive activity but also their expression of HLA and proinflammatory genes. We hypothesized that prevention of the upregulation of inflammatory cytokines and HLA molecules in IFN-γ-primed MSCs would render these cells more immunosuppressive and less immunogenic. In this study, we discovered the following findings supporting this hypothesis: (1) activated human T cells induced the expression of IDO1 in MSCs via IFN-γ secretion and those MSCs in turn inhibited T-cell proliferation in an AHR-dependent fashion; (2) there was no difference in the expression of IDO1 and HLA-DR in MSCs after priming with a low dose (25 IU/mL) versus a high dose (100 IU/mL) of IFN-γ; (3) the transient addition of bortezomib, a proteasome inhibitor, to culture MSCs after IFN-γ priming decreased the expression of HLA-DR, inflammatory cytokine genes and Vcam1 while increasing the expression of IDO1 and the production of L-kynurenine; finally, MSCs primed with a combination of a low dose of IFN-γ and bortezomib were more effective in inhibiting Th17-mediated idiopathic pneumonia syndrome (IPS) and chronic colitis than unprimed MSCs. Our results suggest that bortezomib significantly eliminates the unfavorable effects of IFN-γ priming of MSCs (increased expression of MHC molecules and inflammatory cytokines and cell aggregation genes) and simultaneously increases their immunosuppressive activity by upregulating IDO1. Taken together, our newly established MSC priming method may contribute to MSC-based cell therapy for inflammatory diseases.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 1","pages":"64-76"},"PeriodicalIF":5.2,"publicationDate":"2023-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9224662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncCMRR Plays an Important Role in Cardiac Differentiation by Regulating the Purb/Flk1 Axis.","authors":"Yiwei Yang,&nbsp;Xing Wang,&nbsp;Yu Tan,&nbsp;Yanxin Xu,&nbsp;Xudong Guo,&nbsp;Yukang Wu,&nbsp;Wuchan Wang,&nbsp;Ruiqi Jing,&nbsp;Fugui Zhu,&nbsp;Dan Ye,&nbsp;Qingquan Zhang,&nbsp;Chenqi Lu,&nbsp;Jiuhong Kang,&nbsp;Guiying Wang","doi":"10.1093/stmcls/sxac077","DOIUrl":"https://doi.org/10.1093/stmcls/sxac077","url":null,"abstract":"<p><p>As crucial epigenetic regulators, long noncoding RNAs (lncRNAs) play critical functions in development processes and various diseases. However, the regulatory mechanism of lncRNAs in early heart development is still limited. In this study, we identified cardiac mesoderm-related lncRNA (LncCMRR). Knockout (KO) of LncCMRR decreased the formation potential of cardiac mesoderm and cardiomyocytes during embryoid body differentiation of mouse embryonic stem (ES) cells. Mechanistic analyses showed that LncCMRR functionally interacted with the transcription suppressor PURB and inhibited its binding potential at the promoter region of Flk1, which safeguarded the transcription of Flk1 during cardiac mesoderm formation. We also carried out gene ontology term and signaling pathway enrichment analyses for the differentially expressed genes after KO of LncCMRR, and found significant correlation of LncCMRR with cardiac muscle contraction, dilated cardiomyopathy, and hypertrophic cardiomyopathy. Consistently, the expression level of Flk1 at E7.75 and the thickness of myocardium at E17.5 were significantly decreased after KO of LncCMRR, and the survival rate and heart function index of LncCMRR-KO mice were also significantly decreased as compared with the wild-type group. These findings indicated that the defects in early heart development led to functional abnormalities in adulthood heart of LncCMRR-KO mice. Conclusively, our findings elucidate the main function and regulatory mechanism of LncCMRR in cardiac mesoderm formation, and provide new insights into lncRNA-mediated regulatory network of mouse ES cell differentiation.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 1","pages":"11-25"},"PeriodicalIF":5.2,"publicationDate":"2023-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10712197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local and Systemic Overexpression of COMP-Ang1 Induces Ang1/Tie2-Related Thrombocytopenia and SDF-1/CXCR4-Dependent Anemia.","authors":"Hyun-Jaung Sim,&nbsp;Govinda Bhattarai,&nbsp;Min-Hye Kim,&nbsp;Han-Sol So,&nbsp;Sher Bahadur Poudel,&nbsp;Eui-Sic Cho,&nbsp;Sung-Ho Kook,&nbsp;Jeong-Chae Lee","doi":"10.1093/stmcls/sxac080","DOIUrl":"https://doi.org/10.1093/stmcls/sxac080","url":null,"abstract":"<p><p>While supplemental angiopoietin-1 (Ang1) improves hematopoiesis, excessive Ang1 induces bone marrow (BM) impairment, hematopoietic stem cell (HSC) senescence, and erythropoietic defect. Here, we examined how excessive Ang1 disturbs hematopoiesis and explored whether hematopoietic defects were related to its level using K14-Cre;c-Ang1 and Col2.3-Cre;c-Ang1 transgenic mice that systemically and locally overexpress cartilage oligomeric matrix protein-Ang1, respectively. We also investigated the impacts of Tie2 inhibitor and AMD3100 on hematopoietic development. Transgenic mice exhibited excessive angiogenic phenotypes, but K14-Cre;c-Ang1 mice showed more severe defects in growth and life span with higher presence of Ang1 compared with Col2.3-Cre;c-Ang1 mice. Dissimilar to K14-Cre;c-Ang1 mice, Col2.3-Cre;c-Ang1 mice did not show impaired BM retention or senescence of HSCs, erythropoietic defect, or disruption of the stromal cell-derived factor 1 (SDF-1)/CXCR4 axis. However, these mice exhibited a defect in platelet production depending on the expression of Tie2 and globin transcription factor 1 (GATA-1), but not GATA-2, in megakaryocyte progenitor (MP) cells. Treatment with Tie2 inhibitor recovered GATA-1 expression in MP cells and platelet production without changes in circulating RBC in transgenic mice. Consecutive AMD3100 administration not only induced irrecoverable senescence of HSCs but also suppressed formation of RBC, but not platelets, via correlated decreases in number of erythroblasts and their GATA-1 expression in B6 mice. Our results indicate that genetic overexpression of Ang1 impairs hematopoietic development depending on its level, in which megakaryopoiesis is preferentially impaired via activation of Ang1/Tie2 signaling, whereas erythropoietic defect is orchestrated by HSC senescence, inflammation, and disruption of the SDF-1/CXCR4 axis.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 1","pages":"93-104"},"PeriodicalIF":5.2,"publicationDate":"2023-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9887089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10712207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}