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A DL-4- and TNFα-based culture system to generate high numbers of nonmodified or genetically modified immunotherapeutic human T-lymphoid progenitors

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Cellular & Molecular Immunology 2021年第7期18卷 1662-1676页

作者： Ranjita Devi Moirangthem Kuiying Ma Sabrina Lizot Anne Cordesse Juliette Olivré Corinne de Chappedelaine Akshay Joshi Agata Cieslak John Tchen Nicolas Cagnard Vahid Asnafi Antonio Rausell Laura Simons Julien Zuber Tom Taghon Frank J.T.Staal Françoise Pflumio Emmanuelle Six Marina Cavazzana Chantal Lagresle-Peyrou Tayebeh Soheili Isabelle André Universitéde Paris Imagine InstituteLaboratory of Human LymphohematopoiesisINSERM UMR 1163ParisFrance Laboratory of Onco-Hematology AP-HPHôpital Necker-Enfants Malades.ParisFrance Universitéde Paris Institut Necker-Enfants Malades(INEM)INSERM UMR 1151ParisFrance Plateforme Bio-informatique UniversitéParis DescartesStructure Fédérative de Recherche NeckerINSERM US24/CNRS UMS 3633ParisFrance Universitéde Paris Imagine InstituteLaboratory of Clinical BioinformaticsINSERM UMR 1163ParisFrance Department of Biotherapy Clinical Investigation Center AP-HPHôpital Necker-Enfants MaladesParisFrance Department of Adult Kidney Transplantation AP-HPHôpital NeckerParisFrance cancer Research Institute Ghent(CRIG) GhentBelgium Department of Diagnostic Sciences Faculty of Medicine and Health SciencesGhent UniversityGhentBelgium Department of Immunohematology&Blood Transfusion Leiden University Medical CenterLeidenthe Netherlands team niche and cancer in hematopoiesis Universitéde Paris and UniversitéParis-SaclayINSERMiRCM/IBFJ CEAUMR StabilitéGénétique Cellules Souches et RadiationsFontenay-aux-RosesFrance

Several obstacles to the production,expansion and genetic modification of immunotherapeutic T cells in vitro have restricted the widespread use of T-cell *** the context of HSCT,delayed naïve T-cell recovery contributes to poor outcomes.A novel approach to overcome the major limitations of both T-cell immunotherapy and HSCT would be to transplant human T-lymphoid progenitors(HTLPs),allowing reconstitution of a fully functional naïve T-cell pool in the patient ***,it is challenging to produce HTLPs in the high numbers required to meet clinical ***,we found that adding tumor necrosis factor alpha(TNFα)to a DL-4-based culture system led to the generation of a large number of nonmodified or genetically modified HTLPs possessing highly efficient in vitro and in vivo T-cell potential from either CB HSPCs or mPB HSPCs through accelerated T-cell differentiation and enhanced HTLP cell cycling and *** study provides a clinically suitable cell culture platform to generate high numbers of clinically potent nonmodified or genetically modified HTLPs for accelerating immune recovery after HSCT and for T-cell-based immunotherapy(including CAR T-cell therapy).

关键词： Human T-lymphoid progenitor Tumor necrosis factor alpha Delta-like ligand 4 Hematopoietic stem and progenitor cells Mobilized peripheral blood

A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

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Protein & Cell 2024年第2期15卷 98-120页

作者： Shanshan Yang Chengyu Liu Mengmeng Jiang Xiaoqian Liu Lingling Geng Yiyuan Zhang Shuhui Sun Kang Wang jian Yin Shuai Ma Si Wang Juan Carlos Izpisua Belmonte Weiqi Zhang Jing Qu Guang-Hui Liu Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China Xuanwu Hospital Capital Medical University Beijing 100053China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Aging Biomarker Consortium Beijing 100101China Altos Labs Inc.San DiegoCA 94022USA

Aging increases the risk ofliver diseases and systemic susceptibility to aging-related ***,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely ***,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche *** in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during *** particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular *** study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

关键词： single-nucleus RNA sequencing liver hepatocytes aging senescence SREBP2

Abnormal bone marrow microenvironment: the “harbor” of acute lymphoblastic leukemia cells

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Blood Science 2021年第2期3卷 29-34页

作者： Zehui Chen Yaxin Zheng Yaling Yang Junnan Kang M.James You Chen Tian Department of Hematology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinChina Department of Hematopathology The University of Texas MD Anderson Cancer CenterHoustonTexas 77030USA

Bone marrow(BM)microenvironment regulates and supports the production of blood cells which are necessary to maintain *** analogy to normal hematopoiesis,leukemogenesis is originated from leukemic stem cells(LSCs)which gives rise to more differentiated malignant *** cells occupy BM niches and reconstruct them to support *** abnormal BM niches are the main sanctuary of LSCs where they can evade chemotherapy-induced death and acquire drug *** this review,we focus on the protective effects of BM niche cells on acute lymphoblastic leukemia cells.

关键词： acute lymphoblastic leukemia bone marrow microenvironment osteoblastic niche vascular niche

Insights of stem cell-based endogenous repair of intervertebral disc degeneration

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World Journal of Stem Cells 2020年第4期12卷 266-276页

作者： Yang Liu Yan Li Li-Ping Nan Feng Wang Shi-Feng Zhou Xin-Min Feng Hao Liu Liang Zhang Department of Orthopedics West China Hospital of Sichuan UniversityChengdu 610000Sichuan ProvinceChina Department of Orthopedics Dalian Medical UniversityDalian 116000Liaoning ProvinceChina Department of Oncology The Affiliated Cancer HospitalSchool of MedicineUESTCChengdu 610000Sichuan ProvinceChina Department of Orthopedics Clinical Medical College of Yangzhou UniversityYangzhou 225000Jiangsu ProvinceChina

Low back pain has become more prevalent in recent years,causing enormous economic burden for society and *** therapies used in clinics including conservative treatment and surgery can only relieve *** cell-based treatment such as mesenchymal stem cell transplantation poses problems such as short duration of therapeutic effect and ***,the discovery and identification of stem cell niche and stem/progenitor cells in intervertebral disc bring increased attention to endogenous repair ***,we review the studies involving endogenous repair strategy and present the characteristics and current status of this ***,we also discuss the strategy and perspective of endogenous repair strategy in future.

关键词： Low back pain Intervertebral disc degeneration Stem cell niche Stem/progenitor cell Endogenous repair strategy Stem cell treatment

Genetically controlled humanized microenvironment in mice for pre-clinical study

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Genetically controlled humanized microenvironment in mice fo...

The niche for hematopoietic stem cell expansion: a collaboration network

中国遗传学会第九次全国会员代表大会暨学术研讨会

作者： CHEN Ye JACAMO Rodrigo KONOPLEVA Marina GUAN Min-xin ANDREEFF Michael Institute of Genetics College of Life SciencesZhejiang University Department of Leukemia The University of Texas M.D.Anderson Cancer Center

The importance of the microenvironment for cancer development,progression and resistance to treatment has recently been *** group was first to report the contribution of bone marrow(BM) derived mesenchymal stromal cells(MSC) for tumor development and *** provides dynamic microenvironment(niche) for the maintenance of hematopoietic stem cells(HSC) quiescence and normal hematopoiesis with high local concentrations of growth factors,chemokines and *** evidence has also shown that the BM microenvironment plays a pivotal role in the pathophysiology and propagation of leukemia Leukemia cells undergo spontaneous apoptosis once they are removed from the in vivo microenvironment and placed in suspension cultures without supportive *** understanding of the interactions between leukemia cells and their BM niche is critically important for leukemia *** here describe a novel artificial bone and bone marrow model mimicking the human hematopoietic microenvironment by using human mesenchymal stromat cells(MSCs) and endothelial colony-forming cells(ECFCs).MSCs and ECFCs were isolated from heparinized human bone marrow or peripheral blood through an initial adhesion step,grown in specific media and then subcutaneously injected into the flanks of the NOD/SCID/IL-2rγ mice,where they developed into bone-like tissues with high osteoblast activity after 8 *** stains confirmed the bone structures and also showed that these artificial bones contained typical bone marrow cavities constituting a robust hematopoietic *** vivo imaging with Osteosense confirmed the presence of hydroxylapatite and luciferase imaging of firefly luciferase labeled human leukemic cells the engraftment of MOLM13/Luc/GFP leukemic cells in the extramedullary BM sites,following *** with infiltration of the extramedullary and physiological medullary bone marrow *** critical for MSC support of normal *** hematopoie

关键词： Mouse model Genetically controlled humanized microenvironment Tumor engraftment

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Cellular & Molecular Immunology 2017年第10期14卷 865-867页

作者： Qingfeng Chen Institute of Molecular and Cell Biology Agency for ScienceTechnology and Research(A*STAR)Singapore 138673Singapore Department of Microbiology and Immunology Yong Loo Lin School of MedicineNational Universityof SingaporeSingapore 119228Singapore National cancer Centre Singapore Singapore 169610Singapore Key Laboratory for Major Obstetric Diseases of Guangdong Province The Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510150China

Transplantation of hematopoietic stem/progenitor cells(HSPC)has become one of the most effective treatments for several hematological malignancies,cancers and genetic immune ***,the lack of histocompatible donor sources and the number of stem cells suitable for engraftment are major constraints in the clinic,and these constraints greatly hamper the use of stem cell *** humans,fetal liver and bone marrow are the two major locations of hematopoiesis before and after birth,***,understanding the specialized stem cell microenvironment supporting the self-renewal and expansion of HSPC in fetal liver and bone marrow is not only essential for extending the current knowledge of stem cell biology but is also beneficial to adult regenerative medicine in the clinic.

关键词： hematopoietic expansion specialized

The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies

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Bone Research 2023年第2期11卷 273-291页

作者： Hengwei Zhang Jane LLiesveld Laura MCalvi Brea CLipe Lianping Xing Michael WBecker Edward MSchwarz Shu-Chi A.Yeh Center for Musculoskeletal Research University of Rochester Medical Center601 Elmwood AveBox 665RochesterNY14642USA Department of Pathology and Laboratory Medicine University of Rochester Medical CenterRochesterNYUSA Wilmot cancer Center University of Rochester Medical CenterRochesterNYUSA Department of Medicine Division of Hematology/Oncology and Bone Marrow Transplantation ProgramUniversity of Rochester Medical CenterRochesterNYUSA Department of Medicine Division of Endocrinology/MetabolismUniversity of Rochester Medical CenterRochesterNYUSA Department of Orthopaedics University of Rochester Medical CenterRochesterNYUSA Department of Medicine Division of Allergy/Immunology/RheumatologyUniversity of Rochester Medical CenterRochesterNYUSA Department of Biomedical Engineering University of RochesterNYUSA Department of Physiology/Pharmacology University of Rochester Medical CenterRochesterNYUSA

Prior research establishing that bone interacts in coordination with the bone marrow microenvironment(BMME)to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell *** advances in intravital imaging has suggested that the expansion of hematopoietic stem cells(HSCs)and acute myeloid leukemia cells is restricted to bone marrow microdomains during a distinct stage of bone *** findings indicate that dynamic bone remodeling likely imposes additional heterogeneity within the BMME to yield differential clonal responses.A holistic understanding of the role of bone remodeling in regulating the stem cell niche and how these interactions are altered in age-related hematological malignancies will be critical to the development of novel *** advance this understanding,herein,we provide a synopsis of the cellular and molecular constituents that participate in bone turnover and their known connections to the hematopoietic ***,we elaborate on the coupling between bone remodeling and the BMME in homeostasis and age-related hematological malignancies and after treatment with bone-targeting *** then discuss unresolved questions and ambiguities that remain in the field.

关键词： remodeling homeostasis likely

L1 drives HSC aging and affects prognosis of chronic myelomonocytic leukemia

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Signal Transduction and Targeted Therapy 2020年第1期5卷 774-777页

作者： Ying Wang Jin-ping Zheng Ying Luo Junyi Wang Lingjie Xu Jinyong Wang John M.Sedivy Zhangfa Song Hu Wang Zhenyu Ju Key Laboratory of Aging and cancer Biology of Zhejiang Province Institute of Aging ResearchSchool of MedicineHangzhou Normal UniversityHangzhou 311121China Department of Public Health and Preventive Medicine Changzhi Medical CollegeChangzhiShanxi 046000P.R.China Key Laboratory of Regenerative Medicine of Ministry of Education Guangzhou Regenerative Medicine and Health Guangdong LaboratoryInstitute of Aging and Regenerative MedicineJinan UniversityGuangzhou 510632China CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhouChina Department of Molecular Biology Cell Biology and BiochemistryBrown UniversityProvidenceRI 02903USA Department of Colorectal Surgery Sir Run Run Shaw HospitalZhejiang UniversityHangzhouChina

Dear Editor,Telomere attrition is one of the hallmark of *** Terc knockout mice exhibit impaired hematopoiesis,1 while the underling mechanisms remain poorly *** long interspersed element-1(L1)is the only human retrotransposable elements capable of autonomous retrotransposition,and evolutionarily *** studies reported that L1 is derepressed during the aging process with redistribution and reorganization of the heterochromatin.2 Considering that telomere shortening can cause chromosome instability and rearrangements,3 we speculate that L1 may play a role in impaired hematopoiesis in telomere dysfunctional mice.

关键词： impaired aging autonomous