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1
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Gao Y, Xi Y, Chen W, Meng Y, Su Y. Early predictor for differentiation syndrome in newly diagnosed acute promyelocytic leukaemia patients treated with single-agent arsenic trioxide. Ann Hematol 2024; 103:3947-3954. [PMID: 38684509 DOI: 10.1007/s00277-024-05776-y] [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: 12/20/2023] [Accepted: 04/23/2024] [Indexed: 05/02/2024]
Abstract
Differentiation syndrome (DS) is the second leading cause of death in acute promyelocytic leukaemia (APL) patients. Few studies have tested predictors of DS events. This study aimed to identify optimized predictors of DS events related to APL. The data of 298 consecutive patients who were newly diagnosed with APL between December 2012 and June 2023 were retrospectively investigated. A systematic review of computer-based patient medical records was conducted to obtain clinical data, including baseline characteristics, routine blood examination findings, biochemical indices and clinical manifestations of DS. Among the 298 patients, 158 were classified into the no-DS group, while 140 had DS. Compared with those of patients without DS, the peripheral blast count, age, and WBC count at each time point were significantly different in patients with DS (P < 0.05 for all time points). Generalized linear mixed models (GLMMs) revealed that WBC Double (Coeff. 0.442, P = 0.000) and WBCPeak (Coeff. 0.879, P = 0.000) were independent risk factors for DS. The frequencies of clinical manifestations of unexplained fever (P = 0.003), dyspnoea (P = 0.002), weight gain of more than 5 kg (P = 0.006), pleural effusion (P = 0.001), pulmonary infiltrates (P < 0.001), pericardial effusion (P = 0.002) and renal failure (P = 0.006) were considerably lower in moderate DS patients than in severe DS patients. The WBCDouble occurs earlier than the WBCpeak occurrence, so WBC Double might be a new indicator of DS.
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Affiliation(s)
- Yujuan Gao
- The First Affiliated Hospital of Harbin Medical University, Long Jiang Road, Harbin, 150007, Heilongjiang Province, China
| | - Yuanyuan Xi
- The First Affiliated Hospital of Harbin Medical University, Long Jiang Road, Harbin, 150007, Heilongjiang Province, China
| | - Wenqi Chen
- The First Affiliated Hospital of Harbin Medical University, Long Jiang Road, Harbin, 150007, Heilongjiang Province, China
| | - Yanfen Meng
- The First Affiliated Hospital of Harbin Medical University, Long Jiang Road, Harbin, 150007, Heilongjiang Province, China
| | - Yanhua Su
- The First Affiliated Hospital of Harbin Medical University, Long Jiang Road, Harbin, 150007, Heilongjiang Province, China.
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2
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Van Schoor K, Bruet E, Jones EAV, Migeotte I. Origin and flow-mediated remodeling of the murine and human extraembryonic circulation systems. Front Physiol 2024; 15:1395006. [PMID: 38818524 PMCID: PMC11137303 DOI: 10.3389/fphys.2024.1395006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 04/16/2024] [Indexed: 06/01/2024] Open
Abstract
The transduction of mechanical stimuli produced by blood flow is an important regulator of vascular development. The vitelline and umbilico-placental circulations are extraembryonic vascular systems that are required for proper embryonic development in mammalian embryos. The morphogenesis of the extraembryonic vasculature and the cardiovascular system of the embryo are hemodynamically and molecularly connected. Here we provide an overview of the establishment of the murine and human vitelline and umbilico-placental vascular systems and how blood flow influences various steps in their development. A deeper comprehension of extraembryonic vessel development may aid the establishment of stem-cell based embryo models and provide novel insights to understanding pregnancy complications related to the umbilical cord and placenta.
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Affiliation(s)
- Kristof Van Schoor
- Institut de Recherche Interdisciplinaire Jacques E. Dumont, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Emmanuel Bruet
- Institut de Recherche Interdisciplinaire Jacques E. Dumont, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Elizabeth Anne Vincent Jones
- Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
- Department of Cardiology CARIM School for Cardiovascular Diseases Maastricht University, Maastricht, Netherlands
| | - Isabelle Migeotte
- Institut de Recherche Interdisciplinaire Jacques E. Dumont, Université Libre de Bruxelles (ULB), Brussels, Belgium
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3
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Translational Comparison of the Human and Mouse Yolk Sac Development and Function. Reprod Sci 2023; 30:41-53. [PMID: 35137348 DOI: 10.1007/s43032-022-00872-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/29/2022] [Indexed: 01/06/2023]
Abstract
The yolk sac (YS) is the oldest of the extraembryonic membranes in vertebrates. Considered a transitory structure in the human species, the importance of the YS for a successful pregnancy is often overlooked. Due to the general inaccessibility of healthy human YS tissue for research, the use of experimental animal models is of great value. In order to better understand whether the mouse could be used as a translational model for the study of the human YS under normal and pathological conditions, this review comprehensively describes key developmental aspects of the human and mouse YS, detailing their development and function. YS major similarities in both species comprise the following: (1) histological composition (both being composed of endoderm, mesoderm, and mesothelium layers); (2) endoderm endocytosis, synthesis, secretion, and transport capabilities; and (3) mesoderm onset of haematopoiesis and angiogenesis. Examples of main dissimilarities include (1) persistence across pregnancy (i.e. early pregnancy in humans vs term pregnancy in mice); (2) the existence of a secondary YS in humans; (3) the presence of proliferative primordial germ cells (PGCs) in the human versus their absence in mice; and (4) eversion of histological layers in the mouse. Although these differences should be considered when interpreting data from mouse-based studies, the overall morphofunctional similarities in the YS between these species indicate that the mouse can be potentially used as a translational model for the study of the human YS.
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4
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Gupta S, Krishnan AS, Singh J, Gupta A, Gupta M. Clinicopathological characteristics and management of extramedullary hematopoiesis: Review of an unusual entity. PEDIATRIC HEMATOLOGY ONCOLOGY JOURNAL 2022. [DOI: 10.1016/j.phoj.2022.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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5
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Davenport MP, Smith NL, Rudd BD. Building a T cell compartment: how immune cell development shapes function. Nat Rev Immunol 2020; 20:499-506. [PMID: 32493982 DOI: 10.1038/s41577-020-0332-3] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2020] [Indexed: 02/06/2023]
Abstract
We are just beginning to understand the diversity of the peripheral T cell compartment, which arises from the specialization of different T cell subsets and the plasticity of individual naive T cells to adopt different fates. Although the progeny of a single T cell can differentiate into many phenotypes following infection, individual T cells are biased towards particular phenotypes. These biases are typically ascribed to random factors that occur during and after antigenic stimulation. However, the T cell compartment does not remain static with age, and shifting immune challenges during ontogeny give rise to T cells with distinct functional properties. Here, we argue that the developmental history of naive T cells creates a 'hidden layer' of diversity that persists into adulthood. Insight into this diversity can provide a new perspective on immunity and immunotherapy across the lifespan.
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Affiliation(s)
- Miles P Davenport
- Kirby Institute for Infection and Immunity, University of New South Wales Australia, Sydney, New South Wales, Australia.
| | - Norah L Smith
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA
| | - Brian D Rudd
- Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA
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6
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Potential molecular mechanisms underlying the effect of arsenic on angiogenesis. Arch Pharm Res 2019; 42:962-976. [PMID: 31701373 DOI: 10.1007/s12272-019-01190-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 11/01/2019] [Indexed: 12/12/2022]
Abstract
Arsenic is a potent chemotherapeutic drug that is applied as a treatment for cancer; it exerts its functions through multiple pathways, including angiogenesis inhibition. As angiogenesis is a critical component of the progression of many diseases, arsenic is a feasible treatment option for patients with other angiogenic diseases, including rheumatoid arthritis and psoriasis, among others. However, arsenic is also a well-known carcinogen, demonstrating a pro-angiogenesis effect. This review will focus on the dual effects of arsenic on neovascularization and the relevant mechanisms underlying these effects, aiming to provide a rational understanding of arsenic treatment. In particular, we expect to provide a comprehensive overview of the current knowledge of the mechanisms by which arsenic influences angiogenesis.
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7
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"Hierarchy" and "Holacracy"; A Paradigm of the Hematopoietic System. Cells 2019; 8:cells8101138. [PMID: 31554248 PMCID: PMC6830102 DOI: 10.3390/cells8101138] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/20/2019] [Accepted: 09/23/2019] [Indexed: 02/06/2023] Open
Abstract
The mammalian hematopoietic system has long been viewed as a hierarchical paradigm in which a small number of hematopoietic stem cells (HSCs) are located at the apex. HSCs were traditionally thought to be homogeneous and quiescent in a homeostatic state. However, recent observations, through extramedullary hematopoiesis and clonal assays, have cast doubt on the validity of the conventional interpretation. A key issue is understanding the characteristics of HSCs from different viewpoints, including dynamic physics and social network theory. The aim of this literature review is to propose a new paradigm of our hematopoietic system, in which individual HSCs are actively involved.
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8
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Viswanathan S, Shi Y, Galipeau J, Krampera M, Leblanc K, Martin I, Nolta J, Phinney DG, Sensebe L. Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT®) Mesenchymal Stromal Cell committee position statement on nomenclature. Cytotherapy 2019; 21:1019-1024. [PMID: 31526643 DOI: 10.1016/j.jcyt.2019.08.002] [Citation(s) in RCA: 504] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 08/19/2019] [Indexed: 02/06/2023]
Abstract
The International Society for Cell & Gene Therapy (ISCT®) Mesenchymal Stromal Cell (ISCT MSC) committee offers a position statement to clarify the nomenclature of mesenchymal stromal cells (MSCs). The ISCT MSC committee continues to support the use of the acronym "MSCs" but recommends this be (i) supplemented by tissue-source origin of the cells, which would highlight tissue-specific properties; (ii) intended as MSCs unless rigorous evidence for stemness exists that can be supported by both in vitro and in vivo data; and (iii) associated with robust matrix of functional assays to demonstrate MSC properties, which are not generically defined but informed by the intended therapeutic mode of actions.
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Affiliation(s)
- S Viswanathan
- Arthritis Program, University Health Network, Krembil Research Institute, University Health Network, Cell Therapy Program, University Health Network, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada.
| | - Y Shi
- The First Affiliated Hospital, Soochow University Institutes for Translational Medicine, Suzhou, China; Institute of Health Sciences, Chinese Academy of Sciences, Shanghai, China.
| | - J Galipeau
- Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - M Krampera
- Section of Hematology, Department of Medicine, University of Verona, Verona, Italy
| | - K Leblanc
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden
| | - I Martin
- Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - J Nolta
- Department of Internal Medicine, Stem Cell Program and Institute for Regenerative Cures, University of California Davis, Sacramento, California, USA
| | - D G Phinney
- Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA
| | - L Sensebe
- UMR5273 STROMALab CNRS/EFS/UPS-INSERM U1031, Toulouse, France
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9
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Aqmasheh S, Shamsasanjan K, Akbarzadehlaleh P, Pashoutan Sarvar D, Timari H. Effects of Mesenchymal Stem Cell Derivatives on Hematopoiesis and Hematopoietic Stem Cells. Adv Pharm Bull 2017; 7:165-177. [PMID: 28761818 PMCID: PMC5527230 DOI: 10.15171/apb.2017.021] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Revised: 04/08/2017] [Accepted: 04/18/2017] [Indexed: 12/11/2022] Open
Abstract
Hematopoiesis is a balance among quiescence, self-renewal, proliferation, and differentiation, which is believed to be firmly adjusted through interactions between hematopoietic stem and progenitor cells (HSPCs) with the microenvironment. This microenvironment is derived from a common progenitor of mesenchymal origin and its signals should be capable of regulating the cellular memory of transcriptional situation and lead to an exchange of stem cell genes expression. Mesenchymal stem cells (MSCs) have self-renewal and differentiation capacity into tissues of mesodermal origin, and these cells can support hematopoiesis through release various molecules that play a crucial role in migration, homing, self-renewal, proliferation, and differentiation of HSPCs. Studies on the effects of MSCs on HSPC differentiation can develop modern solutions in the treatment of patients with hematologic disorders for more effective Bone Marrow (BM) transplantation in the near future. However, considerable challenges remain on realization of how paracrine mechanisms of MSCs act on the target tissues, and how to design a therapeutic regimen with various paracrine factors in order to achieve optimal results for tissue conservation and regeneration. The aim of this review is to characterize and consider the related aspects of the ability of MSCs secretome in protection of hematopoiesis.
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Affiliation(s)
- Sara Aqmasheh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasanjan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hamze Timari
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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10
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RNA-seq reveals conservation of function among the yolk sacs of human, mouse, and chicken. Proc Natl Acad Sci U S A 2017; 114:E4753-E4761. [PMID: 28559354 DOI: 10.1073/pnas.1702560114] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
The yolk sac is phylogenetically the oldest of the extraembryonic membranes. The human embryo retains a yolk sac, which goes through primary and secondary phases of development, but its importance is controversial. Although it is known to synthesize proteins, its transport functions are widely considered vestigial. Here, we report RNA-sequencing (RNA-seq) data for the human and murine yolk sacs and compare those data with data for the chicken. We also relate the human RNA-seq data to proteomic data for the coelomic fluid bathing the yolk sac. Conservation of transcriptomes across the species indicates that the human secondary yolk sac likely performs key functions early in development, particularly uptake and processing of macro- and micronutrients, many of which are found in coelomic fluid. More generally, our findings shed light on evolutionary mechanisms that give rise to complex structures such as the placenta. We identify genetic modules that are conserved across mammals and birds, suggesting these modules are part of the core amniote genetic repertoire and are the building blocks for both oviparous and viviparous reproductive modes. We propose that although a choriovitelline placenta is never established physically in the human, the placental villi, the exocoelomic cavity, and the secondary yolk sac function together as a physiological equivalent.
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11
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Cofre J, Abdelhay E. Cancer Is to Embryology as Mutation Is to Genetics: Hypothesis of the Cancer as Embryological Phenomenon. ScientificWorldJournal 2017; 2017:3578090. [PMID: 28553657 PMCID: PMC5434308 DOI: 10.1155/2017/3578090] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 03/20/2017] [Indexed: 01/20/2023] Open
Abstract
Despite numerous advances in cell biology, genetics, and developmental biology, cancer origin has been attributed to genetic mechanisms primarily involving mutations. Embryologists have expressed timidly cancer embryological origin with little success in leveraging the discussion that cancer could involve a set of conventional cellular processes used to build the embryo during morphogenesis. Thus, this "cancer process" allows the harmonious and coherent construction of the embryo structural base, and its implementation as the embryonic process involves joint regulation of differentiation, proliferation, cell invasion, and migration, enabling the human being recreation of every generation. On the other hand, "cancer disease" is the representation of an abnormal state of the cell that might happen in the stem cells of an adult person, in which the mechanism for joint gene regulating of differentiation, proliferation, cell invasion, and migration could be reactivated in an entirely inappropriate context.
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Affiliation(s)
- Jaime Cofre
- Laboratório de Embriologia Molecular e Câncer, Universidade Federal de Santa Catarina, Sala 313b, 88040-900 Florianópolis, SC, Brazil
| | - Eliana Abdelhay
- Divisão de Laboratórios do CEMO, Instituto Nacional do Câncer, Rio de Janeiro, RJ, Brazil
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12
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Yamamoto K, Miwa Y, Abe-Suzuki S, Abe S, Kirimura S, Onishi I, Kitagawa M, Kurata M. Extramedullary hematopoiesis: Elucidating the function of the hematopoietic stem cell niche (Review). Mol Med Rep 2015; 13:587-91. [PMID: 26648325 DOI: 10.3892/mmr.2015.4621] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 02/11/2015] [Indexed: 12/21/2022] Open
Abstract
Extramedullary hematopoiesis (EMH) occurs under various circumstances, including during embryonic/developmental periods, pathological status secondary to insufficient bone marrow function or ineffective hematopoiesis, in hematological disorders, for example malignancies, as well as stromal disorders of the bone. EMH is characterized by hematopoietic cell accumulations in multiple body locations. Common EMH locations observed in clinical and pathological practice include the spleen, liver, lymph nodes and para‑vertebral regions. Among the various organs associated with EMH, the spleen offers a unique site for evaluation of hematopoietic stem cell (HSC)/niche interactions, as this organ is one of the most common sites of EMH. However, the spleen does not have a major role in embryonic/developmental hematopoiesis. A recent study by our group revealed that circulating HSCs may be trapped by chemokine (C‑X‑C motif) ligand 12 (CXCL12)‑positive cells at the margin of sinuses near CXCL12‑positive endothelial cells, resulting in the initiation of the first step of EMH, which is a similar mechanism to bone marrow hematopoiesis. The present review briefly discusses the environment of EMH in extramedullary spaces in order to investigate the mechanisms underlying HSC maintenance, and aid the elucidation of the niche‑stem cell interactions that occur in the bone marrow.
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Affiliation(s)
- Kouhei Yamamoto
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo‑ku, Tokyo 113‑8519, Japan
| | - Yukako Miwa
- Department of Pathology, Kanazawa Medical University Hospital, Kanazawa, Ishikawa 920‑0293, Japan
| | - Shiho Abe-Suzuki
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo‑ku, Tokyo 113‑8519, Japan
| | - Shinya Abe
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo‑ku, Tokyo 113‑8519, Japan
| | - Susumu Kirimura
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo‑ku, Tokyo 113‑8519, Japan
| | - Iichiroh Onishi
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo‑ku, Tokyo 113‑8519, Japan
| | - Masanobu Kitagawa
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo‑ku, Tokyo 113‑8519, Japan
| | - Morito Kurata
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo‑ku, Tokyo 113‑8519, Japan
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13
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Saleh M, Shamsasanjan K, Movassaghpourakbari A, Akbarzadehlaleh P, Molaeipour Z. The Impact of Mesenchymal Stem Cells on Differentiation of Hematopoietic Stem Cells. Adv Pharm Bull 2015; 5:299-304. [PMID: 26504750 DOI: 10.15171/apb.2015.042] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Revised: 04/15/2015] [Accepted: 04/18/2015] [Indexed: 12/30/2022] Open
Abstract
Bone marrow microenvironment contains cellular and acellular compartments. The cellular compartment includes hematopoietic stem cells, mesenchymal stem cells and some other stromal cell types, while the acellular compartment is composed of scaffold proteins known as the extra cellular matrix. Direct cell-cell contact as well as cytokines secreted by mesenchymal stem cells during coculture of hematopoietic stem cells and mesenchymal stem cells play a critical role in hematopoiesis, and determines the fate of hematopoietic stem cells. Several studies have demonstrated the impact of mesenchymal stem cells on self-renewal, expansion, proliferation and differentiation of hematopoietic stem cells in vitro, which have shown different and contradictory results. In this paper, we will investigate the effect of mesenchymal stem cells on differentiation of hematopoietic stem cells in vitro.
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Affiliation(s)
- Mahshid Saleh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasanjan
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ; Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | | | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Tabriz University of Medical Science, Tabriz, Iran
| | - Zahra Molaeipour
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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14
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McGovern N, Chan JKY, Ginhoux F. Dendritic cells in humans--from fetus to adult. Int Immunol 2014; 27:65-72. [PMID: 25323843 DOI: 10.1093/intimm/dxu091] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The human immune system evolves continuously during development from the embryo into the adult, reflecting the ever-changing environment and demands of our body. This ability of our immune system to sense external cues and adapt as we develop is just as important in the early tolerogenic environment of the fetus, as it is in the constantly pathogen-challenged adult. Dendritic cells (DCs), the professional antigen-sensing and antigen-presenting components of the immune system, play a crucial role in this process where they act as sentinels, both initiating and regulating immune responses. Here, we provide an overview of the human immune system in the developing fetus and the adult, with a focus on DC ontogeny and function during these discrete but intimately linked life stages.
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Affiliation(s)
- Naomi McGovern
- Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building #3-4, BIOPOLIS, Singapore 138648, Singapore
| | | | - Florent Ginhoux
- Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, IMMUNOS Building #3-4, BIOPOLIS, Singapore 138648, Singapore Department of Reproductive Medicine, Division of Obstetrics and Gynaecology, KK Women's and Children's Hospital, Singapore 229899, Singapore
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15
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Uz B, Tatonyan SÇ, Sayitoğlu M, Erbilgin Y, Hatırnaz O, Aksu S, Büyükaşık Y, Sayınalp N, Göker H, Ozcebe Oİ, Ozbek U, Haznedaroğlu IC. Local Renin-Angiotensin system in normal hematopoietic and multiple myeloma-related progenitor cells. Turk J Haematol 2014; 31:136-42. [PMID: 25035670 PMCID: PMC4102040 DOI: 10.4274/tjh.2013.0011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 04/17/2013] [Indexed: 12/01/2022] Open
Abstract
Objective: The prominent functions of the local renin-angiotensin system (RAS) in primitive hematopoiesis further support the hypothesis that local autocrine bone marrow RAS could also be active in neoplastic hematopoiesis. The aim of this study is to examine critical RAS elements in normal CD34+ hematopoietic stem cells and multiple myeloma (MM)-related progenitor cells. Materials and Methods: The study group comprised the total bone marrow cells (CBM) of 10 hematologically normal people, the CD34+ stem cell samples (CD34+CBM) of 9 healthy donors for allogeneic peripheral stem cell transplantation, and the CD34+ stem cell samples (CD34+MM) of 9 MM patients undergoing autologous peripheral stem cell transplantation. We searched for the gene expression of the major RAS components in healthy hematopoietic cells and myeloma cells by quantitative real-time polymerase chain reaction analysis. Results: RENIN, angiotensinogen (ANGTS), and angiotensin converting enzyme-I (ACE I) mRNA expression levels of CBM were significantly higher than those in myeloma patients (p=0.03, p=0.002, and p=0.0008, respectively). Moreover, RENIN and ANGTS mRNA expression levels were significantly higher in CD34+ stem cell samples of healthy allogeneic donors compared to those in myeloma patients (p=0.001 and p=0.01). However, ACE I expression levels were similar in CD34+CBM and CD34+MM hematopoietic cells (p=0.89). Conclusion: Although found to be lower than in the CBM and CD34+CBM hematopoietic cells, the local RAS components were also expressed in CD34+MM hematopoietic cells. This point should be kept in mind while focusing on the immunobiology of MM and the processing of autologous cells during the formation of transplantation treatment protocols.
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Affiliation(s)
- Burak Uz
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
| | - Suzin Çatal Tatonyan
- İstanbul University, Institute for Experimental Medicine Research, Department of Genetics, İstanbul, Turkey
| | - Müge Sayitoğlu
- İstanbul University, Institute for Experimental Medicine Research, Department of Genetics, İstanbul, Turkey
| | - Yücel Erbilgin
- İstanbul University, Institute for Experimental Medicine Research, Department of Genetics, İstanbul, Turkey
| | - Ozden Hatırnaz
- İstanbul University, Institute for Experimental Medicine Research, Department of Genetics, İstanbul, Turkey
| | - Salih Aksu
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
| | - Yahya Büyükaşık
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
| | - Nilgün Sayınalp
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
| | - Hakan Göker
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
| | - Osman İ Ozcebe
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
| | - Uğur Ozbek
- İstanbul University, Institute for Experimental Medicine Research, Department of Genetics, İstanbul, Turkey
| | - Ibrahim C Haznedaroğlu
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
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Jeanblanc C, Goodrich AD, Colletti E, Mokhtari S, Porada CD, Zanjani ED, Almeida-Porada G. Temporal definition of haematopoietic stem cell niches in a large animal model of in utero stem cell transplantation. Br J Haematol 2014; 166:268-78. [PMID: 24673111 DOI: 10.1111/bjh.12870] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 02/05/2014] [Indexed: 01/11/2023]
Abstract
The fetal sheep model has served as a biologically relevant and translational model to study in utero haematopoietic stem cell transplantation (IUHSCT), yet little is known about the ontogeny of the bone marrow (BM) niches in this model. Because the BMmicroenvironment plays a critical role in the outcome of haematopoietic engraftment, we have established the correlation between the fetal-sheep and fetal-human BM niche ontogeny, so that studies addressing the role of niche development at the time of IUHSCT could be accurately performed. Immunofluorescence confocal microscopic analysis of sheep fetal bone from gestational days (gd) 25-68 showed that the BM microenvironment commences development with formation of the vascular niche between 25 and 36 gd in sheep; correlating with the events at 10-11 gestational weeks (gw) in humans. Subsequently, between 45 and 51 gd in sheep (c. 14 gw in humans), the osteoblastic/endosteal niche started developing, the presence of CD34(+) CD45(+) cells were promptly detected, and their number increased with gestational age. IUHSCT, performed in sheep at 45 and 65 gd, showed significant haematopoietic engraftment only at the later time point, indicating that a fully functional BM microenvironment improved engraftment. These studies show that sheep niche ontogeny closely parallels human, validating this model for investigating niche influence/manipulation in IUHSCT engraftment.
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Affiliation(s)
- Christine Jeanblanc
- Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada, Reno, NV, USA
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17
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Baron MH, Vacaru A, Nieves J. Erythroid development in the mammalian embryo. Blood Cells Mol Dis 2013; 51:213-9. [PMID: 23932234 DOI: 10.1016/j.bcmd.2013.07.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 06/25/2013] [Indexed: 12/22/2022]
Abstract
Erythropoiesis is the process by which progenitors for red blood cells are produced and terminally differentiate. In all vertebrates, two morphologically distinct erythroid lineages (primitive, embryonic, and definitive, fetal/adult) form successively within the yolk sac, fetal liver, and marrow and are essential for normal development. Red blood cells have evolved highly specialized functions in oxygen transport, defense against oxidation, and vascular remodeling. Here we review key features of the ontogeny of red blood cell development in mammals, highlight similarities and differences revealed by genetic and gene expression profiling studies, and discuss methods for identifying erythroid cells at different stages of development and differentiation.
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Affiliation(s)
- Margaret H Baron
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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18
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Pixley JS, Zanjani ED. In utero transplantation: Disparate ramifications. World J Stem Cells 2013; 5:43-52. [PMID: 23671718 PMCID: PMC3648645 DOI: 10.4252/wjsc.v5.i2.43] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Revised: 01/07/2013] [Accepted: 01/24/2013] [Indexed: 02/06/2023] Open
Abstract
In utero stem cell transplantation, which promises treatment for a host of genetic disorders early in gestation before disease effect stems from Ray Owen’s seminal observation that self-tolerance, is acquired during gestation. To date, in utero transplantation (IUT) has proved useful in characterizing the hematopoietic stem cell. Recent observations support its use as an in vivo method to further understanding of self-tolerance. Preclinical development continues for its application as a treatment for childhood hematolymphoid diseases. In addition, IUT may offer therapeutic options in the treatment of diabetes among other diseases. Thus IUT serves as a technique or system important in both a basic and applied format. This review summarizes these findings.
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Abstract
Hematopoietic stem and progenitor cells (HSPCs) emerge and develop adjacent to blood vessel walls in the yolk sac, aorta-gonad-mesonephros region, embryonic liver, and fetal bone marrow. In adult mouse bone marrow, perivascular cells shape a "niche" for HSPCs. Mesenchymal stem/stromal cells (MSCs), which support hematopoiesis in culture, are themselves derived in part from perivascular cells. In order to define their direct role in hematopoiesis, we tested the ability of purified human CD146(+) perivascular cells, as compared with unfractionated MSCs and CD146(-) cells, to sustain human HSPCs in coculture. CD146(+) perivascular cells support the long-term persistence, through cell-to-cell contact and at least partly via Notch activation, of human myelolymphoid HSPCs able to engraft primary and secondary immunodeficient mice. Conversely, unfractionated MSCs and CD146(-) cells induce differentiation and compromise ex vivo maintenance of HSPCs. Moreover, CD146(+) perivascular cells express, natively and in culture, molecular markers of the vascular hematopoietic niche. Unexpectedly, this dramatic, previously undocumented ability to support hematopoietic stem cells is present in CD146(+) perivascular cells extracted from the nonhematopoietic adipose tissue.
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20
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Local bone marrow renin-angiotensin system in primitive, definitive and neoplastic haematopoiesis. Clin Sci (Lond) 2013; 124:307-23. [PMID: 23157407 DOI: 10.1042/cs20120300] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The locally active ligand peptides, mediators, receptors and signalling pathways of the haematopoietic BM (bone marrow) autocrine/paracrine RAS (renin-angiotensin system) affect the essential steps of definitive blood cell production. Haematopoiesis, erythropoiesis, myelopoiesis, formation of monocytic and lymphocytic lineages, thrombopoiesis and other stromal cellular elements are regulated by the local BM RAS. The local BM RAS is present and active even in primitive embryonic haematopoiesis. ACE (angiotensin-converting enzyme) is expressed on the surface of the first endothelial and haematopoietic cells, forming the marrow cavity in the embryo. ACE marks early haematopoietic precursor cells and long-term blood-forming CD34(+) BM cells. The local autocrine tissue BM RAS may also be active in neoplastic haematopoiesis. Critical RAS mediators such as renin, ACE, AngII (angiotensin II) and angiotensinogen have been identified in leukaemic blast cells. The local tissue RAS influences tumour growth and metastases in an autocrine and paracrine fashion via the modulation of numerous carcinogenic events, such as angiogenesis, apoptosis, cellular proliferation, immune responses, cell signalling and extracellular matrix formation. The aim of the present review is to outline the known functions of the local BM RAS within the context of primitive, definitive and neoplastic haematopoiesis. Targeting the actions of local RAS molecules could represent a valuable therapeutic option for the management of neoplastic disorders.
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21
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Ponte AL, Ribeiro-Fleury T, Chabot V, Gouilleux F, Langonné A, Hérault O, Charbord P, Domenech J. Granulocyte-colony-stimulating factor stimulation of bone marrow mesenchymal stromal cells promotes CD34+ cell migration via a matrix metalloproteinase-2-dependent mechanism. Stem Cells Dev 2012; 21:3162-72. [PMID: 22651889 DOI: 10.1089/scd.2012.0048] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Human hematopoietic stem/progenitor cells (HSPCs) can be mobilized into the circulation using granulocyte-colony stimulating factor (G-CSF), for graft collection in view of hematopoietic transplantation. This process has been related to bone marrow (BM) release of serine proteases and of the matrix metalloproteinase-9 (MMP-9). Yet, the role of these mediators in HSC egress from their niches remains questionable, because they are produced by nonstromal cells (mainly neutrophils and monocytes/macrophages) that are not a part of the niche. We show here that the G-CSF receptor (G-CSFR) is expressed by human BM mesenchymal stromal/stem cells (MSCs), and that G-CSF prestimulation of MSCs enhances the in vitro trans-stromal migration of CD34+ cells. Zymography analysis indicates that pro-MMP-2 (but not pro-MMP-9) is expressed in MSCs, and that G-CSF treatment increases its expression and induces its activation at the cell membrane. We further demonstrate that G-CSF-stimulated migration depends on G-CSFR expression and is mediated by a mechanism that involves MMPs. These results suggest a molecular model whereby G-CSF infusion may drive, by the direct action on MSCs, HSPC egress from BM niches via synthesis and activation of MMPs. In this model, MMP-2 instead of MMP-9 is implicated, which constitutes a major difference with mouse mobilization models.
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Affiliation(s)
- Adriana López Ponte
- UPRES-EA3855, IFR135, Faculté de Médecine, Université François Rabelais Tours, France
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22
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Mizuochi C, Fraser ST, Biasch K, Horio Y, Kikushige Y, Tani K, Akashi K, Tavian M, Sugiyama D. Intra-aortic clusters undergo endothelial to hematopoietic phenotypic transition during early embryogenesis. PLoS One 2012; 7:e35763. [PMID: 22558218 PMCID: PMC3338791 DOI: 10.1371/journal.pone.0035763] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Accepted: 03/22/2012] [Indexed: 01/09/2023] Open
Abstract
Intra-aortic clusters (IACs) attach to floor of large arteries and are considered to have recently acquired hematopoietic stem cell (HSC)-potential in vertebrate early mid-gestation embryos. The formation and function of IACs is poorly understood. To address this issue, IACs were characterized by immunohistochemistry and flow cytometry in mouse embryos. Immunohistochemical analysis revealed that IACs simultaneously express the surface antigens CD31, CD34 and c-Kit. As embryos developed from 9.5 to 10.5 dpc, IACs up-regulate the hematopoietic markers CD41 and CD45 while down-regulating the endothelial surface antigen VE-cadherin/CD144, suggesting that IACs lose endothelial phenotype after 9.5 dpc. Analysis of the hematopoietic potential of IACs revealed a significant change in macrophage CFC activity from 9.5 to 10.5 dpc. To further characterize IACs, we isolated IACs based on CD45 expression. Correspondingly, the expression of hematopoietic transcription factors in the CD45(neg) fraction of IACs was significantly up-regulated. These results suggest that the transition from endothelial to hematopoietic phenotype of IACs occurs after 9.5 dpc.
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Affiliation(s)
- Chiyo Mizuochi
- Department of Hematopoietic Stem Cells, SSP Stem Cell Unit, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan
| | - Stuart T. Fraser
- Laboratory of Blood Cell Development, Disciplines of Physiology, Anatomy and Histology, School of Medical Sciences, University of Sydney, Camperdown, New South Wales, Australia
| | | | - Yuka Horio
- Department of Hematopoietic Stem Cells, SSP Stem Cell Unit, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan
| | - Yoshikane Kikushige
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Kenzaburo Tani
- Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | | | - Daisuke Sugiyama
- Department of Hematopoietic Stem Cells, SSP Stem Cell Unit, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan
- * E-mail:
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Abstract
The development of the adaptive immune system has been studied in the mouse primarily because it is easier to access fetal tissues and because there exists a rich array of probes for analysis of various components of the immune system. While much has been learned from this exercise, it is also clear that different species show substantial temporal variation in the development of the immune system during early life. In mice, for instance, mature α/β T cells first appear in the periphery during the final stages of fetal gestation and only increase in number after birth (Friedberg and Weissman, 1974); in humans, on the other hand, the first mature α/β T cells are seen in peripheral tissues at 10-12 gestational weeks (g.w.) and are circulating in significant numbers by the end of the second trimester (Ceppellini et al., 1971; Haynes et al., 1988; Hayward and Ezer, 1974; Kay et al., 1970). Although the functional implications of these differences remain unclear, it is likely that there are significant biological consequences associated with the relatively early development of the peripheral adaptive immune system in humans, for example, with respect to the development of peripheral tolerance as well as to the response to antigens that might cross the placenta from the mother (e.g., cells bearing noninherited maternal alloantigens, infectious agents, food antigens, and the like). Here, we will review studies of immune system ontogeny in the mouse and in humans, and then focus on the possible functional roles of fetal T cell populations during development and later in life in humans.
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Affiliation(s)
- Jeff E Mold
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
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24
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Coleman CM, Curtin C, Barry FP, O'Flatharta C, Murphy JM. Mesenchymal stem cells and osteoarthritis: remedy or accomplice? Hum Gene Ther 2011; 21:1239-50. [PMID: 20649459 DOI: 10.1089/hum.2010.138] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Multipotent mesenchymal stromal or stem cells (MSCs) are likely to be agents of connective tissue homeostasis and repair. Because the hallmark of osteoarthritis (OA) is degeneration and failure to repair connective tissues it is compelling to think that these cells have a role to play in OA. Indeed, MSCs have been implicated in the pathogenesis of OA and, in turn, progression of the disease has been shown to be therapeutically modulated by MSCs. This review discusses current knowledge on the potential of both marrow- and local joint-derived MSCs in OA, the mode of action of the cells, and possible effects of the osteoarthritic niche on the function of MSCs. The use of stem cells for repair of isolated cartilage lesions and strategies for modulation of OA using local cell delivery are discussed as well as therapeutic options for the future to recruit and appropriately activate endogenous progenitors and/or locally systemically administered MSCs in the early stages of the disease. The use of gene therapy protocols, particularly as they pertain to modulation of inflammation associated with the osteoarthritic niche, offer an additional option in the treatment of this chronic disease. In summary, elucidation of the etiology of OA and development of technologies to detect early disease, allied to an increased understanding of the role MSCs in aging and OA, should lead to more targeted and efficacious treatments for this debilitating chronic disease in the future.
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Affiliation(s)
- Cynthia M Coleman
- Regenerative Medicine Institute, National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland
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25
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Cao N, Yao ZX. The hemangioblast: from concept to authentication. Anat Rec (Hoboken) 2011; 294:580-8. [PMID: 21370498 DOI: 10.1002/ar.21360] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 01/13/2011] [Indexed: 11/06/2022]
Abstract
The hemangioblast hypothesis has been hotly debated for over a century. Hemangioblasts are defined as multipotent cells that can give rise to both hematopoietic cells and endothelial cells. The existence of hemangioblasts has now been confirmed and many important molecules and several signaling pathways are involved in their generation and differentiation. Fibroblast growth factor, renin-angiotensin system and runt-related transcription factor 1 (Runx1) direct the formation of hemangioblasts through highly selective gene expression patterns. On the other hand, the hemogenic endothelium theory and a newly discovered pattern of hematopoietic/endothelial differentiation make the genesis of hemangioblasts more complicated. But how hemangioblasts are formed and how hematopoietic cells or endothelial cells are derived from remains largely unknown. Here we summarize the current knowledge of the signaling pathways and molecules involved in hemangioblast development and suggest some future clinical applications.
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Affiliation(s)
- Nian Cao
- Department of Physiology, Third Military Medical University, Chongqing, China
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26
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Mold JE, Venkatasubrahmanyam S, Burt TD, Michaëlsson J, Rivera JM, Galkina SA, Weinberg K, Stoddart CA, McCune JM. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 2010; 330:1695-9. [PMID: 21164017 PMCID: PMC3276679 DOI: 10.1126/science.1196509] [Citation(s) in RCA: 340] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Although the mammalian immune system is generally thought to develop in a linear fashion, findings in avian and murine species argue instead for the developmentally ordered appearance (or "layering") of distinct hematopoietic stem cells (HSCs) that give rise to distinct lymphocyte lineages at different stages of development. Here we provide evidence of an analogous layered immune system in humans. Our results suggest that fetal and adult T cells are distinct populations that arise from different populations of HSCs that are present at different stages of development. We also provide evidence that the fetal T cell lineage is biased toward immune tolerance. These observations offer a mechanistic explanation for the tolerogenic properties of the developing fetus and for variable degrees of immune responsiveness at birth.
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Affiliation(s)
- Jeff E. Mold
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA
| | | | - Trevor D. Burt
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA
- Department of Pediatrics, Division of Neonatology, University of California, San Francisco
| | - Jakob Michaëlsson
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Jose M. Rivera
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA
| | - Sofiya A. Galkina
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA
| | - Kenneth Weinberg
- Division of Hematology, Oncology, and Stem Cell Transplantation, Department of Pediatrics, Stanford University School of Medicine, CA
| | - Cheryl A. Stoddart
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA
| | - Joseph M. McCune
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA
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27
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Thirabanjasak D, Tantiwongse K, Thorner PS. Angiomyeloproliferative lesions following autologous stem cell therapy. J Am Soc Nephrol 2010; 21:1218-22. [PMID: 20558536 DOI: 10.1681/asn.2009111156] [Citation(s) in RCA: 154] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Some reports suggest that autologous hematopoietic stem cell transplantation holds potential for treatment of renal diseases such as lupus nephritis, but the safety of delivering various stem cell types (hematopoietic, mesenchymal, and endothelial precursors) is not well established. Here, we report a case of lupus nephritis treated by direct renal injection of autologous stem cells recovered from peripheral blood. The patient developed masses at the sites of injection and hematuria. We suspected transitional cell carcinoma but nephrectomy revealed that the masses were angiomyeloproliferative lesions. We believe that this previously undescribed pathologic entity is stem cell-derived or -induced. The biologic potential, including the neoplastic potential, of this lesion is unknown. This case illustrates that the development of angiomyeloproliferative lesions is a possible complication of stem cell therapy.
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Affiliation(s)
- Duangpen Thirabanjasak
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Patumwan, Bangkok, Thailand.
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28
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Terrace JD, Hay DC, Samuel K, Anderson RA, Currie IS, Parks RW, Forbes SJ, Ross JA. Portal venous endothelium in developing human liver contains haematopoietic and epithelial progenitor cells. Exp Cell Res 2010; 316:1637-47. [PMID: 20211168 DOI: 10.1016/j.yexcr.2010.02.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2009] [Revised: 02/22/2010] [Accepted: 02/24/2010] [Indexed: 01/16/2023]
Abstract
Future treatments for chronic liver disease are likely to involve manipulation of liver progenitor cells (LPCs). In the human, data characterising the regenerative response is limited and the origin of adult LPCs is unknown. However, these remain critical factors in the design of cell-based liver therapies. The developing human liver provides an ideal model to study cell lineage derivation from progenitors and to understand how foetal haematopoiesis and liver development might explain the nature of the adult LPC population. In 1st trimester human liver, portal venous endothelium (PVE) expressed adult LPC markers and markers of haematopoietic progenitor cells (HPCs) shared with haemogenic endothelium found in the embryonic dorsal aorta. Sorted PVE cells were able to generate hepatoblast-like cells co-expressing CK18 and CK19 in addition to Dlk/pref-1, E-cadherin, albumin and fibrinogen in vitro. Furthermore, PVE cells could initiate haematopoiesis. These data suggest that PVE shares phenotypical and functional similarities both with adult LPCs and embryonic haemogenic endothelium. This indicates that a temporal relationship might exist between progenitor cells in foetal liver development and adult liver regeneration, which may involve progeny of PVE.
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Affiliation(s)
- John D Terrace
- Centre for Regenerative Medicine, University of Edinburgh Medical School, Edinburgh, Scotland, UK
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29
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Bertho JM, Louiba S, Faure MC, Tourlonias E, Stefani J, Siffert B, Paquet F, Dublineau I. Biodistribution of (137)Cs in a mouse model of chronic contamination by ingestion and effects on the hematopoietic system. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2010; 49:239-248. [PMID: 20157720 DOI: 10.1007/s00411-010-0267-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Accepted: 01/24/2010] [Indexed: 05/28/2023]
Abstract
The aim of this work was to define the possible occurrence of hematological changes during the course of a chronic ingestion of (137)Cs. A mouse model was used, with ingestion through drinking water with a cesium concentration of 20 kBq l(-1). Ingestion started in parent animals before mating, and (137)Cs intake and its effect on the hematopoietic system was studied in offspring at various ages between birth and 20 weeks. (137)Cs content was measured in various organs, indicating that (137)Cs was distributed throughout the organism including lympho-hematopoietic organs, i.e., femurs, spleen and thymus. However, we did not observe any effect on the hematopoietic system, whatever the parameter used. In fact, blood cell counts, mononuclear cell counts and progenitor frequency in bone marrow and spleen, and Flt3-ligand, Erythropoietin, G-CSF and SDF-1 concentration in plasma remained unchanged when compared to control animals. Moreover, phenotypic analysis did not show any change in the proportions of bone marrow cell populations. These results indicate that, although (137)Cs was found in all organs implicated in the hematopoietic system, this did not induce any changes in bone marrow function.
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Affiliation(s)
- Jean-Marc Bertho
- Laboratoire de radiotoxicologie expérimentale DRPH/SRBE, LRTOX, IRSN, BP no. 17, 92262, Fontenay aux roses Cedex, France.
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30
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Mayani H. Biological Differences Between Neonatal and Adult Human Hematopoietic Stem/Progenitor Cells. Stem Cells Dev 2010; 19:285-98. [DOI: 10.1089/scd.2009.0327] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Affiliation(s)
- Hector Mayani
- Hematopoietic Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Mexico City, Mexico
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31
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Abstract
Klimchenko and colleagues use human embryonic stem cells to define a novel bipotential hematopoietic progenitor that gives rise to primitive (yolk sac-type) erythrocytes and megakaryocytes.
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32
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Freyer C, Renfree MB. The mammalian yolk sac placenta. JOURNAL OF EXPERIMENTAL ZOOLOGY PART B-MOLECULAR AND DEVELOPMENTAL EVOLUTION 2009; 312:545-54. [DOI: 10.1002/jez.b.21239] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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33
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Timmermans F, Plum J, Yöder MC, Ingram DA, Vandekerckhove B, Case J. Endothelial progenitor cells: identity defined? J Cell Mol Med 2009; 13:87-102. [PMID: 19067770 PMCID: PMC3823038 DOI: 10.1111/j.1582-4934.2008.00598.x] [Citation(s) in RCA: 365] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
In the past decade, researchers have gained important insights on the role of bone marrow (BM)-derived cells in adult neovascularization. A subset of BM-derived cells, called endothelial progenitor cells (EPCs), has been of particular interest, as these cells were suggested to home to sites of neovascularization and neoendothelialization and differentiate into endothelial cells (ECs) in situ, a process referred to as postnatal vasculogenesis. Therefore, EPCs were proposed as a potential regenerative tool for treating human vascular disease and a possible target to restrict vessel growth in tumour pathology. However, conflicting results have been reported in the field, and the identification, characterization, and exact role of EPCs in vascular biology is still a subject of much discussion. The focus of this review is on the controversial issues in the field of EPCs which are related to the lack of a unique EPC marker, identification challenges related to the paucity of EPCs in the circulation, and the important phenotypical and functional overlap between EPCs, haematopoietic cells and mature ECs. We also discuss our recent findings on the origin of endothelial outgrowth cells (EOCs), showing that this in vitro defined EC population does not originate from circulating CD133+ cells or CD45+ haematopoietic cells.
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Affiliation(s)
- Frank Timmermans
- Department of Clinical Chemistry, Microbiology and Immunology, University of Ghent, University Hospital Ghent, De Pintelaan, Ghent, Belgium
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Harrison J. Biokinetic and dosimetric modelling in the estimation of radiation risks from internal emitters. JOURNAL OF RADIOLOGICAL PROTECTION : OFFICIAL JOURNAL OF THE SOCIETY FOR RADIOLOGICAL PROTECTION 2009; 29:A81-A105. [PMID: 19454809 DOI: 10.1088/0952-4746/29/2a/s06] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
The International Commission on Radiological Protection (ICRP) has developed biokinetic and dosimetric models that enable the calculation of organ and tissue doses for a wide range of radionuclides. These are used to calculate equivalent and effective dose coefficients (dose in Sv Bq(-1) intake), considering occupational and environmental exposures. Dose coefficients have also been given for a range of radiopharmaceuticals used in diagnostic medicine. Using equivalent and effective dose, exposures from external sources and from different radionuclides can be summed for comparison with dose limits, constraints and reference levels that relate to risks from whole-body radiation exposure. Risk estimates are derived largely from follow-up studies of the survivors of the atomic bombings at Hiroshima and Nagasaki in 1945. New dose coefficients will be required following the publication in 2007 of new ICRP recommendations. ICRP biokinetic and dosimetric models are subject to continuing review and improvement, although it is arguable that the degree of sophistication of some of the most recent models is greater than required for the calculation of effective dose to a reference person for the purposes of regulatory control. However, the models are also used in the calculation of best estimates of doses and risks to individuals, in epidemiological studies and to determine probability of cancer causation. Models are then adjusted to best fit the characteristics of the individuals and population under consideration. For example, doses resulting from massive discharges of strontium-90 and other radionuclides to the Techa River from the Russian Mayak plutonium plant in the early years of its operation are being estimated using models adapted to take account of measurements on local residents and other population-specific data. Best estimates of doses to haemopoietic bone marrow, in utero and postnatally, are being used in epidemiological studies of radiation-induced leukaemia. Radon-222 is the one internal emitter for which control of exposure is based on direct information on cancer risks, with extensive information available on lung cancer induction by radon progeny in mines and consistent data on risks in homes. The dose per unit (222)Rn exposure can be calculated by comparing lung cancer risk estimates derived for (222)Rn exposure and for external exposure of the Japanese survivors. Remarkably similar values are obtained by this method and by calculations using the ICRP model of the respiratory tract, providing good support for model assumptions. Other informative comparisons with risks from external exposure can be made for Thorotrast-induced liver cancer and leukaemia, and radium-induced bone cancer. The bone-seeking alpha emitters, plutonium-239 and radium isotopes, are poorer leukaemogens than predicted by models. ICRP dose coefficients are published as single values without consideration of uncertainties. However, it is clear that full consideration of uncertainties is appropriate when considering best estimates of doses and risks to individuals or specific population groups. An understanding of the component uncertainties in the calculation of dose coefficients can be seen as an important goal and should help inform judgements on the control of exposures. The routine consideration of uncertainties in dose assessments, if achievable, would be of questionable value when doses are generally maintained at small fractions of limits.
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Affiliation(s)
- John Harrison
- Health Protection Agency, Radiation Protection Division, CRCE, Chilton, Didcot, Oxon, OX11 0RQ, UK.
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Lau A, Belanger CL, Winn LM. In utero and acute exposure to benzene: Investigation of DNA double-strand breaks and DNA recombination in mice. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2009; 676:74-82. [DOI: 10.1016/j.mrgentox.2009.04.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2008] [Revised: 03/27/2009] [Accepted: 04/01/2009] [Indexed: 11/26/2022]
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Gonzalez S, Amat L, Azqueta C, Madrigal JA, Laïlla JM, Garcia J, Querol S. Factors modulating circulation of hematopoietic progenitor cells in cord blood and neonates. Cytotherapy 2009; 11:35-42. [PMID: 19034720 DOI: 10.1080/14653240802499148] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Hematopoietic progenitor cells (HPC) circulate at high levels at birth and disappear rapidly afterwards, but the underlying mechanism it is not known. The aim of this study was to assess circulating HPC in cord blood at different gestational ages and shortly after birth and concomitantly study the biologic markers involved in this phenomenon. METHODS All samples were analyzed for CD34(+) cells, colony-forming units (CFU) and cytokines. RESULTS The results obtained confirmed a slight decrease in HPC concentration during the late stage of fetal life (R(2)=0.41). After birth, CD34(+) cells showed a rapid decline from circulation: 25+/-29% at 3 h, 51+/-42% at 12 h and 80+/-48% at 60 h. CFU cleared following a similar pattern. Cord plasma showed higher concentrations of stem cell factor (SCF), fetal liver tyrosine kinase 3-ligand (FLT3l), erythrpoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and interleukin-11 (IL-11) compared with an adult control. Interestingly, the EPO concentration in newborn plasma correlated with the kinetics of HPC decline after birth. Moreover, we observed an up-regulation of l-selectin and a down-regulation of CXCR4 expression in CD34(+) cells 3 h after birth. DISCUSSION These data combined suggest that an active homing process results in the clearance of HPC from the circulation immediately after birth.
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Affiliation(s)
- S Gonzalez
- Gynecology and Obstetrics Service, Hospital Universitari Sant Joan de Deu, Esplugues de Llobregat, Spain
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Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood 2008; 112:4507-11. [PMID: 18689547 DOI: 10.1182/blood-2008-04-152967] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Down syndrome (DS) children have a high frequency of acute megakaryoblastic leukemia (AMKL) in early childhood. At least 2 in utero genetic events are required, although not sufficient, for DS-AMKL: trisomy 21 (T21) and N-terminal-truncating GATA1 mutations. To investigate the role of T21 in DS-AMKL, we compared second trimester hemopoiesis in DS without GATA1 mutations to gestation-matched normal controls. In all DS fetal livers (FLs), but not marrows, megakaryocyte-erythroid progenitor frequency was increased (55.9% +/- 4% vs 17.1% +/- 3%, CD34(+)CD38(+) cells; P < .001) with common myeloid progenitors (19.6% +/- 2% vs 44.0% +/- 7%) and granulocyte-monocyte (GM) progenitors (15.8% +/- 4% vs 34.5% +/- 9%) commensurately reduced. Clonogenicity of DS-FL versus normal FL CD34(+) cells was markedly increased (78% +/- 7% vs 15% +/- 3%) affecting megakaryocyte-erythroid ( approximately 7-fold higher) and GM and colony-forming unit-granulocyte, erythrocyte macrophage, megakaryocyte (CFU-GEMM) progenitors. Replating efficiency of CFU-GEMM was also markedly increased. These data indicate that T21 itself profoundly disturbs FL hemopoiesis and they provide a testable hypothesis to explain the increased susceptibility to GATA1 mutations in DS-AMKL and DS-associated transient myeloproliferative disorder.
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Abstract
The hemangioblast hypothesis was proposed a century ago. The existence of hemangioblasts is now demonstrated in mouse and human embryonic stem cell (ESC)-derived embryoid bodies (EBs), in the mouse and zebrafish gastrula, and in adults. The hemangioblast is believed to derive from mesodermal cells, and is enriched in the Bry+Flk1+ and Flk1+Scl+ cell populations in EBs and in the posterior primitive streak of the mouse gastrula and in the ventral mesoderm of the zebrafish gastrula. However, recent studies suggest that the hemangioblast does not give rise to all endothelial and hematopoietic lineages in mouse and zebrafish embryos. Although several signaling pathways are known to involve the generation of hemangioblasts, it remains largely unknown how the hemangioblast is formed and what are the master genes controlling hemangioblast development. This review will summarize our current knowledge, challenges, and future directions on molecular and developmental aspects of the hemangioblast.
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Affiliation(s)
- Jing-Wei Xiong
- The Nephrology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 01219, USA.
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Wan J, Winn LM. In utero exposure to benzene increases embryonic c-Myb and Pim-1 protein levels in CD-1 mice. Toxicol Appl Pharmacol 2008; 228:326-33. [DOI: 10.1016/j.taap.2007.12.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2007] [Revised: 12/06/2007] [Accepted: 12/06/2007] [Indexed: 10/22/2022]
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Affiliation(s)
- Jiwang Zhang
- Oncology Institute, Department of Pathology, Loyola University Medical Center, Chicago, IL 60153, USA
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Medvinsky A, Taoudi S, Mendes S, Dzierzak E. Analysis and manipulation of hematopoietic progenitor and stem cells from murine embryonic tissues. CURRENT PROTOCOLS IN STEM CELL BIOLOGY 2008; Chapter 2:Unit 2A.6. [PMID: 18770635 DOI: 10.1002/9780470151808.sc02a06s4] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Hematopoietic development begins in several locations in the mammalian embryo: yolk sac, aorta-gonad-mesonephros region (AGM), and the chorio-allantoic placenta. Generation of the most potent cells, adult definitive hematopoietic stem cells (HSCs), occurs within the body of the mouse embryo at midgestation in the AGM region. Similarly, at the equivalent developmental time in the human embryo, the AGM region has been shown to contain multipotent progenitors. Hence, the mouse embryo serves as an excellent model to study hematopoietic development. To further studies on the ontogeny of the adult hematopoietic system, the focus of this unit is on the experimental methods used in analysis of the AGM region.
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Affiliation(s)
- Alexander Medvinsky
- Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom
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Identification of mesenchymal stem cells in aorta-gonad-mesonephros and yolk sac of human embryos. Blood 2007; 111:2436-43. [PMID: 18045971 DOI: 10.1182/blood-2007-07-099333] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells that can generate various microenvironment components in bone marrow, ensuring a precise control over self-renewal and multilineage differentiation of hematopoietic stem cells. Nevertheless, their spatiotemporal correlation with embryonic hematopoiesis remains rudimentary, particularly in relation to the human being. Here, we reported that human aorta-gonad-mesonephros (AGM) resided with bona fide MSCs. They were highly proliferative as fibroblastoid population bearing uniform surface markers (CD45(-), CD34(-), CD105(+), CD73(+), CD29(+), and CD44(+)), expressed pluripotential molecules Oct-4 and Nanog, and clonally demonstrated trilineage differentiation capacity (osteocytes, chondrocytes, and adipocytes). The frequency and absolute number of MSCs in aorta plus surrounding mesenchyme (E26-E27) were 0.3% and 164, respectively. Moreover, they were functionally equivalent to MSCs from adult bone marrow, that is, supporting long-term hematopoiesis and suppressing T-lymphocyte proliferation in vitro. In comparison, the matching yolk sac contained bipotent mesenchymal precursors that propagated more slowly and failed to generate chondrocytes in vitro. Together with previous knowledge, we propose that a proportion of MSCs initially develop in human AGM prior to their emergence in embryonic circulation and fetal liver.
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Badillo AT, Flake AW. The regulatory role of stromal microenvironments in fetal hematopoietic ontogeny. ACTA ACUST UNITED AC 2007; 2:241-6. [PMID: 17625260 DOI: 10.1007/s12015-006-0052-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/1999] [Revised: 11/30/1999] [Accepted: 11/30/1999] [Indexed: 11/26/2022]
Abstract
Fetal hematopoietic development occurs through the successive expansion and differentiation of hematopoietic stem cells in distinct anatomic sites. The temporal pattern of fetal hematopoietic ontogeny suggests a coordinated developmental sequence whereby the preceding organ sustains the basic, immediate hematopoietic needs of the embryo allowing time for the development of niches within the subsequent organ with more complex supportive functions. We examine the hypothesis that there is a period of stromal genesis and circulating mesenchymal precursor cells, which gives rise to specialized niches within each of the definitive fetal hematopoietic organs, and these niches regulate hematopoietic stem cells fate determination. This article reviews fetal hematopoietic and stromal development and the current understanding of the development, composition, and regulation of the fetal stem cell niche.
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Affiliation(s)
- Andrea T Badillo
- The Children's Institute for Surgical Science, The Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA
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Jones JA, Gray MR, Oliveira BE, Koch M, Castellot JJ. CCN5 expression in mammals : I. Embryonic and fetal tissues of mouse and human. J Cell Commun Signal 2007; 1:127-43. [PMID: 18481203 PMCID: PMC2275877 DOI: 10.1007/s12079-007-0012-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2007] [Accepted: 09/06/2007] [Indexed: 02/08/2023] Open
Abstract
The six proteins of the CCN family have important roles in development, angiogenesis, cell motility, proliferation, and other fundamental cell processes. To date, CCN5 distribution in developing rodents and humans has not been mapped comprehensively. CCN5 strongly inhibits adult smooth muscle cell proliferation and motility. Its anti-proliferative action predicts that CCN5 would not be present in developing tissues until the proliferation phase of tissue morphogenesis is complete. However, estrogen induces CCN5 expression in epithelial and smooth muscle cells, suggesting that CCN5 might be widely expressed in embryonic tissues exposed to high levels of estrogen. 9-16 day murine embryos and fetuses and 3-7 month human fetal tissues were analyzed by immunohistochemistry. CCN5 was detected in nearly all developing tissues. CCN5 protein expression was initially present in most tissues, and at later times in development tissue-specific expression differences were observed. CCN5 expression was particularly strong in vascular tissues, cardiac muscle, bronchioles, myotendinous junctions, and intestinal smooth muscle and epithelium. CCN5 expression was initially absent in bone cartilaginous forms but was increasingly expressed during bone endochondral ossification. Widespread CCN5 mRNA expression was detected in GD14.5 mice. Although CCN2 and CCN5 protein expression patterns in some adult pathologic conditions are inversely expressed, this expression pattern was not found in developing mouse and human tissues. The widespread expression pattern of CCN5 in most embryonic and fetal tissues suggests a diverse range of functions for CCN5.
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Affiliation(s)
- Jennifer A. Jones
- Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA USA
| | - Mark R. Gray
- Department of Anatomy and Cell Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
| | - Beatriz Enes Oliveira
- Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA USA
- Instituto de Ciencias Biomedicas Abel Salazar, 4099-003 Porto, Portugal
| | - Manuel Koch
- Center for Biochemistry, Department of Dermatology, Medical Faculty, University of Cologne, Cologne, Germany
| | - John J. Castellot
- Program in Cell, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA USA
- Department of Anatomy and Cell Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
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Weisel KC, Fibbe WE, Kanz L. Meeting summary: International Symposium and Workshop on Hematopoietic Stem Cells VI, University of Tübingen, Germany, September 14-16, 2006. Exp Hematol 2007; 35:1005-14. [PMID: 17588469 DOI: 10.1016/j.exphem.2007.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2007] [Revised: 03/23/2007] [Accepted: 03/26/2007] [Indexed: 11/28/2022]
Affiliation(s)
- Katja C Weisel
- Department of Hematology, Oncology and Immunology, University Medical Center II, Tübingen, Germany
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Zambidis ET, Sinka L, Tavian M, jokubaitis V, Park TS, Simmons P, Péault B. Emergence of human angiohematopoietic cells in normal development and from cultured embryonic stem cells. Ann N Y Acad Sci 2007; 1106:223-32. [PMID: 17360801 PMCID: PMC3510976 DOI: 10.1196/annals.1392.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Human hematopoiesis proceeds transiently in the extraembryonic yolk sac and embryonic, then fetal liver before being stabilized in the bone marrow during the third month of gestation. In addition to this classic developmental sequence, we have previously shown that the aorta-gonad-mesonephros (AGM) embryonic territory produces stem cells for definitive hematopoiesis from 27 to 40 days of human development, through an intermediate blood-forming endothelium stage. These studies have relied on the use of traditional markers of human hematopoietic and endothelial cells. In addition, we have recently identified and characterized a novel surface molecule, BB9, which typifies the earliest founders of the human angiohematopoietic system. BB9, which was initially identified with a monoclonal antibody raised to Stro-1(+) bone marrow stromal cells, recognizes in the adult the most primitive Thy-1(+) CD133(+) Lin(-), non-obese diabetic--severe combined immunodeficiency disease (NOD-SCID) mouse engrating hematopoietic stem cells (HSCs). In the 3- to 4-week embryo, BB9 expression typifies a subset of splanchnopleural mesodermal cells that migrate dorsally and colonize the ventral aspect of the aorta where they establish a population of hemogenic endothelial cells. We have indeed confirmed that hematopoietic potential in the human embryo, as assessed by long-term culture-initiating cell (LTC-IC) and SCID mouse reconstituting cell (SRC) activities, is confined to BB9-expressing cells. We have further validated these results in the model of human embryonic stem cells (hESCs) in which we have modeled, through the development of hematopoietic embryoid bodies (EBs), primitive and definitive hematopoieses. In this setting, we have documented the emergence of BB9(+) hemangioblast-like clonogenic angiohematopoietic progenitors that currently represent the earliest known founders of the human vascular and blood systems.
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Affiliation(s)
- Elias T. Zambidis
- Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA
| | - Lidia Sinka
- INSERM U602, H�pital Paul Brousse, Villejuif 94807, France
| | - Manuela Tavian
- INSERM U602, H�pital Paul Brousse, Villejuif 94807, France
| | | | - Tea Soon Park
- Stem Cell Research Center at Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15213, USA
| | - Paul Simmons
- The University of Texas Health Science Center, Houston, Texas 77030, USA
| | - Bruno Péault
- Stem Cell Research Center at Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15213, USA
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Abstract
Extramedullary proliferations of bone marrow elements are infrequently encountered in routine pathology practice. On occasion, they can present diagnostic difficulties when seen in unusual or unanticipated sites. This review serves to cover aspects of underlying embryogenesis of myeloid elements, as well as sites and circumstance of benign proliferations of myeloid elements along with their occasional confusion with neoplastic myeloid proliferations. Benign proliferations associated with hematologic disorders and hematopoietic growth factors are discussed. Immunohistochemical evaluation of myeloid proliferations is considered as well.
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Trivedi P, Hematti P. Simultaneous generation of CD34+ primitive hematopoietic cells and CD73+ mesenchymal stem cells from human embryonic stem cells cocultured with murine OP9 stromal cells. Exp Hematol 2007; 35:146-54. [PMID: 17198883 DOI: 10.1016/j.exphem.2006.09.003] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2006] [Revised: 09/06/2006] [Accepted: 09/07/2006] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Human embryonic stem cells (hESCs) have been shown to generate CD34(+) primitive hematopoietic cells after several days of coculturing with the OP9 murine stromal cell line. CD73(+) multipotent mesenchymal cells have also been isolated from hESC/OP9 cocultures after several weeks. We hypothesized that generation of CD34(+) hematopoietic cells and CD73(+) mesenchymal stem cells (MSCs) may follow similar kinetics, so we investigated the generation of CD73(+) cells in the first 2 weeks of hESC/OP9 cocultures, at a time when CD34(+) cells are generated. MATERIALS AND METHODS We cocultured hESCs with OP9 cells and examined the time course of appearance of human CD34(+) and CD73(+) cells using flow cytometry. We tested the hematopoietic progenitor potentials of CD34(+) cells generated using hematopoietic colony-forming assays, and the multipotent mesenchymal properties of CD73(+) cells generated using in vitro differentiation assays. RESULTS We observed that in the first 2 weeks of the hESC/OP9 coculture system CD34(+) hematopoietic and CD73(+) MSC generation follows a similar pattern. We sorted the CD34(+) cells and showed that they can generate hematopoietic progenitor colonies. Starting with cocultured cells on day 8, and through an enrichment procedure, we also could generate a pure population of MSCs. These hESC-derived MSCs had typical morphological and cell surface marker characteristics of adult bone marrow-derived MSCs, and could be differentiated toward osteogenic, adipogenic, and chondrogenic cells in vitro, a hallmark property of MSCs. CONCLUSIONS OP9 cells when cocultured with hESCs support simultaneous generation of CD34(+) primitive hematopoietic cells and CD73(+) MSCs from hESCs.
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Affiliation(s)
- Parul Trivedi
- Department of Medicine, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA
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Abstract
Hematopoietic stem cells (HSCs) develop during embryogenesis in a complex process that involves multiple anatomical sites. Once HSC precursors have been specified from mesoderm, they have to mature into functional HSCs and undergo self-renewing divisions to generate a pool of HSCs. During this process,developing HSCs migrate through various embryonic niches, which provide signals for their establishment and the conservation of their self-renewal ability. These processes have to be recapitulated to generate HSCs from embryonic stem cells. Elucidating the interactions between developing HSCs and their niches should facilitate the generation and expansion of HSCs in vitro to exploit their clinical potential.
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Affiliation(s)
- Hanna K A Mikkola
- Department of Molecular, Cell and Developmental Biology, Jonsson Comprehensive Cancer Center, Institute for Stem Cell Biology and Medicine, University of California, Los Angeles, CA 90095, USA.
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Winkler IG, Lévesque JP. Mechanisms of hematopoietic stem cell mobilization: When innate immunity assails the cells that make blood and bone. Exp Hematol 2006; 34:996-1009. [PMID: 16863906 DOI: 10.1016/j.exphem.2006.04.005] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2006] [Indexed: 01/13/2023]
Abstract
Mobilization is now used worldwide to collect large numbers of hematopoietic stem and progenitor cells (HSPCs) for transplantation. Although the first mobilizing agents were discovered largely by accident, discovery of more efficient mobilizing agents will require a better understanding of the molecular mechanisms responsible. During the past 5 years, a number of mechanisms have been identified, shedding new light on the dynamics of the hematopoietic system in vivo and on the intricate relationship between hematopoiesis, innate immunity, and bone. After briefly reviewing the mechanisms by which circulating HSPCs home into the bone marrow and what keeps them there, the current knowledge of mechanisms responsible for HSPC mobilization in response to hematopoietic growth factors such as granulocyte colony-stimulating factor, chemotherapy, chemokines, and polyanions will be discussed together with current strategies developed to further increase HSPC mobilization.
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Affiliation(s)
- Ingrid G Winkler
- Haematopoietic Stem Cell Laboratory, Cancer Biotherapies Program, Mater Medical Research Institute, University of Queensland, South Brisbane, Queensland, Australia
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