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Ludwig-Husemann A, Schertl P, Shrivastava A, Geckle U, Hafner J, Schaarschmidt F, Willenbacher N, Freudenberg U, Werner C, Lee-Thedieck C. A Multifunctional Nanostructured Hydrogel as a Platform for Deciphering Niche Interactions of Hematopoietic Stem and Progenitor Cells. Adv Healthc Mater 2024; 13:e2304157. [PMID: 38870600 DOI: 10.1002/adhm.202304157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 06/10/2024] [Indexed: 06/15/2024]
Abstract
For over half a century, hematopoietic stem cells (HSCs) have been used for transplantation therapy to treat severe hematologic diseases. Successful outcomes depend on collecting sufficient donor HSCs as well as ensuring efficient engraftment. These processes are influenced by dynamic interactions of HSCs with the bone marrow niche, which can be revealed by artificial niche models. Here, a multifunctional nanostructured hydrogel is presented as a 2D platform to investigate how the interdependencies of cytokine binding and nanopatterned adhesive ligands influence the behavior of human hematopoietic stem and progenitor cells (HSPCs). The results indicate that the degree of HSPC polarization and motility, observed when cultured on gels presenting the chemokine SDF-1α and a nanoscale-defined density of a cellular (IDSP) or extracellular matrix (LDV) α4β1 integrin binding motif, are differently influenced on hydrogels functionalized with the different ligand types. Further, SDF-1α promotes cell polarization but not motility. Strikingly, the degree of differentiation correlates negatively with the nanoparticle spacing, which determines ligand density, but only for the cellular-derived IDSP motif. This mechanism potentially offers a means of predictably regulating early HSC fate decisions. Consequently, the innovative multifunctional hydrogel holds promise for deciphering dynamic HSPC-niche interactions and refining transplantation therapy protocols.
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Affiliation(s)
- Anita Ludwig-Husemann
- Institute of Cell Biology and Biophysics, Leibniz University Hannover, Herrenhäuser Str. 2, 30419, Hannover, Germany
- Institute of Functional Interfaces, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | - Peter Schertl
- Institute of Cell Biology and Biophysics, Leibniz University Hannover, Herrenhäuser Str. 2, 30419, Hannover, Germany
| | - Ananya Shrivastava
- Institute of Cell Biology and Biophysics, Leibniz University Hannover, Herrenhäuser Str. 2, 30419, Hannover, Germany
| | - Udo Geckle
- Institute for Applied Materials - Energy Storage Systems, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | - Johanna Hafner
- Institute for Mechanical Process Engineering and Mechanics, Applied Mechanics Group, Karlsruhe Institute of Technology (KIT), Gotthard-Franz-Str. 3, 76131, Karlsruhe, Germany
| | - Frank Schaarschmidt
- Institute of Cell Biology and Biophysics, Leibniz University Hannover, Herrenhäuser Str. 2, 30419, Hannover, Germany
| | - Norbert Willenbacher
- Institute for Mechanical Process Engineering and Mechanics, Applied Mechanics Group, Karlsruhe Institute of Technology (KIT), Gotthard-Franz-Str. 3, 76131, Karlsruhe, Germany
| | - Uwe Freudenberg
- Leibniz Institute of Polymer Research Dresden e.V, Max Bergmann Center of Biomaterials, Hohe Str. 6, 01069, Dresden, Germany
| | - Carsten Werner
- Leibniz Institute of Polymer Research Dresden e.V, Max Bergmann Center of Biomaterials, Hohe Str. 6, 01069, Dresden, Germany
- Center for Regenerative Therapies Dresden, Technical University Dresden, Fetscherstr. 105, 01307, Dresden, Germany
| | - Cornelia Lee-Thedieck
- Institute of Cell Biology and Biophysics, Leibniz University Hannover, Herrenhäuser Str. 2, 30419, Hannover, Germany
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Ruminski PG, Rettig MP, DiPersio JF. Development of VLA4 and CXCR4 Antagonists for the Mobilization of Hematopoietic Stem and Progenitor Cells. Biomolecules 2024; 14:1003. [PMID: 39199390 PMCID: PMC11353233 DOI: 10.3390/biom14081003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 07/29/2024] [Accepted: 08/02/2024] [Indexed: 09/01/2024] Open
Abstract
The treatment of patients diagnosed with hematologic malignancies typically includes hematopoietic stem cell transplantation (HSCT) as part of a therapeutic standard of care. The primary graft source of hematopoietic stem and progenitor cells (HSPCs) for HSCT is mobilized from the bone marrow into the peripheral blood of allogeneic donors or patients. More recently, these mobilized HSPCs have also been the source for gene editing strategies to treat diseases such as sickle-cell anemia. For a HSCT to be successful, it requires the infusion of a sufficient number of HSPCs that are capable of adequate homing to the bone marrow niche and the subsequent regeneration of stable trilineage hematopoiesis in a timely manner. Granulocyte-colony-stimulating factor (G-CSF) is currently the most frequently used agent for HSPC mobilization. However, it requires five or more daily infusions to produce an adequate number of HSPCs and the use of G-CSF alone often results in suboptimal stem cell yields in a significant number of patients. Furthermore, there are several undesirable side effects associated with G-CSF, and it is contraindicated for use in sickle-cell anemia patients, where it has been linked to serious vaso-occlusive and thrombotic events. The chemokine receptor CXCR4 and the cell surface integrin α4β1 (very late antigen 4 (VLA4)) are both involved in the homing and retention of HSPCs within the bone marrow microenvironment. Preclinical and/or clinical studies have shown that targeted disruption of the interaction of the CXCR4 or VLA4 receptors with their endogenous ligands within the bone marrow niche results in the rapid and reversible mobilization of HSPCs into the peripheral circulation and is synergistic when combined with G-CSF. In this review, we discuss the roles CXCR4 and VLA4 play in bone marrow homing and retention and will summarize more recent development of small-molecule CXCR4 and VLA4 inhibitors that, when combined, can synergistically improve the magnitude, quality and convenience of HSPC mobilization for stem cell transplantation and ex vivo gene therapy after the administration of just a single dose. This optimized regimen has the potential to afford a superior alternative to G-CSF for HSPC mobilization.
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Affiliation(s)
| | | | - John F. DiPersio
- Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63105, USA
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Zhao Y, Guo R, Cao X, Zhang Y, Sun R, Lu W, Zhao M. Role of chemokines in T-cell acute lymphoblastic Leukemia: From pathogenesis to therapeutic options. Int Immunopharmacol 2023; 121:110396. [PMID: 37295031 DOI: 10.1016/j.intimp.2023.110396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/11/2023]
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a highly heterogeneous and aggressive subtype of hematologic malignancy, with limited therapeutic options due to the complexity of its pathogenesis. Although high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation have improved outcomes for T-ALL patients, there remains an urgent need for novel treatments in cases of refractory or relapsed disease. Recent research has demonstrated the potential of targeted therapies aimed at specific molecular pathways to improve patient outcomes. Chemokine-related signals, both upstream and downstream, modulate the composition of distinct tumor microenvironments, thereby regulating a multitude of intricate cellular processes such as proliferation, migration, invasion and homing. Furthermore, the progress in research has made significant contributions to precision medicine by targeting chemokine-related pathways. This review article summarizes the crucial roles of chemokines and their receptors in T-ALL pathogenesis. Moreover, it explores the advantages and disadvantages of current and potential therapeutic options that target chemokine axes, including small molecule antagonists, monoclonal antibodies, and chimeric antigen receptor T-cells.
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Affiliation(s)
- YiFan Zhao
- First Center Clinic College of Tianjin Medical University, Tianjin 300192, China
| | - RuiTing Guo
- First Center Clinic College of Tianjin Medical University, Tianjin 300192, China
| | - XinPing Cao
- First Center Clinic College of Tianjin Medical University, Tianjin 300192, China
| | - Yi Zhang
- First Center Clinic College of Tianjin Medical University, Tianjin 300192, China
| | - Rui Sun
- School of Medicine, Nankai University, Tianjin 300192, China
| | - WenYi Lu
- Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, China
| | - MingFeng Zhao
- Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, China.
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Soldati S, Bär A, Vladymyrov M, Glavin D, McGrath JL, Gosselet F, Nishihara H, Goelz S, Engelhardt B. High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4 + T cell arrest on the inflamed BBB under flow in vitro. J Neuroinflammation 2023; 20:123. [PMID: 37221552 PMCID: PMC10204262 DOI: 10.1186/s12974-023-02797-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 05/02/2023] [Indexed: 05/25/2023] Open
Abstract
INTRODUCTION The humanized anti-α4 integrin blocking antibody natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS) that is associated with the risk of progressive multifocal leukoencephalopathy (PML). While extended interval dosing (EID) of NTZ reduces the risk for PML, the minimal dose of NTZ required to maintain its therapeutic efficacy remains unknown. OBJECTIVE Here we aimed to identify the minimal NTZ concentration required to inhibit the arrest of human effector/memory CD4+ T cell subsets or of PBMCs to the blood-brain barrier (BBB) under physiological flow in vitro. RESULTS Making use of three different human in vitro BBB models and in vitro live-cell imaging we observed that NTZ mediated inhibition of α4-integrins failed to abrogate T cell arrest to the inflamed BBB under physiological flow. Complete inhibition of shear resistant T cell arrest required additional inhibition of β2-integrins, which correlated with a strong upregulation of endothelial intercellular adhesion molecule (ICAM)-1 on the respective BBB models investigated. Indeed, NTZ mediated inhibition of shear resistant T cell arrest to combinations of immobilized recombinant vascular cell adhesion molecule (VCAM)-1 and ICAM-1 was abrogated in the presence of tenfold higher molar concentrations of ICAM-1 over VCAM-1. Also, monovalent NTZ was less potent than bivalent NTZ in inhibiting T cell arrest to VCAM-1 under physiological flow. In accordance with our previous observations ICAM-1 but not VCAM-1 mediated T cell crawling against the direction of flow. CONCLUSION Taken together, our in vitro observations show that high levels of endothelial ICAM-1 abrogate NTZ mediated inhibition of T cell interaction with the BBB. EID of NTZ in MS patients may thus require consideration of the inflammatory status of the BBB as high levels of ICAM-1 may provide an alternative molecular cue allowing for pathogenic T cell entry into the CNS in the presence of NTZ.
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Affiliation(s)
- Sasha Soldati
- Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland
| | - Alexander Bär
- Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland
| | - Mykhailo Vladymyrov
- Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland
| | - Dale Glavin
- Department of Biomedical Engineering, University of Rochester, Rochester, NY USA
| | - James L. McGrath
- Department of Biomedical Engineering, University of Rochester, Rochester, NY USA
| | - Fabien Gosselet
- Blood-Brain Barrier Laboratory, University of Artois, Lens, France
| | - Hideaki Nishihara
- Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland
- Present Address: Department of Neurotherapeutics, Yamaguchi University, Yamaguchi, Japan
| | | | - Britta Engelhardt
- Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland
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Rincón-Ortega L, Valencia-Expósito A, Kabanova A, González-Reyes A, Martin-Bermudo MD. Integrins control epithelial stem cell proliferation in the Drosophila ovary by modulating the Notch pathway. Front Cell Dev Biol 2023; 11:1114458. [PMID: 36926523 PMCID: PMC10011466 DOI: 10.3389/fcell.2023.1114458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/07/2023] [Indexed: 03/08/2023] Open
Abstract
Cell proliferation and differentiation show a remarkable inverse relationship. The temporal coupling between cell cycle withdrawal and differentiation of stem cells (SCs) is crucial for epithelial tissue growth, homeostasis and regeneration. Proliferation vs. differentiation SC decisions are often controlled by the surrounding microenvironment, of which the basement membrane (BM; a specialized form of extracellular matrix surrounding cells and tissues), is one of its main constituents. Years of research have shown that integrin-mediated SC-BM interactions regulate many aspects of SC biology, including the proliferation-to-differentiation switch. However, these studies have also demonstrated that the SC responses to interactions with the BM are extremely diverse and depend on the cell type and state and on the repertoire of BM components and integrins involved. Here, we show that eliminating integrins from the follicle stem cells (FSCs) of the Drosophila ovary and their undifferentiated progeny increases their proliferation capacity. This results in an excess of various differentiated follicle cell types, demonstrating that cell fate determination can occur in the absence of integrins. Because these phenotypes are similar to those found in ovaries with decreased laminin levels, our results point to a role for the integrin-mediated cell-BM interactions in the control of epithelial cell division and subsequent differentiation. Finally, we show that integrins regulate proliferation by restraining the activity of the Notch/Delta pathway during early oogenesis. Our work increases our knowledge of the effects of cell-BM interactions in different SC types and should help improve our understanding of the biology of SCs and exploit their therapeutic potential.
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Affiliation(s)
- Lourdes Rincón-Ortega
- Centro Andaluz de Biología del Desarrollo, CSIC/Universidad Pablo de Olavide/JA, Sevilla, Spain
| | | | - Anna Kabanova
- Centro Andaluz de Biología del Desarrollo, CSIC/Universidad Pablo de Olavide/JA, Sevilla, Spain
| | - Acaimo González-Reyes
- Centro Andaluz de Biología del Desarrollo, CSIC/Universidad Pablo de Olavide/JA, Sevilla, Spain
| | - Maria D Martin-Bermudo
- Centro Andaluz de Biología del Desarrollo, CSIC/Universidad Pablo de Olavide/JA, Sevilla, Spain
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Skelding KA, Barry DL, Theron DZ, Lincz LF. Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia. Int J Mol Sci 2022; 24:563. [PMID: 36614005 PMCID: PMC9820412 DOI: 10.3390/ijms24010563] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/05/2022] [Accepted: 12/22/2022] [Indexed: 12/30/2022] Open
Abstract
Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among stromal, haematopoietic progenitor and leukaemic cells. Traditional therapies targeting leukaemic cells have failed to improve long term survival rates, and as such, the bone marrow niche has become a promising new source of potential therapeutic targets, particularly for relapsed and refractory AML. This review briefly discusses the role of the bone marrow microenvironment in AML development and progression, and as a source of novel therapeutic targets for AML. The main focus of this review is on drugs that modulate/target this bone marrow microenvironment and have been examined in in vivo models or clinically.
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Affiliation(s)
- Kathryn A. Skelding
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW 2308, Australia
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Daniel L. Barry
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW 2308, Australia
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Danielle Z. Theron
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW 2308, Australia
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Lisa F. Lincz
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- Hunter Hematology Research Group, Calvary Mater Newcastle Hospital, Waratah, NSW 2298, Australia
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7
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Delgado M, Lennon-Duménil AM. How cell migration helps immune sentinels. Front Cell Dev Biol 2022; 10:932472. [PMID: 36268510 PMCID: PMC9577558 DOI: 10.3389/fcell.2022.932472] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 09/13/2022] [Indexed: 12/01/2022] Open
Abstract
The immune system relies on the migratory capacity of its cellular components, which must be mobile in order to defend the host from invading micro-organisms or malignant cells. This applies in particular to immune sentinels from the myeloid lineage, i.e. macrophages and dendritic cells. Cell migration is already at work during mammalian early development, when myeloid cell precursors migrate from the yolk sac, an extra embryonic structure, to colonize tissues and form the pool of tissue-resident macrophages. Later, this is accompanied by a migration wave of precursors and monocytes from the bone marrow to secondary lymphoid organs and the peripheral tissues. They differentiate into DCs and monocyte-derived macrophages. During adult life, cell migration endows immune cells with the ability to patrol their environment as well as to circulate between peripheral tissues and lymphoid organs. Hence migration of immune cells is key to building an efficient defense system for an organism. In this review, we will describe how cell migratory capacity regulates the various stages in the life of myeloid cells from development to tissue patrolling, and migration to lymph nodes. We will focus on the role of the actin cytoskeletal machinery and its regulators, and how it contributes to the establishment and function of the immune system.
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Zhang J, Qi L, Wang T, An J, Zhou B, Fang Y, Liu Y, Shan M, Hong D, Wu D, Xu Y, Liu T. FEV Maintains Homing and Expansion by Activating ITGA4 Transcription in Primary and Relapsed AML. Front Oncol 2022; 12:890346. [PMID: 35875066 PMCID: PMC9300928 DOI: 10.3389/fonc.2022.890346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 06/17/2022] [Indexed: 11/13/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive hematological malignancy that recurs in approximately 50% of cases. Elevated homing and uncontrolled expansion are characteristics of AML cells. Here, we identified that Fifth Ewing Variant (FEV) regulates the homing and expansion of AML cells. We found that FEV was re-expressed in 30% of primary AML samples and in almost all relapsed AML samples, and FEV expression levels were significantly higher in relapsed samples compared to primary samples. Interference of FEV expression in AML cell lines delayed leukemic progression and suppressed homing and proliferation. Moreover, FEV directly activated integrin subunit alpha 4 (ITGA4) transcription in a dose-dependent manner. Inhibition of integrin α4 activity with natalizumab (NZM) reduced the migration and colony-forming abilities of blasts and leukemic-initiating cells (LICs) in both primary and relapsed AML. Thus, our study suggested that FEV maintains the homing and expansion of AML cells by activating ITGA4 transcription and that targeting ITGA4 inhibits the colony-forming and migration capacities of blasts and LICs. Thus, these findings suggested that the FEV-ITGA4 axis may be a therapeutic target for both primary and relapsed AML.
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Affiliation(s)
- Jubin Zhang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Lijuan Qi
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Tanzhen Wang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Jingnan An
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Biqi Zhou
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yanglan Fang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yujie Liu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Meng Shan
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Dengli Hong
- Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- *Correspondence: Tianhui Liu, ; Yang Xu, ; Depei Wu,
| | - Yang Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- *Correspondence: Tianhui Liu, ; Yang Xu, ; Depei Wu,
| | - Tianhui Liu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- *Correspondence: Tianhui Liu, ; Yang Xu, ; Depei Wu,
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Krenn PW, Montanez E, Costell M, Fässler R. Integrins, anchors and signal transducers of hematopoietic stem cells during development and in adulthood. Curr Top Dev Biol 2022; 149:203-261. [PMID: 35606057 DOI: 10.1016/bs.ctdb.2022.02.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Hematopoietic stem cells (HSCs), the apex of the hierarchically organized blood cell production system, are generated in the yolk sac, aorta-gonad-mesonephros region and placenta of the developing embryo. To maintain life-long hematopoiesis, HSCs emigrate from their site of origin and seed in distinct microenvironments, called niches, of fetal liver and bone marrow where they receive supportive signals for self-renewal, expansion and production of hematopoietic progenitor cells (HPCs), which in turn orchestrate the production of the hematopoietic effector cells. The interactions of hematopoietic stem and progenitor cells (HSPCs) with niche components are to a large part mediated by the integrin superfamily of adhesion molecules. Here, we summarize the current knowledge regarding the functional properties of integrins and their activators, Talin-1 and Kindlin-3, for HSPC generation, function and fate decisions during development and in adulthood. In addition, we discuss integrin-mediated mechanosensing for HSC-niche interactions, ex vivo protocols aimed at expanding HSCs for therapeutic use, and recent approaches targeting the integrin-mediated adhesion in leukemia-inducing HSCs in their protecting, malignant niches.
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Affiliation(s)
- Peter W Krenn
- Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany; Department of Biosciences and Medical Biology, Cancer Cluster Salzburg, Paris-Lodron University of Salzburg, Salzburg, Austria.
| | - Eloi Montanez
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona and Bellvitge Biomedical Research Institute, L'Hospitalet del Llobregat, Barcelona, Spain
| | - Mercedes Costell
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas, Universitat de València, Burjassot, Spain; Institut Universitari de Biotecnologia i Biomedicina, Universitat de València, Burjassot, Spain
| | - Reinhard Fässler
- Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany
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The extracellular matrix of hematopoietic stem cell niches. Adv Drug Deliv Rev 2022; 181:114069. [PMID: 34838648 PMCID: PMC8860232 DOI: 10.1016/j.addr.2021.114069] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/18/2021] [Accepted: 11/21/2021] [Indexed: 12/21/2022]
Abstract
Comprehensive overview of different classes of ECM molecules in the HSC niche. Overview of current knowledge on role of biophysics of the HSC niche. Description of approaches to create artificial stem cell niches for several application. Importance of considering ECM in drug development and testing. Hematopoietic stem cells (HSCs) are the life-long source of all types of blood cells. Their function is controlled by their direct microenvironment, the HSC niche in the bone marrow. Although the importance of the extracellular matrix (ECM) in the niche by orchestrating niche architecture and cellular function is widely acknowledged, it is still underexplored. In this review, we provide a comprehensive overview of the ECM in HSC niches. For this purpose, we first briefly outline HSC niche biology and then review the role of the different classes of ECM molecules in the niche one by one and how they are perceived by cells. Matrix remodeling and the emerging importance of biophysics in HSC niche function are discussed. Finally, the application of the current knowledge of ECM in the niche in form of artificial HSC niches for HSC expansion or targeted differentiation as well as drug testing is reviewed.
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11
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Mehatre SH, Roy IM, Biswas A, Prit D, Schouteden S, Huelsken J, Verfaillie CM, Khurana S. Niche-Mediated Integrin Signaling Supports Steady-State Hematopoiesis in the Spleen. THE JOURNAL OF IMMUNOLOGY 2021; 206:1549-1560. [PMID: 33637617 DOI: 10.4049/jimmunol.2001066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 01/20/2021] [Indexed: 11/19/2022]
Abstract
Outside-in integrin signaling regulates cell fate decisions in a variety of cell types, including hematopoietic stem cells (HSCs). Our earlier published studies showed that interruption of periostin (POSTN) and integrin-αv (ITGAV) interaction induces faster proliferation in HSCs with developmental stage-dependent functional effects. In this study, we examined the role of POSTN-ITGAV axis in lymphohematopoietic activity in spleen that hosts a rare population of HSCs, the functional regulation of which is not clearly known. Vav-iCre-mediated deletion of Itgav in the hematopoietic system led to higher proliferation rates, resulting in increased frequency of primitive HSCs in the adult spleen. However, in vitro CFU-C assays demonstrated a poorer differentiation potential following Itgav deletion. This also led to a decrease in the white pulp area with a significant decline in the B cell numbers. Systemic deletion of its ligand, POSTN, phenocopied the effects noted in Vav-Itgav-/- mice. Histological examination of Postn-deficient spleen also showed an increase in the spleen trabecular areas. Importantly, these are the myofibroblasts of the trabecular and capsular areas that expressed high levels of POSTN within the spleen tissue. In addition, vascular smooth muscle cells also expressed POSTN. Through CFU-S12 assays, we showed that hematopoietic support potential of stroma in Postn-deficient splenic hematopoietic niche was defective. Overall, we demonstrate that POSTN-ITGAV interaction plays an important role in spleen lymphohematopoiesis.
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Affiliation(s)
- Shubham Haribhau Mehatre
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India
| | - Irene Mariam Roy
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India
| | - Atreyi Biswas
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India
| | - Devila Prit
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India
| | - Sarah Schouteden
- Interdepartmental Stem Cell Institute, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; and
| | - Joerg Huelsken
- École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Catherine M Verfaillie
- Interdepartmental Stem Cell Institute, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; and
| | - Satish Khurana
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India;
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12
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Lin Y, Anderson JD, Rahnama LMA, Gu SV, Knowlton AA. Exosomes in disease and regeneration: biological functions, diagnostics, and beneficial effects. Am J Physiol Heart Circ Physiol 2020; 319:H1162-H1180. [PMID: 32986962 PMCID: PMC7792703 DOI: 10.1152/ajpheart.00075.2020] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 07/30/2020] [Accepted: 08/20/2020] [Indexed: 12/12/2022]
Abstract
Exosomes are a subtype of extracellular vesicles. They range from 30 to 150 nm in diameter and originate from intraluminal vesicles. Exosomes were first identified as the mechanism for releasing unnecessary molecules from reticulocytes as they matured to red blood cells. Since then, exosomes have been shown to be secreted by a broad spectrum of cells and play an important role in the cardiovascular system. Different stimuli are associated with increased exosome release and result in different exosome content. The release of harmful DNA and other molecules via exosomes has been proposed as a mechanism to maintain cellular homeostasis. Because exosomes contain parent cell-specific proteins on the membrane and in the cargo that is delivered to recipient cells, exosomes are potential diagnostic biomarkers of various types of diseases, including cardiovascular disease. As exosomes are readily taken up by other cells, stem cell-derived exosomes have been recognized as a potential cell-free regenerative therapy to repair not only the injured heart but other tissues as well. The objective of this review is to provide an overview of the biological functions of exosomes in heart disease and tissue regeneration. Therefore, state-of-the-art methods for exosome isolation and characterization, as well as approaches to assess exosome functional properties, are reviewed. Investigation of exosomes provides a new approach to the study of disease and biological processes. Exosomes provide a potential "liquid biopsy," as they are present in most, if not all, biological fluids that are released by a wide range of cell types.
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Affiliation(s)
- Yun Lin
- Molecular and Cellular Cardiology, Cardiovascular Medicine, University of California, Davis, California
| | | | - Lily M A Rahnama
- Molecular and Cellular Cardiology, Cardiovascular Medicine, University of California, Davis, California
| | - Shenwen V Gu
- Molecular and Cellular Cardiology, Cardiovascular Medicine, University of California, Davis, California
| | - Anne A Knowlton
- Molecular and Cellular Cardiology, Cardiovascular Medicine, University of California, Davis, California
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13
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Schüler SC, Gebert N, Ori A. Stem cell aging: The upcoming era of proteins and metabolites. Mech Ageing Dev 2020; 190:111288. [DOI: 10.1016/j.mad.2020.111288] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 06/04/2020] [Accepted: 06/16/2020] [Indexed: 02/07/2023]
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14
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Zanetti C, Krause DS. "Caught in the net": the extracellular matrix of the bone marrow in normal hematopoiesis and leukemia. Exp Hematol 2020; 89:13-25. [PMID: 32755619 DOI: 10.1016/j.exphem.2020.07.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/28/2020] [Accepted: 07/30/2020] [Indexed: 12/14/2022]
Abstract
The influence of the bone marrow microenvironment on normal hematopoiesis, but also leukemia, has largely been accepted. However, the focus has been predominantly on the role of various cell types or cytokines maintaining hematopoietic stem cells or protecting leukemia stem cells from different therapies. A frequently overlooked component of the bone marrow microenvironment is the extracellular matrix, which not only provides a mechanical scaffold, but also serves as a source of growth factors. We discuss here how extracellular matrix proteins directly or indirectly modulate hematopoietic stem cell physiology and influence leukemia progression. It is hoped that existing and future studies on this topic may propel forward the possibility of augmenting normal hematopoiesis and improving therapies for leukemia, for instance, by targeting of the extracellular matrix in the bone marrow.
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Affiliation(s)
- Costanza Zanetti
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany
| | - Daniela S Krause
- German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Germany; Frankfurt Cancer Institute, Frankfurt, Germany; Faculty of Medicine, Johann Wolfgang Goethe University, Frankfurt, Germany.
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15
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Kumar R, Pereira RS, Zanetti C, Minciacchi VR, Merten M, Meister M, Niemann J, Dietz MS, Rüssel N, Schnütgen F, Tamai M, Akahane K, Inukai T, Oellerich T, Kvasnicka HM, Pfeifer H, Nicolini FE, Heilemann M, Van Etten RA, Krause DS. Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia. Leukemia 2020; 34:2087-2101. [PMID: 32439895 PMCID: PMC7387317 DOI: 10.1038/s41375-020-0866-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 04/29/2020] [Accepted: 05/11/2020] [Indexed: 12/30/2022]
Abstract
Therapy resistance in leukemia may be due to cancer cell-intrinsic and/or -extrinsic mechanisms. Mutations within BCR-ABL1, the oncogene giving rise to chronic myeloid leukemia (CML), lead to resistance to tyrosine kinase inhibitors (TKI), and some are associated with clinically more aggressive disease and worse outcome. Using the retroviral transduction/transplantation model of CML and human cell lines we faithfully recapitulate accelerated disease course in TKI resistance. We show in various models, that murine and human imatinib-resistant leukemia cells positive for the oncogene BCR-ABL1T315I differ from BCR-ABL1 native (BCR-ABL1) cells with regards to niche location and specific niche interactions. We implicate a pathway via integrin β3, integrin-linked kinase (ILK) and its role in deposition of the extracellular matrix (ECM) protein fibronectin as causative of these differences. We demonstrate a trend towards a reduced BCR-ABL1T315I+ tumor burden and significantly prolonged survival of mice with BCR-ABL1T315I+ CML treated with fibronectin or an ILK inhibitor in xenogeneic and syngeneic murine transplantation models, respectively. These data suggest that interactions with ECM proteins via the integrin β3/ILK-mediated signaling pathway in BCR-ABL1T315I+ cells differentially and specifically influence leukemia progression. Niche targeting via modulation of the ECM may be a feasible therapeutic approach to consider in this setting.
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Affiliation(s)
- Rahul Kumar
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596, Frankfurt am Main, Germany
| | - Raquel S Pereira
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596, Frankfurt am Main, Germany
| | - Costanza Zanetti
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596, Frankfurt am Main, Germany
| | - Valentina R Minciacchi
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596, Frankfurt am Main, Germany
| | - Maximilian Merten
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596, Frankfurt am Main, Germany
| | - Melanie Meister
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596, Frankfurt am Main, Germany
| | - Julian Niemann
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596, Frankfurt am Main, Germany
| | - Marina S Dietz
- Institute for Physical and Theoretical Chemistry, Goethe-University Frankfurt, Frankfurt am Main, Germany
| | - Nina Rüssel
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596, Frankfurt am Main, Germany
| | - Frank Schnütgen
- Department of Internal Medicine, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany
- Frankfurt Cancer Institute (FCI), Goethe University, Frankfurt am Main, Germany
| | - Minori Tamai
- Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan
| | - Koshi Akahane
- Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan
| | - Takeshi Inukai
- Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan
| | - Thomas Oellerich
- Department of Internal Medicine, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany
- Frankfurt Cancer Institute (FCI), Goethe University, Frankfurt am Main, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hans Michael Kvasnicka
- Senckenberg Institute of Pathology, Goethe University Frankfurt, 60590, Frankfurt am Main, Germany
| | - Heike Pfeifer
- Department of Internal Medicine, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany
| | - Franck E Nicolini
- Department of Hematology and INSERM U 1052, CRCL, Centre Léon Bérard, 69373, Lyon Cedex, France
| | - Mike Heilemann
- Institute for Physical and Theoretical Chemistry, Goethe-University Frankfurt, Frankfurt am Main, Germany
| | - Richard A Van Etten
- Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, 92697, USA
| | - Daniela S Krause
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596, Frankfurt am Main, Germany.
- Department of Internal Medicine, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany.
- Frankfurt Cancer Institute (FCI), Goethe University, Frankfurt am Main, Germany.
- German Cancer Consortium (DKTK), Heidelberg, Germany.
- German Cancer Research Center (DKFZ), Heidelberg, Germany.
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16
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Fujishiro A, Iwasa M, Fujii S, Maekawa T, Andoh A, Tohyama K, Takaori-Kondo A, Miura Y. Menatetrenone facilitates hematopoietic cell generation in a manner that is dependent on human bone marrow mesenchymal stromal/stem cells. Int J Hematol 2020; 112:316-330. [PMID: 32572826 DOI: 10.1007/s12185-020-02916-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 06/06/2020] [Accepted: 06/11/2020] [Indexed: 12/24/2022]
Abstract
Vitamin K2 in the form of menatetrenone has clinical benefits for osteoporosis and cytopenia. Given the dominant role of mesenchymal-osteolineage cells in the regulation of hematopoiesis, we investigated whether menatetrenone alters the hematopoiesis-supportive capability of human bone marrow mesenchymal stromal/stem cells (BM-MSCs). Menatetrenone up-regulated fibronectin protein expression in BM-MSCs without affecting their proliferation and differentiation capabilities. In addition, menatetrenone treatment of BM-MSCs enhanced generation of the CD34+ cell population in co-cultures through acceleration of the cell cycle. This effect was associated with cell-cell interactions mediated by VLA-4 and fibronectin. This proposal was supported by cytokine array and quantitative real-time PCR analyses, in which there were no significant differences between the expression levels of hematopoiesis-associated soluble factors in naïve and menatetrenone-treated BM-MSCs. Profiling of hematopoietic cells in co-cultures with menatetrenone-treated BM-MSCs demonstrated that they included significantly more CD34+CD38+ hematopoietic progenitor cells and cells skewed toward myeloid and megakaryocytic lineages than those in co-cultures with untreated BM-MSCs. Notably, myelodysplastic syndrome-derived cells were induced to undergo apoptosis when co-cultured with BM-MSCs, and this effect was enhanced by menatetrenone. Overall, our findings indicate that pharmacological treatment with menatetrenone bestows a unique hematopoiesis-supportive capability on BM-MSCs, which may contribute to the clinical improvement of cytopenia.
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Affiliation(s)
- Aya Fujishiro
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. .,Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Setatsukinowacho, Otsu, Shiga, 520-2192, Japan.
| | - Masaki Iwasa
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.,Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Setatsukinowacho, Otsu, Shiga, 520-2192, Japan
| | - Sumie Fujii
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.,Department of Hematology and Oncology, Kyoto University Graduate School for Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Taira Maekawa
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Akira Andoh
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Setatsukinowacho, Otsu, Shiga, 520-2192, Japan
| | - Kaoru Tohyama
- Department of Laboratory Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan
| | - Akifumi Takaori-Kondo
- Department of Hematology and Oncology, Kyoto University Graduate School for Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Yasuo Miura
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.,Department of Hematology and Oncology, Kyoto University Graduate School for Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
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17
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Carden MA, Fasano RM, Meier ER. Not all red cells sickle the same: Contributions of the reticulocyte to disease pathology in sickle cell anemia. Blood Rev 2019; 40:100637. [PMID: 31735458 DOI: 10.1016/j.blre.2019.100637] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 09/05/2019] [Accepted: 10/01/2019] [Indexed: 12/17/2022]
Abstract
Sickle cell anemia (SCA) is associated with morbidity and early death. While the switch from fetal to sickle hemoglobin during the first months of life results in hemolytic anemia with reticulocytosis, the role of the reticulocyte in the pathophysiology and prognosis of SCA is not well-defined. Reticulocytes have unique cytoskeletal and membrane components that allow them to be distinguished from mature sickle erythrocytes in the circulation. Reticulocytes in patients with SCA are less dense than more mature and 'sickled' erythrocytes, and have increased adhesive properties. The circulating reticulocyte number in peripheral blood may assist in predicting disease severity in SCA; characterization of patient-specific reticulocyte properties during infancy and childhood may assist in predicting therapeutic response to therapies. Here, we review the biological and clinical data regarding reticulocytes and their potential impact on SCA pathophysiology and disease severity.
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Affiliation(s)
- Marcus A Carden
- Departments of Pediatrics and Medicine, UNC School of Medicine, UNC Blood Research Center, 170 Manning Drive, POB-CB#7236, Chapel Hill, North Carolina 27599, USA.
| | - Ross M Fasano
- Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 1405 Clifton Road NE, Atlanta, GA 30322, USA.
| | - Emily Riehm Meier
- Indiana Hemophilia and Thrombosis Center, 8326 Naab Road, Indianapolis, Indiana 46220, USA.
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18
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Chiu YG, Aljitawi OS. VCAM-1+ macrophages usher hematopoietic stem and progenitor cell to vascular niche "hotspots". ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:S116. [PMID: 31576323 DOI: 10.21037/atm.2019.05.48] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Yahui Grace Chiu
- Department of Hematology and Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Omar S Aljitawi
- Department of Hematology and Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
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19
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Bone marrow sinusoidal endothelium as a facilitator/regulator of cell egress from the bone marrow. Crit Rev Oncol Hematol 2019; 137:43-56. [DOI: 10.1016/j.critrevonc.2019.01.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 01/12/2019] [Accepted: 01/29/2019] [Indexed: 02/06/2023] Open
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20
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Hayashi Y, Sezaki M, Takizawa H. Development of the hematopoietic system: Role of inflammatory factors. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2019; 8:e341. [PMID: 30916895 DOI: 10.1002/wdev.341] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 02/25/2019] [Accepted: 02/27/2019] [Indexed: 12/24/2022]
Abstract
Hematopoietic stem cells (HSCs) have two defining features, multipotency and self-renewal, both of which are tightly controlled by cell autonomous programs and environmental factors throughout the lifetime of an organism. During development, HSCs are born in the aorta-gonad-mesonephros region, and migrate to distinct hematopoietic organs such as the placenta, fetal liver and spleen, continuously self-renewing and expanding to reach a homeostatic number. HSCs ultimately seed the bone marrow around the time of birth and become dormant to sustain lifelong hematopoiesis. In this review, we will summarize the recent findings on the role of inflammatory factors regulating HSC development, that is, emergence, trafficking and differentiation. An understanding of HSC kinetics during developmental processes will provide useful knowledge on HSC behavior under physiological and pathophysiological conditions. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells.
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Affiliation(s)
- Yoshikazu Hayashi
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Maiko Sezaki
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hitoshi Takizawa
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
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21
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Monga SPS, Tang Y, Candotti F, Rashid A, Wildner O, Mishra B, Iqbal S, Mishra L. Expansion of Hepatic and Hematopoietic Stem Cells Utilizing Mouse Embryonic Liver Explants. Cell Transplant 2017; 10:81-89. [DOI: 10.3727/000000001783986945] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Affiliation(s)
- Satdarshan P. S. Monga
- Laboratory of GI Development and Molecular Biology, DVAMC, Washington, DC 20422, and Fels Cancer Institute, Temple University, Philadelphia, PA, 19140
| | - Yi Tang
- Laboratory of GI Development and Molecular Biology, DVAMC, Washington, DC 20422, and Fels Cancer Institute, Temple University, Philadelphia, PA, 19140
| | - Fabio Candotti
- Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892
| | - Asif Rashid
- GI Pathology, Johns Hopkins University Hospital, Baltimore, MD 21287
| | - Oliver Wildner
- Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892
| | - Bibhuti Mishra
- Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892
| | - Shareen Iqbal
- Laboratory of GI Development and Molecular Biology, DVAMC, Washington, DC 20422, and Fels Cancer Institute, Temple University, Philadelphia, PA, 19140
| | - Lopa Mishra
- Laboratory of GI Development and Molecular Biology, DVAMC, Washington, DC 20422, and Fels Cancer Institute, Temple University, Philadelphia, PA, 19140
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22
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Freie BW, Dutt P, Clapp DW. Correction of Fanconi Anemia Type C Phenotypic Abnormalities Using a Clinically Suitable Retroviral Vector Infection Protocol. Cell Transplant 2017; 5:385-93. [PMID: 8727007 DOI: 10.1177/096368979600500305] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Fanconi anemia (FA) is a complex autosomal recessive disease with hematologic manifestations characterized by a progressive hypoplastic anemia, hypersensitivity to clastogenic agents, and an increased incidence of acute myelogenous leukemia. The cDNA that corrects one of four FA complementation subtypes, named Fanconi anemia Type C (FAC) has recently been identified. We constructed a simplified recombinant retrovirus (vMFGFAC) encoding only the FAC cDNA, and tested its ability to correct the FAC defect in a lymphocytic cell line and primary mobilized blood progenitor cells. In addition, the gene transfer efficiency using a clinically applicable gene transfer protocol into normal primitive hematopoietic progenitor cells, high proliferating potential colony forming cells (HPP-CFC), derived from CD34+ purified cord blood cells was examined. The gene transfer efficiency was significantly enhanced when cells were transduced with supernatant while adherent to a 30/35 KD fragment of fibronectin, FN30/35, and was similar to efficiency obtained by coculture with retrovirus packaging cells. Transduction of an FAC deficient lymphoid cell line with vMFGFAC supernatant resulted in an enhanced cell viability, and G-CSF mobilized peripheral blood cells from an FAC-deficient patient transduced with the vMFGFAC virus demonstrated enhanced progenitor cell colony formation. These data indicate that the vMFGFAC virus allows functional complementation of FAC in lymphoblasts and primary hematopoietic progenitors, and that primitive cord blood hematopoietic stem/progenitor cells can be transduced at an efficiency comparable to protocols using cocultivation if adherent to FN 30/35 fragment.
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Affiliation(s)
- B W Freie
- Herman B Wells Research Center, Indiana University School of Medicine, Indianapolis 46202, USA
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23
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Kräter M, Jacobi A, Otto O, Tietze S, Müller K, Poitz DM, Palm S, Zinna VM, Biehain U, Wobus M, Chavakis T, Werner C, Guck J, Bornhauser M. Bone marrow niche-mimetics modulate HSPC function via integrin signaling. Sci Rep 2017; 7:2549. [PMID: 28566689 PMCID: PMC5451425 DOI: 10.1038/s41598-017-02352-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 04/10/2017] [Indexed: 12/25/2022] Open
Abstract
The bone marrow (BM) microenvironment provides critical physical cues for hematopoietic stem and progenitor cell (HSPC) maintenance and fate decision mediated by cell-matrix interactions. However, the mechanisms underlying matrix communication and signal transduction are less well understood. Contrary, stem cell culture is mainly facilitated in suspension cultures. Here, we used bone marrow-mimetic decellularized extracellular matrix (ECM) scaffolds derived from mesenchymal stromal cells (MSCs) to study HSPC-ECM interaction. Seeding freshly isolated HSPCs adherent (AT) and non-adherent (SN) cells were found. We detected enhanced expansion and active migration of AT-cells mediated by ECM incorporated stromal derived factor one. Probing cell mechanics, AT-cells displayed naïve cell deformation compared to SN-cells indicating physical recognition of ECM material properties by focal adhesion. Integrin αIIb (CD41), αV (CD51) and β3 (CD61) were found to be induced. Signaling focal contacts via ITGβ3 were identified to facilitate cell adhesion, migration and mediate ECM-physical cues to modulate HSPC function.
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Affiliation(s)
- Martin Kräter
- Medical Clinic I, University Hospital Carl Gustav Carus, Dresden, Saxony, 01307, Germany
| | - Angela Jacobi
- Biotechnology Center, Technische Universität Dresden, Dresden, Saxony, 01307, Germany
| | - Oliver Otto
- Centre for Innovation Competence - Humoral Immune Reactions in Cardiovascular Diseases, University of Greifswald, Greifswald, Mecklenburg-Western Pomerania, 17489, Germany
| | - Stefanie Tietze
- Medical Clinic I, University Hospital Carl Gustav Carus, Dresden, Saxony, 01307, Germany
- Biotechnology Center, Technische Universität Dresden, Dresden, Saxony, 01307, Germany
| | - Katrin Müller
- Medical Clinic I, University Hospital Carl Gustav Carus, Dresden, Saxony, 01307, Germany
| | - David M Poitz
- Department of Internal Medicine and Cardiology, Technische Universität Dresden, Dresden, Saxony, 01307, Germany
| | - Sandra Palm
- Medical Clinic I, University Hospital Carl Gustav Carus, Dresden, Saxony, 01307, Germany
| | - Valentina M Zinna
- Medical Clinic I, University Hospital Carl Gustav Carus, Dresden, Saxony, 01307, Germany
| | - Ulrike Biehain
- Medical Clinic I, University Hospital Carl Gustav Carus, Dresden, Saxony, 01307, Germany
| | - Manja Wobus
- Medical Clinic I, University Hospital Carl Gustav Carus, Dresden, Saxony, 01307, Germany
| | - Triantafyllos Chavakis
- Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Saxony, 01307, Germany
- Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Saxony, 01307, Germany
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Saxony, 01307, Germany
| | - Carsten Werner
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, Dresden, Saxony, 01307, Germany
| | - Jochen Guck
- Biotechnology Center, Technische Universität Dresden, Dresden, Saxony, 01307, Germany
| | - Martin Bornhauser
- Medical Clinic I, University Hospital Carl Gustav Carus, Dresden, Saxony, 01307, Germany.
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Saxony, 01307, Germany.
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24
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Vitamin C in Stem Cell Biology: Impact on Extracellular Matrix Homeostasis and Epigenetics. Stem Cells Int 2017; 2017:8936156. [PMID: 28512473 PMCID: PMC5415867 DOI: 10.1155/2017/8936156] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 03/05/2017] [Indexed: 12/30/2022] Open
Abstract
Transcription factors and signaling molecules are well-known regulators of stem cell identity and behavior; however, increasing evidence indicates that environmental cues contribute to this complex network of stimuli, acting as crucial determinants of stem cell fate. l-Ascorbic acid (vitamin C (VitC)) has gained growing interest for its multiple functions and mechanisms of action, contributing to the homeostasis of normal tissues and organs as well as to tissue regeneration. Here, we review the main functions of VitC and its effects on stem cells, focusing on its activity as cofactor of Fe+2/αKG dioxygenases, which regulate the epigenetic signatures, the redox status, and the extracellular matrix (ECM) composition, depending on the enzymes' subcellular localization. Acting as cofactor of collagen prolyl hydroxylases in the endoplasmic reticulum, VitC regulates ECM/collagen homeostasis and plays a key role in the differentiation of mesenchymal stem cells towards osteoblasts, chondrocytes, and tendons. In the nucleus, VitC enhances the activity of DNA and histone demethylases, improving somatic cell reprogramming and pushing embryonic stem cell towards the naive pluripotent state. The broad spectrum of actions of VitC highlights its relevance for stem cell biology in both physiology and disease.
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25
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Khurana S, Schouteden S, Manesia JK, Santamaria-Martínez A, Huelsken J, Lacy-Hulbert A, Verfaillie CM. Outside-in integrin signalling regulates haematopoietic stem cell function via Periostin-Itgav axis. Nat Commun 2016; 7:13500. [PMID: 27905395 PMCID: PMC5146274 DOI: 10.1038/ncomms13500] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 10/11/2016] [Indexed: 01/08/2023] Open
Abstract
Integrins play an important role in haematopoietic stem cell (HSC) maintenance in the bone marrow niche. Here, we demonstrate that Periostin (Postn) via interaction with Integrin-αv (Itgav) regulates HSC proliferation. Systemic deletion of Postn results in peripheral blood (PB) anaemia, myelomonocytosis and lymphopenia, while the number of phenotypic HSCs increases in the bone marrow. Postn−/− mice recover faster from radiation injury with concomitant loss of primitive HSCs. HSCs from Postn−/− mice show accumulation of DNA damage generally associated with aged HSCs. Itgav deletion in the haematopoietic system leads to a similar PB phenotype and HSC-intrinsic repopulation defects. Unaffected by Postn, Vav-Itgav−/− HSCs proliferate faster in vitro, illustrating the importance of Postn-Itgav interaction. Finally, the Postn-Itgav interaction inhibits the FAK/PI3K/AKT pathway in HSCs, leading to increase in p27Kip1 expression resulting in improved maintenance of quiescent HSCs. Together, we demonstrate a role for Itgav-mediated outside-in signalling in regulation of HSC proliferation and stemness. Integrins regulate haematopoietic stem cell (HSC) homeostasis and engraftment into the bone marrow (BM) niche upon transplantation. Here, the authors show that HSC quiescence and function in the BM is regulated by the interaction of PERIOSTIN and INTEGRIN αv and subsequent increase in p27Kip1.
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Affiliation(s)
- Satish Khurana
- Inter-departmental Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium
| | - Sarah Schouteden
- Inter-departmental Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium
| | - Javed K Manesia
- Inter-departmental Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium
| | | | - Joerg Huelsken
- École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
| | - Adam Lacy-Hulbert
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
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26
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Identification of factors promoting ex vivo maintenance of mouse hematopoietic stem cells by long-term single-cell quantification. Blood 2016; 128:1181-92. [DOI: 10.1182/blood-2016-03-705590] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 05/14/2016] [Indexed: 12/11/2022] Open
Abstract
Key Points
AFT024-induced HSC maintenance correlates with early survival/proliferation whereas early death is a major reason for HSC loss in culture. Dermatopontin is required for ex vivo HSC maintenance, and also improves HSC clonogenicity in stroma-based and stroma-free cultures.
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27
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Hardy CL. Specificity of Hematopoietic Stem and Progenitor Cell Homing to Bone Marrow: A Perspective. Hematology 2016; 5:391-401. [DOI: 10.1080/10245332.2000.11746535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Affiliation(s)
- Cheryl L. Hardy
- G.V. (Sonny) Montgomery Department of Veterans Affairs Medical Center, Department of Medicine, University of Mississippi School of Medicine, Jackson, MS
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28
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Birbrair A, Frenette PS. Niche heterogeneity in the bone marrow. Ann N Y Acad Sci 2016; 1370:82-96. [PMID: 27015419 DOI: 10.1111/nyas.13016] [Citation(s) in RCA: 203] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 01/08/2016] [Accepted: 01/12/2016] [Indexed: 12/15/2022]
Abstract
In adult mammals, hematopoietic stem cells (HSCs) are defined by their abilities to self-renew and to differentiate to form all blood cell lineages. These rare multipotent cells occupy specific locations in the bone marrow (BM) microenvironment. The specific microenvironment regulating HSCs, commonly referred to as the niche, comprises multiple cell types whose exact contributions are under active investigation. Understanding cellular cross talk involving HSCs in the BM microenvironment is of fundamental importance for harnessing therapies against benign and malignant blood diseases. In this review, we summarize and evaluate recent advances in our understanding of niche heterogeneity and its influence on HSC function.
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Affiliation(s)
- Alexander Birbrair
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York.,Departments of Medicine and Cell Biology, Albert Einstein College of Medicine, Bronx, New York
| | - Paul S Frenette
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York.,Departments of Medicine and Cell Biology, Albert Einstein College of Medicine, Bronx, New York
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29
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Asri A, Sabour J, Atashi A, Soleimani M. Homing in hematopoietic stem cells: focus on regulatory role of CXCR7 on SDF1a/CXCR4 axis. EXCLI JOURNAL 2016; 15:134-43. [PMID: 27092040 PMCID: PMC4827072 DOI: 10.17179/excli2014-585] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 12/19/2014] [Indexed: 12/20/2022]
Abstract
Hematopoietic stem cells (HSCs) form a rare population of multipotent stem cells, which give rise to all hematopoietic lineages. HSCs home to bone marrow niches and circulate between blood and bone marrow. Many factors, especially SDF1a, affect the circulation of HSCs, but these have not been fully recognized. SDF1a has been shown to bind CXCR7 in addition to CXCR4 and can also function as SDF1a/CXCR4 modulator. CXCR7 plays a role in HSCs homing via SDF1a gradient and is a mediator of CXCR4/SDF1a axis. This review describes the current concepts and questions concerning CXCR7/CXCR4/SDF1a axis as an important key in hematopoietic stem cells homing with particular emphasis on CXCR7 receptor. Homing of HSCs is an essential step for successful hematopoietic stem cell transplantation.
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Affiliation(s)
- Amir Asri
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Javid Sabour
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amir Atashi
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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30
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Large-scale hematopoietic differentiation of human induced pluripotent stem cells provides granulocytes or macrophages for cell replacement therapies. Stem Cell Reports 2015; 4:282-96. [PMID: 25680479 PMCID: PMC4325194 DOI: 10.1016/j.stemcr.2015.01.005] [Citation(s) in RCA: 155] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Revised: 01/07/2015] [Accepted: 01/08/2015] [Indexed: 12/15/2022] Open
Abstract
Interleukin-3 (IL-3) is capable of supporting the proliferation of a broad range of hematopoietic cell types, whereas granulocyte colony-stimulating factor (G-CSF) and macrophage CSF (M-CSF) represent critical cytokines in myeloid differentiation. When this was investigated in a pluripotent-stem-cell-based hematopoietic differentiation model, IL-3/G-CSF or IL-3/M-CSF exposure resulted in the continuous generation of myeloid cells from an intermediate myeloid-cell-forming complex containing CD34+ clonogenic progenitor cells for more than 2 months. Whereas IL-3/G-CSF directed differentiation toward CD45+CD11b+CD15+CD16+CD66b+ granulocytic cells of various differentiation stages up to a segmented morphology displaying the capacity of cytokine-directed migration, respiratory burst response, and neutrophil-extracellular-trap formation, exposure to IL-3/M-CSF resulted in CD45+CD11b+CD14+CD163+CD68+ monocyte/macrophage-type cells capable of phagocytosis and cytokine secretion. Hence, we show here that myeloid specification of human pluripotent stem cells by IL-3/G-CSF or IL-3/M-CSF allows for prolonged and large-scale production of myeloid cells, and thus is suited for cell-fate and disease-modeling studies as well as gene- and cell-therapy applications.
Myeloid specification of human PSCs by IL-3-/M-CSF, G-CSF, or GM-CSF Large-scale and continuous generation of M2-MΦ or granulocytes by M-CSF or G-CSF Functional iPSC-derived macrophages or granulocytes similar to in-vivo-derived cells
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31
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Murakami JL, Xu B, Franco CB, Hu X, Galli SJ, Weissman IL, Chen CC. Evidence that β7 Integrin Regulates Hematopoietic Stem Cell Homing and Engraftment Through Interaction with MAdCAM-1. Stem Cells Dev 2015; 25:18-26. [PMID: 26422691 DOI: 10.1089/scd.2014.0551] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
α4β7 integrin is a cell adhesion receptor that is crucial for the migration of hematopoietic progenitors and mature effector cells in the periphery, but its role in adult hematopoiesis is controversial. We identified a subset of hematopoietic stem cells (HSCs) in the bone marrow (BM) that expressed β7 integrin. These β7(+) HSCs were capable of multilineage, long-term reconstitution and had an inherent competitive advantage over β7(-) HSCs. On the other hand, HSCs that lacked β7 integrin (β7KO) had reduced engraftment potential. Interestingly, quantitative RT-PCR and flow cytometry revealed that β7KO HSCs expressed lower levels of the chemokine receptor CXCR4. Accordingly, β7KO HSCs exhibited impaired migration abilities in vitro and BM homing capabilities in vivo. Lethal irradiation induced expression of the α4β7 integrin ligand-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on BM endothelial cells. Moreover, blocking MAdCAM-1 reduced the homing of HSCs and impaired the survival of recipient mice. Altogether, these data indicate that β7 integrin, when expressed by HSCs, interacted with its endothelial ligand MAdCAM-1 in the BM microenvironment, thereby promoting HSC homing and engraftment.
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Affiliation(s)
- Jodi L Murakami
- 1 Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute of City of Hope , Duarte, California.,2 City of Hope Irell & Manella Graduate School of Biological Sciences , Duarte, California.,3 Gehr Family Center for Leukemia Research at City of Hope , Duarte, California
| | - Baohui Xu
- 4 Department of Surgery, Stanford University School of Medicine , Stanford, California
| | - Christopher B Franco
- 5 Department of Pathology, Stanford University School of Medicine , Stanford, California.,6 Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine , Stanford, California
| | - Xingbin Hu
- 1 Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute of City of Hope , Duarte, California.,7 Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University , Xi'an, People's Republic of China
| | - Stephen J Galli
- 5 Department of Pathology, Stanford University School of Medicine , Stanford, California.,8 Department of Microbiology and Immunology, Stanford University School of Medicine , Stanford, California
| | - Irving L Weissman
- 5 Department of Pathology, Stanford University School of Medicine , Stanford, California.,6 Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine , Stanford, California
| | - Ching-Cheng Chen
- 1 Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute of City of Hope , Duarte, California.,2 City of Hope Irell & Manella Graduate School of Biological Sciences , Duarte, California.,3 Gehr Family Center for Leukemia Research at City of Hope , Duarte, California
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32
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Dutta P, Hoyer FF, Grigoryeva LS, Sager HB, Leuschner F, Courties G, Borodovsky A, Novobrantseva T, Ruda VM, Fitzgerald K, Iwamoto Y, Wojtkiewicz G, Sun Y, Da Silva N, Libby P, Anderson DG, Swirski FK, Weissleder R, Nahrendorf M. Macrophages retain hematopoietic stem cells in the spleen via VCAM-1. ACTA ACUST UNITED AC 2015; 212:497-512. [PMID: 25800955 PMCID: PMC4387283 DOI: 10.1084/jem.20141642] [Citation(s) in RCA: 130] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 02/13/2015] [Indexed: 12/21/2022]
Abstract
Dutta et al. show that targeting VACM-1 expression in splenic macrophages impairs extramedullary hematopoiesis, thus reducing inflammation in mouse ischemic heart and atherosclerotic plaques. Splenic myelopoiesis provides a steady flow of leukocytes to inflamed tissues, and leukocytosis correlates with cardiovascular mortality. Yet regulation of hematopoietic stem cell (HSC) activity in the spleen is incompletely understood. Here, we show that red pulp vascular cell adhesion molecule 1 (VCAM-1)+ macrophages are essential to extramedullary myelopoiesis because these macrophages use the adhesion molecule VCAM-1 to retain HSCs in the spleen. Nanoparticle-enabled in vivo RNAi silencing of the receptor for macrophage colony stimulation factor (M-CSFR) blocked splenic macrophage maturation, reduced splenic VCAM-1 expression and compromised splenic HSC retention. Both, depleting macrophages in CD169 iDTR mice or silencing VCAM-1 in macrophages released HSCs from the spleen. When we silenced either VCAM-1 or M-CSFR in mice with myocardial infarction or in ApoE−/− mice with atherosclerosis, nanoparticle-enabled in vivo RNAi mitigated blood leukocytosis, limited inflammation in the ischemic heart, and reduced myeloid cell numbers in atherosclerotic plaques.
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Affiliation(s)
- Partha Dutta
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Friedrich Felix Hoyer
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Lubov S Grigoryeva
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Hendrik B Sager
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Florian Leuschner
- Department of Cardiology, Medical University Hospital Heidelberg, D-69120 Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, D-69120 Heidelberg, Germany
| | - Gabriel Courties
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | | | | | - Vera M Ruda
- Alnylam Pharmaceuticals, Cambridge, MA 02142
| | | | - Yoshiko Iwamoto
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Gregory Wojtkiewicz
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Yuan Sun
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Nicolas Da Silva
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Peter Libby
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115
| | - Daniel G Anderson
- David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142 David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142 David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142 Division of Health Science Technology, Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139
| | - Filip K Swirski
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Ralph Weissleder
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 Department of Systems Biology, Harvard Medical School, Boston, MA 02115
| | - Matthias Nahrendorf
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
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33
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Lane SW, Williams DA, Watt FM. Modulating the stem cell niche for tissue regeneration. Nat Biotechnol 2014; 32:795-803. [PMID: 25093887 PMCID: PMC4422171 DOI: 10.1038/nbt.2978] [Citation(s) in RCA: 420] [Impact Index Per Article: 38.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 07/06/2014] [Indexed: 02/06/2023]
Abstract
The field of regenerative medicine holds considerable promise for treating diseases that are currently intractable. Although many researchers are adopting the strategy of cell transplantation for tissue repair, an alternative approach to therapy is to manipulate the stem cell microenvironment, or niche, to facilitate repair by endogenous stem cells. The niche is highly dynamic, with multiple opportunities for intervention. These include administration of small molecules, biologics or biomaterials that target specific aspects of the niche, such as cell-cell and cell-extracellular matrix interactions, to stimulate expansion or differentiation of stem cells, or to cause reversion of differentiated cells to stem cells. Nevertheless, there are several challenges in targeting the niche therapeutically, not least that of achieving specificity of delivery and responses. We envisage that successful treatments in regenerative medicine will involve different combinations of factors to target stem cells and niche cells, applied at different times to effect recovery according to the dynamics of stem cell-niche interactions.
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Affiliation(s)
- Steven W Lane
- Division of Immunology, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, Queensland, Australia
| | - David A Williams
- 1] Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Harvard Stem Cell Institute, Boston, Massachusetts, USA
| | - Fiona M Watt
- Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London, UK
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Nayak RC, Chang KH, Vaitinadin NS, Cancelas JA. Rho GTPases control specific cytoskeleton-dependent functions of hematopoietic stem cells. Immunol Rev 2014; 256:255-68. [PMID: 24117826 DOI: 10.1111/imr.12119] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The Rho family of guanosine triphosphatases (GTPases) is composed of members of the Ras superfamily of proteins. They are GTP-bound molecules with a modest intrinsic GTPase activity that can be accelerated upon activation/localization of specialized guanine nucleotide exchange factors. Members of this family act as molecular switches and are required for coordinated cytoskeletal rearrangements that are crucial in a set of specialized functions of mammalian stem cells. These functions include self-renewal, adhesion, and migration. Mouse gene-targeting studies have provided convincing evidence of the indispensable and dispensable roles of individual members of the Rho GTPase family and the putative upstream and downstream mediators in stem cell-specific functions. The role of Rho GTPases and related signaling pathways previously seen in other cell types and organisms have been confirmed in mammalian hematopoietic stem cells (HSCs), and new signaling pathways and unexpected functions unique to HSCs have been identified and dissected. This review summarizes our current understanding of the role of Rho family of GTPases on HSC and progenitor activity through cytoskeleton-mediated signaling pathways, providing insight about relevant signaling pathways that regulate mammalian stem cell self-renewal, adhesion, and migration.
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Affiliation(s)
- Ramesh C Nayak
- Stem Cell Program, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
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35
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Morimoto C, Kobayashi H, Nishijima R, Tanaka H, Iwata S. Role of the β1 integrin molecule in T-cell activation and migration. Mod Rheumatol 2014; 10:8-15. [PMID: 24383527 DOI: 10.3109/s101650070032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Abstract β1 integrins play crucial roles in a variety of cell processes such as adhesion, migration, proliferation, and differentiation of lymphocytes. To understand the molecular mechanisms of these various biological effects, it is particularly important to analyze cell signaling through the β1 integrins. Our previous study showed that PLC-γ, pp125FAK (focal adhesion kinase), pp105, paxillin, p59fyn, p56lck, and ERK1/2 are phosphorylated in their tyrosine residues upon engagement of β1 integrins. We identified pp105 as Cas (Crk-associated substrate)-related protein and successfully cloned its cDNA. pp105 is a Cas homologue predominantly expressed in the cells of lymphoid lineage, which led us to designate it Cas-L. Like p130Cas, Cas-L contains a single SH3 domain and multiple SH2-binding sites (YXXP motif), which are suggested to bind SH2 domains of Crk, Nck, and SHPTP2. Subsequent studies revealed that pp125FAK binds Cas-L on its SH3 domain and phosphorylates its tyrosine residues upon β1 integrin stimulation. Since Cas-L is preferentially expressed in lymphocytes, it is conceivable that Cas-L plays an important role in lymphocyte-specific signals. We have shown that Cas-L is involved in the T-cell receptor (TCR)/CD3 signaling pathway as well as the β1 integrin signaling pathway. Cas-L is transiently phosphorylated following CD3 crosslinking and tyrosine-phosphorylated Cas-L binds to Crk and C3G. Furthermore, a Cas-L mutant (Cas-LΔSH3), which lacks the binding site for FAK, is still tyrosine-phosphorylated upon CD3 crosslinking but not upon β1 integrin crosslinking, suggesting that FAK is not involved in CD3-dependent Cas-L phosphorylation. Finally, we have identified a crucial role of Cas-L in β1 integrin-mediated T-cell co-stimulation. We have found that this co-stimulatory pathway is impaired in the Jurkat T-cell line, and that the expression level of Cas-L is reduced in the Jurkat cells compared to peripheral T-cells. The transfection of Cas-L cDNA into Jurkat cells restored the β1 integrin-mediated co-stimulation, while the transfection of Cas-LΔSH3 mutant failed to do so, which contrasts with the case of CD3-mediated signaling. These results indicate that Cas-L plays a key role, through the association and phosphorylation by FAK, in β1 integrin-mediated T-cell co-stimulation. Moreover, tyrosine phosphorylation of Cas-L is critical for T-cell receptor and β1 integrin-induced T-lymphocyte migration. Taken together, Cas-L might be the bi-modal docking protein which assembles the signals through β1 integrins and TCR/CD3, and which participates in a variety of T-cell functions.
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Affiliation(s)
- C Morimoto
- Department of Clinical Immunology and AIDS Research Center, The Institute of Medical Science, The University of Tokyo , 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 , Japan
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Sueblinvong V, Neveu WA, Neujahr DC, Mills ST, Rojas M, Roman J, Guidot DM. Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury. ACTA ACUST UNITED AC 2014; 5:19-30. [PMID: 24596659 PMCID: PMC3939026 DOI: 10.4236/abb.2014.51004] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Fibrotic lung diseases increase with age. Previously we determined that senescence increases tissue expression of fibronectin EDA (Fn-EDA) and decreases fibroblast expression of Thy-1, and that fibrocytes contribute to fibrosis following bleomycin-induced lung injury in mice. In this study we hypothesized that fibroblasts lacking Thy-1 expression produce an extracellular matrix that promotes fibrocyte retention and myofibroblast transdifferentiation, thereby promoting fibrogenesis. Young and old mice were treated with bleomycin intratracheally; fibrocytes in the bone marrow, blood, and lungs were quantified, and lung fibroblast Thy-1 expression assessed. Bone marrow-derived fibrocytes were cultured on matrices derived from Thy-1(+) or Thy-1(-) fibroblasts ± the pro-fibrotic cytokine TGFβ1. Older mice had more fibrocytes in their bone marrows at baseline and more fibrocytes in their lungs following bleomycin treatment. In parallel, lung fibroblasts in older mice had lower expression of Thy-1 at baseline that increased transiently 7 days after bleomycin treatment but then rapidly waned such that 14 days after bleomycin treatment Thy-1 expression was again markedly lower. Fibrocytes cultured on matrices derived from Thy-1(-) fibroblasts + TGFβ1 had increased gene expression for collagen type 1, fibronectin, Fn-EDA, and α-smooth muscle actin. In parallel, whereas the matrices derived from Thy-1(-) fibroblasts stimulated phosphorylation of Akt in cultured fibrocytes, the matrices derived from Thy-1(+) fibroblasts induced apoptosis. These findings suggest that senescence increases fibrocyte recruitment to the lung following injury and that loss of Thy-1 expression by lung fibroblasts promotes fibrocyte retention and myofibroblast trans-differentiation that renders the "aging lung" susceptible to fibrosis.
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Affiliation(s)
- Viranuj Sueblinvong
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Wendy A Neveu
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - David C Neujahr
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA ; McKelvey Lung Transplantation Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Stephen T Mills
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Mauricio Rojas
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jesse Roman
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Louisville, Louisville, KY, USA
| | - David M Guidot
- Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA ; Division of Pulmonary, Allergy and Critical Care Medicine, Atlanta VAMC, Decatur, GA, USA
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37
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Kita K, Xiu F, Jeschke MG. Ex vivo expansion of hematopoietic stem and progenitor cells: Recent advances. World J Hematol 2014; 3:18. [DOI: 10.5315/wjh.v3.i2.18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
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38
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Kim KJ, Cho CM, Kim BG, Lee YA, Kim BJ, Kim YH, Kim CG, Schmidt JA, Ryu BY. Lentiviral modification of enriched populations of bovine male gonocytes. J Anim Sci 2013; 92:106-18. [PMID: 24166994 DOI: 10.2527/jas.2013-6885] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Undifferentiated germ cells have the capacity to develop into sperm capable of fertilizing oocytes and contributing genetic material to subsequent generations. The most primitive prepubertal undifferentiated germ cells include gonocytes and undifferentiated spermatogonia, including spermatogonial stem cells (SSC). Gonocytes, present in the testis at birth, differentiate into SSC, which maintain spermatogenesis for the remainder of the male's life. Because of their capacity to contribute to lifelong spermatogenesis, undifferentiated germ cells are attractive targets for genetic modification to produce transgenic animals, including cattle. To maximize the efficiency of genetic modification of bovine gonocytes and SSC, effective enrichment techniques need to be developed. Selection of bovine gonocytes using differential plating was improved 8-fold (P < 0.001) when using a combination of extracellular matrix proteins, including laminin, fibronectin, collagen type IV, and gelatin, compared to using laminin and gelatin alone. Selected cells labeled with PKH26 formed colonies of donor-derived germ cells after transplantation into recipient mouse testes, indicating putative stem cell function. Significantly more colonies (P < 0.001) per 1 × 10(5) viable transplanted cells were formed from isolated nonadherent cells (203 ± 23.2) compared to adherent (20 ± 2.7) or Percoll (45.5 ± 4.5) selected cells. After selection, some gonocytes were transduced using a lentiviral vector containing the transgene for the enhanced green fluorescent protein. Transduction efficiency was 17%. Collectively, these data demonstrate effective methods for the selection and genetic modification of bovine undifferentiated germ cells.
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Affiliation(s)
- K-J Kim
- Department of Animal Science and Technology, Chung-Ang University, Ansung, Gyeonggi-do 456-756, Korea
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Taniguchi Ishikawa E, Chang KH, Nayak R, Olsson HA, Ficker AM, Dunn SK, Madhu MN, Sengupta A, Whitsett JA, Grimes HL, Cancelas JA. Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated β1/β2-integrin trafficking. Nat Commun 2013; 4:1660. [PMID: 23552075 PMCID: PMC3627399 DOI: 10.1038/ncomms2645] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Accepted: 02/22/2013] [Indexed: 01/05/2023] Open
Abstract
Kruppel-like factor 5 (Klf5) regulates pluripotent stem cell self-renewal but its role in somatic stem cells is unknown. Here we show that Klf5 deficient haematopoietic stem cells and progenitors (HSC/P) fail to engraft after transplantation. This HSC/P defect is associated with impaired bone marrow homing and lodging and decreased retention in bone marrow, and with decreased adhesion to fibronectin and expression of membrane-bound β1/β2-integrins. In vivo inducible gain-of-function of Klf5 in HSCs increases HSC/P adhesion. The expression of Rab5 family members, mediators of β1/β2-integrin recycling in the early endosome, is decreased in Klf5Δ/Δ HSC/Ps. Klf5 binds directly to the promoter of Rab5a/b and overexpression of Rab5b rescues the expression of activated β1/β2-integrins, adhesion and bone marrow homing of Klf5Δ/Δ HSC/Ps. Altogether, these data indicate that Klf5 is indispensable for adhesion, homing, lodging and retention of HSC/Ps in the bone marrow through Rab5-dependent post-translational regulation of β1/β2 integrins.
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Affiliation(s)
- E Taniguchi Ishikawa
- Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0055, USA
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Lee HJ, Li N, Evans SM, Diaz MF, Wenzel PL. Biomechanical force in blood development: extrinsic physical cues drive pro-hematopoietic signaling. Differentiation 2013; 86:92-103. [PMID: 23850217 DOI: 10.1016/j.diff.2013.06.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 06/17/2013] [Accepted: 06/19/2013] [Indexed: 02/07/2023]
Abstract
The hematopoietic system is dynamic during development and in adulthood, undergoing countless spatial and temporal transitions during the course of one's life. Microenvironmental cues in the many unique hematopoietic niches differ, characterized by distinct soluble molecules, membrane-bound factors, and biophysical features that meet the changing needs of the blood system. Research from the last decade has revealed the importance of substrate elasticity and biomechanical force in determination of stem cell fate. Our understanding of the role of these factors in hematopoiesis is still relatively poor; however, the developmental origin of blood cells from the endothelium provides a model for comparison. Many endothelial mechanical sensors and second messenger systems may also determine hematopoietic stem cell fate, self renewal, and homing behaviors. Further, the intimate contact of hematopoietic cells with mechanosensitive cell types, including osteoblasts, endothelial cells, mesenchymal stem cells, and pericytes, places them in close proximity to paracrine signaling downstream of mechanical signals. The objective of this review is to present an overview of the sensors and intracellular signaling pathways activated by mechanical cues and highlight the role of mechanotransductive pathways in hematopoiesis.
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Affiliation(s)
- Hyun Jung Lee
- Children's Regenerative Medicine Program, Department of Pediatric Surgery, University of Texas Medical School at Houston, Houston, TX 77030, USA; Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Kim YH, Kim BJ, Kim BG, Lee YA, Kim KJ, Chung HJ, Hwang S, Woo JS, Park JK, Schmidt JA, Pang MG, Ryu BY. Stage-specific embryonic antigen-1 expression by undifferentiated spermatogonia in the prepubertal boar testis1. J Anim Sci 2013; 91:3143-54. [DOI: 10.2527/jas.2012-6139] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Affiliation(s)
- Y.-H. Kim
- Department of Animal Science & Technology, Chung-Ang University, Anseong, Gyeonggi-do 456-756, Korea
| | - B.-J. Kim
- Department of Animal Science & Technology, Chung-Ang University, Anseong, Gyeonggi-do 456-756, Korea
| | - B.-G. Kim
- Department of Animal Science & Technology, Chung-Ang University, Anseong, Gyeonggi-do 456-756, Korea
| | - Y.-A. Lee
- Department of Animal Science & Technology, Chung-Ang University, Anseong, Gyeonggi-do 456-756, Korea
| | - K.-J. Kim
- Department of Animal Science & Technology, Chung-Ang University, Anseong, Gyeonggi-do 456-756, Korea
| | - H.-J. Chung
- Animal Biotechnology Division, National Institute of Animal Science, RDA, Chuksan-gil 77, Suwon, Gyeonggi-do 441-706, Korea
| | - S. Hwang
- Animal Biotechnology Division, National Institute of Animal Science, RDA, Chuksan-gil 77, Suwon, Gyeonggi-do 441-706, Korea
| | - J.-S. Woo
- Animal Biotechnology Division, National Institute of Animal Science, RDA, Chuksan-gil 77, Suwon, Gyeonggi-do 441-706, Korea
| | - J.-K. Park
- Animal Biotechnology Division, National Institute of Animal Science, RDA, Chuksan-gil 77, Suwon, Gyeonggi-do 441-706, Korea
| | - J. A. Schmidt
- Department of Science, Spokane Community College, 1810 N Greene St., Spokane, WA 99217-5399
| | - M.-G. Pang
- Department of Animal Science & Technology, Chung-Ang University, Anseong, Gyeonggi-do 456-756, Korea
| | - B.-Y. Ryu
- Department of Animal Science & Technology, Chung-Ang University, Anseong, Gyeonggi-do 456-756, Korea
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Yen CY, Huang CY, Hou MF, Yang YH, Chang CH, Huang HW, Chen CH, Chang HW. Evaluating the performance of fibronectin 1 (FN1), integrin α4β1 (ITGA4), syndecan-2 (SDC2), and glycoprotein CD44 as the potential biomarkers of oral squamous cell carcinoma (OSCC). Biomarkers 2012; 18:63-72. [DOI: 10.3109/1354750x.2012.737025] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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TGF-beta-1 up-regulates extra-cellular matrix production in mouse hepatoblasts. Mech Dev 2012; 130:195-206. [PMID: 23041440 DOI: 10.1016/j.mod.2012.09.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2012] [Revised: 09/09/2012] [Accepted: 09/15/2012] [Indexed: 12/12/2022]
Abstract
Fetal liver is the major embryonic hematopoietic organ and is extrinsically colonized by circulating hematopoietic stem cells (HSCs). Integrin beta-1 expression on HSCs is crucial for colonization, suggesting that interaction of Integrin beta-1 with extra-cellular matrix (ECM) factors promotes HSC adherence to fetal liver. However, little is known about how ECM production is regulated in fetal liver. Here we used flow cytometry to sort fetal liver compartments and detected ECM gene and protein expression predominantly in sorted hepatoblasts. mRNA and protein analysis suggested that TGF-beta-1 expressed by hepatoblasts, sinusoid endothelial cells and hematopoietic cells, binds to the TGF-beta receptor type-2 expressed on hepatoblasts to stimulate ECM production. Intra-cardiac injection of TGF-inhibitors into mouse embryos dramatically decreased fetal liver ECM gene expression. Taken together, our observations suggest that hepatoblasts predominantly produce ECM factors under control of TGF-beta-1 in fetal liver.
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Trotta T, Di Gioia S, Piro D, Lepore S, Cantatore S, Porro C, Castellani S, Petrella A, Fortunato F, Maffione AB, Conese M. Effect of acute lung injury on VLA-4 and CXCR4 expression in resident and circulating hematopoietic stem/progenitor cells. ACTA ACUST UNITED AC 2012; 85:252-64. [PMID: 23018206 DOI: 10.1159/000341172] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Accepted: 06/19/2012] [Indexed: 11/19/2022]
Abstract
BACKGROUND The effect of acute lung injury on adhesion molecule expression in hematopoietic stem/progenitor cells (HSPCs) is poorly understood. OBJECTIVES The aim of this study was to determine whether there is a relationship -between pulmonary inflammation, expression of VLA-4 (CD49d), LFA-1 (CD11a), L-selectin (CD62L), CXCR4, and chemotaxis in resident HSPCs, as well as the level of circulating HSPCs. METHODS Following intratracheal administration of a single LPS bolus in C57Bl/6 mice, the number of inflammatory cells, differential counts, and amounts of cytokines/ chemokines were studied in cytospins and bronchoalveolar lavage fluid (BALF) specimens. Expressions of adhesion -molecules and CXCR4 were analyzed in HSPCs by flow cytometry, as well as SDF-1-directed chemotaxis. Levels of HSPCs in the blood were studied in ungated and circulating subpopulations. RESULTS In coincidence with a peak of airway neutrophils, cytokine (IL-1β, TNF-α, and IL-6), chemokine (KC, MIP-2, and SDF-1) levels in BALF and the number of marrow HSPCs expressing CD49d and CXCR4 significantly increased at 48 h. The number of CD49d- and CXCR4-positive HSPCs dropped at 72 h. The HSPC subset comprising bigger cells behaved the same for CD49d. Chemotaxis of the marrow HSPC subset of bigger cells was higher in LPS-treated animals than in controls at 72 h. Finally, we could detect a significant decrease in circulating Sca-1(+) cells in the mononuclear population at 72 h in LPS-treated mice. CONCLUSIONS Our data provide evidence for a temporal relationship between pulmonary inflammation, CD49d and CXCR4 expression fluctuation in resident HSPCs, and the level of circulating HSPCs.
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Affiliation(s)
- Teresa Trotta
- Department of Clinical and Experimental Sciences, University of Foggia, Foggia, Italy
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Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HWM, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M. Myocardial infarction accelerates atherosclerosis. Nature 2012; 487:325-9. [PMID: 22763456 PMCID: PMC3401326 DOI: 10.1038/nature11260] [Citation(s) in RCA: 844] [Impact Index Per Article: 64.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Accepted: 05/25/2012] [Indexed: 12/14/2022]
Abstract
During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaque in the arterial wall and cause its rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, apoE−/− mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. When seeking the source of surplus monocytes in plaque, we found that myocardial infarction liberated hematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signaling. The progenitors then seeded the spleen yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.
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Affiliation(s)
- Partha Dutta
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
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Tada T, Fukuta K. Expression of cell adhesion molecules at the collapse and recovery of haematopoiesis in bone marrow of mouse. Anat Histol Embryol 2012; 39:403-10. [PMID: 20545639 DOI: 10.1111/j.1439-0264.2010.01009.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
After bone marrow transplantation (BMT) and lethal irradiation, vascular endothelial cells play an important role in the homing of haematopoietic cells and recovery of haematopoiesis. We investigated the expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1) and fibronectin in the endothelial cells of bone marrow in a collapsed state after lethal irradiation and in a recovery state after BMT in mice. After lethal irradiation, the expression of MAdCAM-1, VCAM-1 and fibronectin increased on the luminal surface of endothelial cells. In the recovery state, the expression of MAdCAM-1 and VCAM-1 was increased from 2 to 4 days after BMT, but fibronectin levels remained constant, except for a temporary increase at 4 days after BMT. The number of homing cells, however, was markedly decreased in parallel with the reduction in the haematopoietic compartment at 2 and 4 days after lethal irradiation. Next, to analyse the influence of fibronectin expression after BMT on homing activity, we performed double BMT experiment. The number of homing cells in double BMT experiment maintained high level from 2 h to 2 days after secondary BMT. Our data suggest that homing of bone marrow cells is activated until fibronectin-mediated endothelial cell repair and that transplanted haematopoietic stem/progenitor cells inhibit fibronectin expression for endothelial cell repair until the homing is completed. Therefore, the homing of haematopoietic cells in bone marrow depends on the condition of the bone marrow endothelial cells, as well as the cell adhesion molecules.
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Affiliation(s)
- T Tada
- Laboratory of Animal Morphology and Function, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa-ku, Nagoya, Japan.
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Potentiated activation of VLA-4 and VLA-5 accelerates proplatelet-like formation. Ann Hematol 2012; 91:1633-43. [PMID: 22644786 DOI: 10.1007/s00277-012-1498-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2012] [Accepted: 05/14/2012] [Indexed: 10/28/2022]
Abstract
Fibronectin (FN) plays important roles in the proliferation, differentiation, and maintenance of megakaryocytic-lineage cells through FN receptors. However, substantial role of FN receptors and their functional assignment in proplatelet-like formation (PPF) of megakaryocytes are not yet fully understood. Herein, we investigated the effects of FN receptors on PPF using the CHRF-288 human megakaryoblastic cell line, which expresses VLA-4 and VLA-5 as FN receptors. FN and phorbol 12-myristate 13-acetate (PMA) were essential for inducing PPF in CHRF-288 cells. Blocking experiments using anti-β1-integrin monoclonal antibodies indicated that the adhesive interaction with FN via VLA-4 and VLA-5 were required for PPF. PPF induced by FN plus PMA was accelerated when CHRF-288 cells were enforced adhering to FN by TNIIIA2, a peptide derived from tenascin-C, which we recently found to induce β1-integrin activation. Adhesion to FN enhanced PMA-stimulated activation of extracellular signal-regulated protein kinase 1 (ERK1)/2 and enforced adhesion to FN via VLA-4 and VLA-5 by TNIIIA2-accelerated activation of ERK1/2 with FN plus PMA. However, c-Jun amino-terminal kinase 1 (JNK1), p38, and phosphoinositide-3 kinase (PI3K)/Akt were not stimulated by FN plus PMA, even with TNIIIA2. Thus, the enhanced activation of ERK1/2 by FN, PMA plus TNIIIA2 was responsible for acceleration of PPF with FN plus PMA.
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48
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Macanas-Pirard P, Leisewitz A, Broekhuizen R, Cautivo K, Barriga FM, Leisewitz F, Gidi V, Riquelme E, Montecinos VP, Swett P, Besa P, Ramirez P, Ocqueteau M, Kalergis AM, Holt M, Rettig M, DiPersio JF, Nervi B. Bone marrow stromal cells modulate mouse ENT1 activity and protect leukemia cells from cytarabine induced apoptosis. PLoS One 2012; 7:e37203. [PMID: 22629369 PMCID: PMC3358339 DOI: 10.1371/journal.pone.0037203] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2011] [Accepted: 04/16/2012] [Indexed: 01/05/2023] Open
Abstract
Background Despite a high response rate to chemotherapy, the majority of patients with acute myeloid leukemia (AML) are destined to relapse due to residual disease in the bone marrow (BM). The tumor microenvironment is increasingly being recognized as a critical factor in mediating cancer cell survival and drug resistance. In this study, we propose to identify mechanisms involved in the chemoprotection conferred by the BM stroma to leukemia cells. Methods Using a leukemia mouse model and a human leukemia cell line, we studied the interaction of leukemia cells with the BM microenvironment. We evaluated in vivo and in vitro leukemia cell chemoprotection to different cytotoxic agents mediated by the BM stroma. Leukemia cell apoptosis was assessed by flow cytometry and western blotting. The activity of the equilibrative nucleoside transporter 1 (ENT1), responsible for cytarabine cell incorporation, was investigated by measuring transport and intracellular accumulation of 3H-adenosine. Results Leukemia cell mobilization from the bone marrow into peripheral blood in vivo using a CXCR4 inhibitor induced chemo-sensitization of leukemia cells to cytarabine, which translated into a prolonged survival advantage in our mouse leukemia model. In vitro, the BM stromal cells secreted a soluble factor that mediated significant chemoprotection to leukemia cells from cytarabine induced apoptosis. Furthermore, the BM stromal cell supernatant induced a 50% reduction of the ENT1 activity in leukemia cells, reducing the incorporation of cytarabine. No protection was observed when radiation or other cytotoxic agents such as etoposide, cisplatin and 5-fluorouracil were used. Conclusion The BM stroma secretes a soluble factor that significantly protects leukemia cells from cytarabine-induced apoptosis and blocks ENT1 activity. Strategies that modify the chemo-protective effects mediated by the BM microenvironment may enhance the benefit of conventional chemotherapy for patients with AML.
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MESH Headings
- Animals
- Antimetabolites, Antineoplastic/pharmacology
- Antimetabolites, Antineoplastic/therapeutic use
- Apoptosis/drug effects
- Apoptosis/physiology
- Bone Marrow Cells/drug effects
- Bone Marrow Cells/metabolism
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Cytarabine/pharmacology
- Cytarabine/therapeutic use
- Equilibrative Nucleoside Transporter 1/metabolism
- Humans
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Mice
- Stromal Cells/drug effects
- Stromal Cells/metabolism
- Tumor Cells, Cultured
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Affiliation(s)
- Patricia Macanas-Pirard
- Departamento de Hematología y Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Andrea Leisewitz
- Departamento de Hematología y Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Richard Broekhuizen
- Departamento de Hematología y Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Kelly Cautivo
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Francisco M. Barriga
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Francisco Leisewitz
- Departamento de Hematología y Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Victoria Gidi
- Departamento de Hematología y Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Erick Riquelme
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Viviana P. Montecinos
- Departamento de Hematología y Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pilar Swett
- Departamento de Hematología y Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pelayo Besa
- Departamento de Hematología y Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo Ramirez
- Departamento de Hematología y Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Mauricio Ocqueteau
- Departamento de Hematología y Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M. Kalergis
- Departamento de Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Matthew Holt
- Oncology Division, Washington University School of Medicine, Saint Louis, Missouri, United States of America
| | - Michael Rettig
- Oncology Division, Washington University School of Medicine, Saint Louis, Missouri, United States of America
| | - John F. DiPersio
- Oncology Division, Washington University School of Medicine, Saint Louis, Missouri, United States of America
| | - Bruno Nervi
- Departamento de Hematología y Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- * E-mail:
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Ashton RS, Keung AJ, Peltier J, Schaffer DV. Progress and prospects for stem cell engineering. Annu Rev Chem Biomol Eng 2012; 2:479-502. [PMID: 22432628 DOI: 10.1146/annurev-chembioeng-061010-114105] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Stem cells offer tremendous biomedical potential owing to their abilities to self-renew and differentiate into cell types of multiple adult tissues. Researchers and engineers have increasingly developed novel discovery technologies, theoretical approaches, and cell culture systems to investigate microenvironmental cues and cellular signaling events that control stem cell fate. Many of these technologies facilitate high-throughput investigation of microenvironmental signals and the intracellular signaling networks and machinery processing those signals into cell fate decisions. As our aggregate empirical knowledge of stem cell regulation grows, theoretical modeling with systems and computational biology methods has and will continue to be important for developing our ability to analyze and extract important conceptual features of stem cell regulation from complex data. Based on this body of knowledge, stem cell engineers will continue to develop technologies that predictably control stem cell fate with the ultimate goal of being able to accurately and economically scale up these systems for clinical-grade production of stem cell therapeutics.
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Affiliation(s)
- Randolph S Ashton
- Department of Chemical Engineering, University of California, Berkeley, CA 94720, USA
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50
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Canonical wnt signaling regulates hematopoiesis in a dosage-dependent fashion. Cell Stem Cell 2012; 9:345-56. [PMID: 21982234 DOI: 10.1016/j.stem.2011.07.017] [Citation(s) in RCA: 251] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2011] [Revised: 06/06/2011] [Accepted: 07/29/2011] [Indexed: 02/04/2023]
Abstract
Canonical Wnt signaling has been implicated in the regulation of hematopoiesis. By employing a Wnt-reporter mouse, we observed that Wnt signaling is differentially activated during hematopoiesis, suggesting an important regulatory role for specific Wnt signaling levels. To investigate whether canonical Wnt signaling regulates hematopoiesis in a dosage-dependent fashion, we analyzed the effect of different mutations in the Adenomatous polyposis coli gene (Apc), a negative modulator of the canonical Wnt pathway. By combining different targeted hypomorphic alleles and a conditional deletion allele of Apc, a gradient of five different Wnt signaling levels was obtained in vivo. We here show that different, lineage-specific Wnt dosages regulate hematopoietic stem cells (HSCs), myeloid precursors, and T lymphoid precursors during hematopoiesis. Differential, lineage-specific optimal Wnt dosages provide a unifying concept that explains the differences reported among inducible gain-of-function approaches, leading to either HSC expansion or depletion of the HSC pool.
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