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Cell Stem Cell May 2018Evidence of the diversity and multi-layered organization of the hematopoietic system is leading to new insights that may inform ex vivo production of blood cells.... (Review)
Review
Evidence of the diversity and multi-layered organization of the hematopoietic system is leading to new insights that may inform ex vivo production of blood cells. Interestingly, not all long-lived hematopoietic cells derive from hematopoietic stem cells (HSCs). Here we review the current knowledge on HSC-dependent cell lineages and HSC-independent tissue-resident hematopoietic cells and how they arise during embryonic development. Classical embryological and genetic experiments, cell fate tracing data, single-cell imaging, and transcriptomics studies provide information on the molecular/cell trajectories that form the complete hematopoietic system. We also discuss the current developmentally informed efforts toward generating engraftable and multilineage blood cells.
Topics: Animals; Hematopoietic Stem Cells; Humans
PubMed: 29727679
DOI: 10.1016/j.stem.2018.04.015 -
International Journal of Molecular... Apr 2022The mammalian hematopoietic system is remarkably efficient in meeting an organism's vital needs, yet is highly sensitive and exquisitely regulated. Much of the... (Review)
Review
The mammalian hematopoietic system is remarkably efficient in meeting an organism's vital needs, yet is highly sensitive and exquisitely regulated. Much of the organismal control over hematopoiesis comes from the regulation of hematopoietic stem cells (HSCs) by specific microenvironments called niches in bone marrow (BM), where HSCs reside. The experimental studies of the last two decades using the most sophisticated and advanced techniques have provided important data on the identity of the niche cells controlling HSCs functions and some mechanisms underlying niche-HSC interactions. In this review we discuss various aspects of organization and functioning of the HSC cell niche in bone marrow. In particular, we review the anatomy of BM niches, various cell types composing the niche, niches for more differentiated cells, metabolism of HSCs in relation to the niche, niche aging, leukemic transformation of the niche, and the current state of HSC niche modeling in vitro.
Topics: Animals; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Hematopoiesis; Hematopoietic Stem Cells; Mammals; Stem Cell Niche
PubMed: 35457280
DOI: 10.3390/ijms23084462 -
Cells Mar 2023The haematopoietic system plays an essential role in our health and survival. It is comprised of a range of mature blood and immune cell types, including oxygen-carrying... (Review)
Review
The haematopoietic system plays an essential role in our health and survival. It is comprised of a range of mature blood and immune cell types, including oxygen-carrying erythrocytes, platelet-producing megakaryocytes and infection-fighting myeloid and lymphoid cells. Self-renewing multipotent haematopoietic stem cells (HSCs) and a range of intermediate haematopoietic progenitor cell types differentiate into these mature cell types to continuously support haematopoietic system homeostasis throughout life. This process of haematopoiesis is tightly regulated in vivo and primarily takes place in the bone marrow. Over the years, a range of in vitro culture systems have been developed, either to expand haematopoietic stem and progenitor cells or to differentiate them into the various haematopoietic lineages, based on the use of recombinant cytokines, co-culture systems and/or small molecules. These approaches provide important tractable models to study human haematopoiesis in vitro. Additionally, haematopoietic cell culture systems are being developed and clinical tested as a source of cell products for transplantation and transfusion medicine. This review discusses the in vitro culture protocols for human HSC expansion and differentiation, and summarises the key factors involved in these biological processes.
Topics: Humans; Hematopoietic Stem Cells; Cell Differentiation; Megakaryocytes; Hematopoiesis; Bone Marrow
PubMed: 36980237
DOI: 10.3390/cells12060896 -
Development (Cambridge, England) Jan 2018Hematopoietic stem cells (HSCs) develop in discrete anatomical niches, migrating during embryogenesis from the aorta-gonad-mesonephros (AGM) region to the fetal liver,... (Review)
Review
Hematopoietic stem cells (HSCs) develop in discrete anatomical niches, migrating during embryogenesis from the aorta-gonad-mesonephros (AGM) region to the fetal liver, and finally to the bone marrow, where most HSCs reside throughout adult life. These niches provide supportive microenvironments that specify, expand and maintain HSCs. Understanding the constituents and molecular regulation of HSC niches is of considerable importance as it could shed new light on the mechanistic principles of HSC emergence and maintenance, and provide novel strategies for regenerative medicine. However, controversy exists concerning the cellular complexity of the bone marrow niche, and our understanding of the different HSC niches during development remains limited. In this Review, we summarize and discuss what is known about the heterogeneity of the HSC niches at distinct stages of their ontogeny, from the embryo to the adult bone marrow, drawing predominantly on data from mouse studies.
Topics: Aging; Animals; Aorta; Cell Lineage; Female; Gonads; Hematologic Neoplasms; Hematopoietic Stem Cells; Hematopoietic System; Humans; Male; Mesonephros; Mice; Placenta; Pregnancy; Stem Cell Niche; Stromal Cells; Sympathetic Nervous System
PubMed: 29358215
DOI: 10.1242/dev.139691 -
International Journal of Molecular... May 2023The hematopoietic system performs the most vital functions in the human body, integrating the work of various organs while producing enormous numbers of mature cells...
The hematopoietic system performs the most vital functions in the human body, integrating the work of various organs while producing enormous numbers of mature cells daily [...].
Topics: Humans; Hematopoietic System; Hematopoietic Stem Cell Transplantation
PubMed: 37240328
DOI: 10.3390/ijms24108983 -
Cell Stem Cell Jul 2015Despite great advances in understanding the mechanisms underlying blood production, lineage specification at the level of multipotent progenitors (MPPs) remains poorly...
Despite great advances in understanding the mechanisms underlying blood production, lineage specification at the level of multipotent progenitors (MPPs) remains poorly understood. Here, we show that MPP2 and MPP3 are distinct myeloid-biased MPP subsets that work together with lymphoid-primed MPP4 cells to control blood production. We find that all MPPs are produced in parallel by hematopoietic stem cells (HSCs), but with different kinetics and at variable levels depending on hematopoietic demands. We also show that the normally rare myeloid-biased MPPs are transiently overproduced by HSCs in regenerating conditions, hence supporting myeloid amplification to rebuild the hematopoietic system. This shift is accompanied by a reduction in self-renewal activity in regenerating HSCs and reprogramming of MPP4 fate toward the myeloid lineage. Our results support a dynamic model of blood development in which HSCs convey lineage specification through independent production of distinct lineage-biased MPP subsets that, in turn, support lineage expansion and differentiation.
Topics: Animals; Cell Differentiation; Cell Lineage; Cellular Reprogramming; Gene Expression; Hematopoiesis; Hematopoietic Stem Cells; Lymphoid Progenitor Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Multipotent Stem Cells; Myeloid Progenitor Cells; Regeneration
PubMed: 26095048
DOI: 10.1016/j.stem.2015.05.003 -
Advances in Experimental Medicine and... 2019Hematopoietic stem cells (HSCs) maintain lifelong production of mature blood cells and regenerate the hematopoietic system after cytotoxic injury. Use of expanding cell... (Review)
Review
Hematopoietic stem cells (HSCs) maintain lifelong production of mature blood cells and regenerate the hematopoietic system after cytotoxic injury. Use of expanding cell surface marker panels and advanced functional analyses have revealed the presence of several immunophenotypically different HSC subsets with distinct self-renewal and repopulating capacity and bias toward selective lineage differentiation. This chapter summarizes current understanding of the phenotypic and functional heterogeneity within the HSC pool, with emphasis on the immunophenotypes and functional features of several known HSC subsets, and their roles in steady-state and emergency hematopoiesis, and in aging. The chapter also highlights some of the future research directions to elucidate further the biology and function of different HSC subsets in health and disease states.
Topics: Animals; Cell Differentiation; Hematopoiesis; Hematopoietic Stem Cells; Humans
PubMed: 31487025
DOI: 10.1007/978-3-030-24108-7_10 -
Leukemia Dec 2022Current dogma is that there exists a hematopoietic pluripotent stem cell, resident in the marrow, which is quiescent, but with tremendous proliferative and... (Review)
Review
Current dogma is that there exists a hematopoietic pluripotent stem cell, resident in the marrow, which is quiescent, but with tremendous proliferative and differentiative potential. Furthermore, the hematopoietic system is essentially hierarchical with progressive differentiation from the pluripotent stem cells to different classes of hematopoietic cells. However, results summarized here indicate that the marrow pluripotent hematopoietic stem cell is actively cycling and thus continually changing phenotype. As it progresses through cell cycle differentiation potential changes as illustrated by sequential changes in surface expression of B220 and GR-1 epitopes. Further data indicated that the potential of purified hematopoietic stem cells extends to multiple other non-hematopoietic cells. It appears that marrow stem cells will give rise to epithelial pulmonary cells at certain points in cell cycle. Thus, it appears that the marrow "hematopoietic" stem cell is also a stem cell for other non-hematopoietic tissues. These observations give rise to the concept of a universal stem cell. The marrow stem cell is not limited to hematopoiesis and its differentiation potential continually changes as it transits cell cycle. Thus, there is a universal stem cell in the marrow which alters its differentiation potential as it progresses through cell cycle. This potential is expressed when it resides in tissues compatible with its differentiation potential, at a particular point in cell cycle transit, or when it interacts with vesicles from that tissue.
Topics: Bone Marrow Cells; Hematopoietic Stem Cells; Hematopoiesis; Cell Differentiation; Cell Cycle
PubMed: 36307485
DOI: 10.1038/s41375-022-01715-w -
Cells Sep 2019The 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.... (Review)
Review
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.
Topics: Animals; Epigenesis, Genetic; Gene Regulatory Networks; Hematopoiesis, Extramedullary; Hematopoietic Stem Cells; Humans; Stem Cell Niche
PubMed: 31554248
DOI: 10.3390/cells8101138 -
Haematologica Jan 2016Over the last decades, incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system, have been developed... (Review)
Review
Over the last decades, incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system, have been developed and now represent an important research tool in the field. The most significant contributions made by means of humanized mice are the identification of normal and leukemic hematopoietic stem cells, the characterization of the human hematopoietic hierarchy, and their use as preclinical therapy models for malignant hematopoietic disorders. Successful xenotransplantation depends on three major factors: tolerance by the mouse host, correct spatial location, and appropriately cross-reactive support and interaction factors such as cytokines and major histocompatibility complex molecules. Each of these can be modified. Experimental approaches include the genetic modification of mice to faithfully express human support factors as non-cross-reactive cytokines, to create free niche space, the co-transplantation of human mesenchymal stem cells, the implantation of humanized ossicles or other stroma, and the implantation of human thymic tissue. Besides the source of hematopoietic cells, the conditioning regimen and the route of transplantation also significantly affect human hematopoietic development in vivo. We review here the achievements, most recent developments, and the remaining challenges in the generation of pre-clinically-predictive systems for human hematology and immunology, closely resembling the human situation in a xenogeneic mouse environment.
Topics: Animals; Hematopoietic System; Heterografts; Humans; Lymphatic System; Mesenchymal Stem Cell Transplantation; Mice; Mice, SCID; Thymus Gland
PubMed: 26721800
DOI: 10.3324/haematol.2014.115212