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• W1982202983 abstract "Despite its complexity, blood is probably the best understood developmental system, largely due to seminal experimentation in the mouse. Clinically, hematopoietic stem cell (HSC) transplantation represents the most widely deployed regenerative therapy, but human HSCs have only been characterized relatively recently. The discovery that immune-deficient mice could be engrafted with human cells provided a powerful approach for studying HSCs. We highlight 2 decades of studies focusing on isolation and molecular regulation of human HSCs, therapeutic applications, and early lineage commitment steps, and compare mouse and humanized models to identify both conserved and species-specific mechanisms that will aid future preclinical research. Despite its complexity, blood is probably the best understood developmental system, largely due to seminal experimentation in the mouse. Clinically, hematopoietic stem cell (HSC) transplantation represents the most widely deployed regenerative therapy, but human HSCs have only been characterized relatively recently. The discovery that immune-deficient mice could be engrafted with human cells provided a powerful approach for studying HSCs. We highlight 2 decades of studies focusing on isolation and molecular regulation of human HSCs, therapeutic applications, and early lineage commitment steps, and compare mouse and humanized models to identify both conserved and species-specific mechanisms that will aid future preclinical research. Blood is one of the most highly regenerative tissues, with approximately one trillion (1012) cells arising daily in adult human bone marrow (BM). Early anatomists examining the BM noted a wide variety of cellular morphologies corresponding to cells of various blood lineages and stages of differentiation. To explain this diversity, Russian biologist A. Maximow astutely postulated that hematopoiesis is organized as a cellular hierarchy derived from a common precursor, a hematopoietic stem cell (HSC) (Maximow, 1909Maximow A. Der Lymphozyt als gemeinsame Stammzelle der verschiedenen Blutelemente in der embryonalen Entwicklung und im postfetalen Leben der Säugetiere.Folia Haematol. (Frankf.). 1909; 8: 125-134Google Scholar). The best evidence for the existence of HSCs came during the atomic era. The lethal consequence of radiation was found to be due to BM failure, but exposed recipients could be rescued following injection of spleen or marrow cells from unirradiated donors (Lorenz et al., 1951Lorenz E. Uphoff D. Reid T.R. Shelton E. Modification of irradiation injury in mice and guinea pigs by bone marrow injections.J. Natl. Cancer Inst. 1951; 12: 197-201PubMed Google Scholar). Although these studies firmly established the existence of blood-forming cells and the benefits of regenerating the blood system upon HSC transplantation (HSCT), they could not resolve whether there were multiple stem cells restricted to each blood lineage, or whether a single multipotential HSC existed. The study of hematopoiesis moved from observational to functional when Till and McCulloch showed that the regenerative potential of HSCs could be assayed with clonal in vivo repopulation assays, thus establishing the existence of multipotential HSCs (Becker et al., 1963Becker A.J. McCulloch E.A. Till J.E. Cytological Demonstration of the Clonal Nature of Spleen Colonies Derived from Transplanted Mouse Marrow Cells.Nature. 1963; 197: 452-454Crossref PubMed Scopus (390) Google Scholar, Till and McCulloch, 1961Till J.E. McCulloch E.A. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells.Radiat. Res. 1961; 14: 213-222Crossref PubMed Google Scholar). This finding stimulated others to develop clonal in vitro assays that, combined with the advent of a wide array of cell surface antibodies and flow sorting, have culminated in today's finely detailed view of the blood system as a developmental hierarchy with multipotent HSCs at the apex and terminally differentiated cells on the bottom. HSCs are critical for lifelong blood production and are uniquely defined by their capacity to durably self-renew, or generate daughter stem cells, while still contributing to the pool of differentiating cells. As they differentiate, HSCs give rise to a series of progenitor cell intermediates that undergo a gradual fate restriction to assume the identity of a mature blood cell. Lineage relationships between stem cells, progenitors, and mature cells form a complex “roadmap” that can guide investigations of the molecular basis for these developmental transitions. Much of our understanding of hematopoiesis comes from the mouse because, operationally, HSCs can only be identified and measured with functional repopulation assays, raising an obvious barrier to studying human HSCs. However, with the advent of xenotransplantation, robust in vitro clonal assays, and refined sorting strategies, significant progress toward defining the human blood hierarchy has been made. We will divide this review into three parts, the first describing the advances in purification of human HSCs, the second focusing on the molecular regulation of human HSCs and how it can be harnessed for therapy, and the third on how human lineage commitment occurs. Since the seminal experiments demonstrating that blood lineages are derived from multipotent cells that form macroscopic colonies in the spleen (CFU-S) following transplantation (Till and McCulloch, 1961Till J.E. McCulloch E.A. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells.Radiat. Res. 1961; 14: 213-222Crossref PubMed Google Scholar), the mouse has become an indispensable model system for studying normal and malignant hematopoiesis. Genetic approaches that direct loss or gain of gene function to precisely defined cellular compartments have identified the basic developmental principles that control the emergence of hemogenic tissues during ontogeny and maintain lifelong hematopoiesis in the adult. The molecular regulation of HSCs elucidated from studies in the mouse is documented in a number of reviews (Orkin and Zon, 2008Orkin S.H. Zon L.I. Hematopoiesis: an evolving paradigm for stem cell biology.Cell. 2008; 132: 631-644Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar). Despite these advances, the need to complement mouse studies with those in primary human cells has been driven by the growing appreciation for species-specific differences in basic biology and hematology, and their more direct relevance in developing therapeutics. Mouse strains used in research are inbred, and it is often difficult to predict how the choice of a specific genetic background can influence the observed phenotype. By contrast, human populations are genetically diverse, and this variation becomes an intrinsic parameter in human studies that experimental models must take into account. Mice and humans differ in size, ecology, lifespan, and age to reproductive maturity, imposing different selective tradeoffs in dealing with tumorigenesis, genotoxic stress, telomerase function, and other factors. Larger body size increases the proliferative demand on human stem and progenitor cells, altering the balance between self-renewal and differentiation, as well as quiescence and cycling. Longer lifespan in humans greatly increases the risk of accumulating deleterious mutations, which imposes greater pressure on tumor suppression. As a result, human cells are more resistant to transformation (Hahn and Weinberg, 2002Hahn W.C. Weinberg R.A. Rules for making human tumor cells.N. Engl. J. Med. 2002; 347: 1593-1603Crossref PubMed Scopus (579) Google Scholar). Collectively, these considerations motivated the development of genetic tools and in vivo repopulation assays to study human stem cells (Dick, 2008Dick J.E. Stem cell concepts renew cancer research.Blood. 2008; 112: 4793-4807Crossref PubMed Scopus (364) Google Scholar). Although the focus on primary cells is highly relevant for human biology, the possibility always remains that some results may be artifacts of the surrogate in vitro or xenograft assay methods. While our review is focused on recent studies in humanized models, we will point out the frequent conservation and occasional key differences between mice and humans. Our view is that mouse and human cell models are complementary, and studies often need to be carried out in parallel. Inspired by the successful application of CFU-S assay to identify clonogenic progenitors in the mouse, investigation of human hematopoiesis first focused on colony-forming progenitors using in vitro CFU-C assay (Moore et al., 1973Moore M.A. Williams N. Metcalf D. In vitro colony formation by normal and leukemic human hematopoietic cells: characterization of the colony-forming cells.J. Natl. Cancer Inst. 1973; 50: 603-623Crossref PubMed Google Scholar, Pike and Robinson, 1970Pike B.L. Robinson W.A. Human bone marrow colony growth in agar-gel.J. Cell. Physiol. 1970; 76: 77-84Crossref PubMed Google Scholar). Using feeder layers from human peripheral blood (PB) to stimulate colony formation, Pike and Robinson demonstrated that rare cells in human BM generated CFU-Cs in agar. In the mouse, use of alternate feeder layers composed of adherent stromal cells revealed that primitive cell types, such as CFU-S, could be maintained in vitro (Dexter and Lajtha, 1974Dexter T.M. Lajtha L.G. Proliferation of haemopoietic stem cells in vitro.Br. J. Haematol. 1974; 28: 525-530Crossref PubMed Google Scholar). By adapting these conditions, human CFU-Cs were continuously produced over weeks in culture (Gartner and Kaplan, 1980Gartner S. Kaplan H.S. Long-term culture of human bone marrow cells.Proc. Natl. Acad. Sci. USA. 1980; 77: 4756-4759Crossref PubMed Google Scholar, Sutherland et al., 1989Sutherland H. Eaves C. Eaves A. Dragowska W. Lansdorp P. Characterization and partial purification of human marrow cells capable of initiating long-term hematopoiesis in vitro.Blood. 1989; 74: 1563-1570Crossref PubMed Google Scholar). The precursor cells giving rise to CFUs were referred to as long-term culture-initiating cells (LTC-ICs) and were positioned upstream of CFU-Cs. There were steady improvements in the LTC-IC assay with the use of cytokine-secreting stroma to augment multilineage differentiation and LTC-IC longevity (Sutherland et al., 1991Sutherland H.J. Eaves C.J. Lansdorp P.M. Thacker J.D. Hogge D.E. Differential regulation of primitive human hematopoietic cells in long-term cultures maintained on genetically engineered murine stromal cells.Blood. 1991; 78: 666-672PubMed Google Scholar). LTC-ICs are not a homogeneous population, but exhibit significant variation in their ability to sustain the cultures and maintain lympho-myeloid differentiation (Hao et al., 1996Hao Q.L. Thiemann F.T. Petersen D. Smogorzewska E.M. Crooks G.M. Extended long-term culture reveals a highly quiescent and primitive human hematopoietic progenitor population.Blood. 1996; 88: 3306-3313PubMed Google Scholar). While the LTC-IC assay represented a robust surrogate assay for multipotent cells, the relationship between LTC-ICs and HSCs, defined by repopulation potential, remained unclear, prompting the need for in vivo models for human cells. Over 20 years have passed since primary human hematopoietic cells were first engrafted in immune-deficient mice (Figure 1). The first breakthrough in humanized mouse models was the discovery of the severe combined immune-deficient (Scid) mouse lacking B and T cells (Fulop and Phillips, 1990Fulop G.M. Phillips R.A. The scid mutation in mice causes a general defect in DNA repair.Nature. 1990; 347: 479-482Crossref PubMed Scopus (286) Google Scholar, Bosma et al., 1983Bosma G.C. Custer R.P. Bosma M.J. A severe combined immunodeficiency mutation in the mouse.Nature. 1983; 301: 527-530Crossref PubMed Google Scholar). Three independent approaches were initially used to engraft human hematopoietic cells in Scid mice. By infusing PB leukocytes (Scid-PBL model), Mosier et al. reconstituted human T and B cells capable of producing specific antibodies to tetanus toxin (Mosier et al., 1988Mosier D.E. Gulizia R.J. Baird S.M. Wilson D.B. Transfer of a functional human immune system to mice with severe combined immunodeficiency.Nature. 1988; 335: 256-259Crossref PubMed Scopus (940) Google Scholar, Mosier et al., 1991Mosier D. Gulizia R. Baird S. Wilson D. Spector D. Spector S. Human Immunodeficiency virus infection of human-PBL-SCID mice.Science. 1991; 251: 791-794Crossref PubMed Google Scholar). By surgically grafting human fetal tissues into Scid mice (Scid-hu model) and transplanting HLA-mismatched fetal liver cells, McCune et al. showed sustained production of donor human B and T cells indicative of stem/progenitor activity (McCune et al., 1988McCune J.M. Namikawa R. Kaneshima H. Shultz L.D. Lieberman M. Weissman I.L. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function.Science. 1988; 241: 1632-1639Crossref PubMed Google Scholar, Namikawa et al., 1988Namikawa R. Kaneshima H. Lieberman M. Weissman I.L. McCune J.M. Infection of the SCID-hu mouse by HIV-1.Science. 1988; 242: 1684-1686Crossref PubMed Google Scholar). These studies showed that human lymphocytes could survive and circulate in Scid mice, and be infected with HIV-1, establishing the first humanized AIDS models. Our group took a third approach that was based on human BMT and murine HSC assays. Lymphoid cells are long lived, while myeloid cells require rapid replenishment from progenitors and eventually from HSCs. Since no myeloid engraftment was observed in the Scid-hu model, and only limited numbers of macrophages were present in the Scid-PBL model, it remained unclear whether human HSCs could engraft and proliferate in immunodeficient mice. A formal demonstration of this requires serial assessment of myeloid cell potential after transplant. However, lack of cross-reactivity between the then newly discovered mouse and human myeloid growth factors was a concern. With this in mind, our group transplanted human BM cells intravenously into sublethally irradiated immune-deficient mice (bg/nu/xid and Scid) infused with human IL-3, GM-CSF, and SCF cytokines, and myeloid colony formation was tracked in the marrow of transplanted mice (Kamel-Reid and Dick, 1988Kamel-Reid S. Dick J.E. Engraftment of immune-deficient mice with human hematopoietic stem cells.Science. 1988; 242: 1706-1709Crossref PubMed Google Scholar, Lapidot et al., 1992Lapidot T. Pflumio F. Doedens M. Murdoch B. Williams D.E. Dick J.E. Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in scid mice.Science. 1992; 255: 1137-1141Crossref PubMed Google Scholar). The results were clear: myeloid progenitors were generated even 4 months after transplant. Contemporaneous detection of B cells indicated that the engraftment was long term and multipotent, fulfilling two key criteria of HSCs. The cells that initiated engraftment in xenotransplants were operationally defined as Scid-repopulating cells (SRCs). This model provided a direct quantitative in vivo assay to measure human HSC activity and a means to undertake isolation of human HSCs. The genotypes of immune-deficient mouse strains are ordered chronologically. The upper panel shows the extent of immunodeficiency and humanization of each model. Humanization is achieved by expressing human proteins as purified protein, as purified transgenes, or from the locus of their mouse homolog (knockin, K.I.). To overcome the limitations due to poor cross-reactivity between mouse and human cytokines, mice that transgenically (Tg) produce human SCF, GM-CSF, and IL-3 (SGM3 mice), or that have the human TPO replacing the mouse locus, have been produced. Other humanization strategies include reducing human graft rejection by constitutively expressing human SIRPα, or increasing human T cell function by constitutive expression of human HLA class I or class II. These models are described in greater detail elsewhere (Shultz et al., 2007Shultz L.D. Ishikawa F. Greiner D.L. Humanized mice in translational biomedical research.Nat. Rev. Immunol. 2007; 7: 118-130Crossref PubMed Scopus (506) Google Scholar, Willinger et al., 2011Willinger T. Rongvaux A. Strowig T. Manz M.G. Flavell R.A. Improving human hemato-lymphoid-system mice by cytokine knock-in gene replacement.Trends Immunol. 2011; 32: 321-327Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). The lower panel depicts the relative extent of support for human cells achieved in each strain. The general level of engraftment is indicated by the plotted line while the letters indicate the type of engraftment (proportions of the various human hematopoietic lineages) detected in each model. The comparison between different models is not strictly quantitative because engraftment levels and lineages generated highly depend on the source of primary human cells and transplantation protocol. All Rag2−/−Il2Rgc−/− strains are on the BALB/c background. NRG, NOD-Rag1−/−IL2Rg−/−; B2m, beta-2-microglobulin; NOD-Scid B2m−/−. The Scid model was limited; high levels of innate immune function and spontaneous emergence of B and T cells with age impeded human engraftment. To generate improved xenograft models, Shultz and colleagues backcrossed the Scid mutation onto nonobese diabetic (NOD) mice harboring defects in innate immunity. The resultant NOD-scid mice supported higher levels of human engraftment (Shultz et al., 1995Shultz L. Schweitzer P. Christianson S. Gott B. Schweitzer I. Tennent B. McKenna S. Mobraaten L. Rajan T. Greiner D. et al.Multiple defects in innate and adaptive immunological function in NOD/LtSz-scid mice.J. Immunol. 1995; 154: 180-191PubMed Google Scholar). Interestingly, other backgrounds with the Scid mutation, such as nonobese resistant (NOR) or BALB/c, were nonsupportive (Shultz et al., 2007Shultz L.D. Ishikawa F. Greiner D.L. Humanized mice in translational biomedical research.Nat. Rev. Immunol. 2007; 7: 118-130Crossref PubMed Scopus (506) Google Scholar). Thus, background-specific genetic factors determine the capacity to engraft human cells. This conclusion was supported by studies in our laboratory showing that NOD, but not NOR, marrow stroma supported human LTC-IC (Takenaka et al., 2007Takenaka K. Prasolava T.K. Wang J.C. Mortin-Toth S.M. Khalouei S. Gan O.I. Dick J.E. Danska J.S. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells.Nat. Immunol. 2007; 8: 1313-1323Crossref PubMed Scopus (151) Google Scholar). NOD mice are highly susceptible to spontaneous type 1 diabetes, and many insulin-dependent diabetes (Idd) loci were identified. Through a long positional cloning approach, the gene responsible for this supportive phenotype was identified to be Sirpa within the Idd13 locus (Takenaka et al., 2007Takenaka K. Prasolava T.K. Wang J.C. Mortin-Toth S.M. Khalouei S. Gan O.I. Dick J.E. Danska J.S. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells.Nat. Immunol. 2007; 8: 1313-1323Crossref PubMed Scopus (151) Google Scholar). Sirpa is a highly polymorphic transmembrane protein expressed on myeloid cells, and binding to its ligand CD47 inhibits phagocytosis. Human CD47 ubiquitously expressed on hematopoietic cells binds to NOD Sirpa with high affinity and induces host macrophage tolerance after transplant of human HSCs (Jaiswal et al., 2009Jaiswal S. Jamieson C.H. Pang W.W. Park C.Y. Chao M.P. Majeti R. Traver D. van Rooijen N. Weissman I.L. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis.Cell. 2009; 138: 271-285Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, Takenaka et al., 2007Takenaka K. Prasolava T.K. Wang J.C. Mortin-Toth S.M. Khalouei S. Gan O.I. Dick J.E. Danska J.S. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells.Nat. Immunol. 2007; 8: 1313-1323Crossref PubMed Scopus (151) Google Scholar). By contrast, NOR Sirpa does not bind human CD47, and NOD-scid mice with the NOR-Sirpa allele cannot be engrafted with human HSCs, establishing the importance of macrophages in HSC transplantation. A major drawback to the NOD-scid model is the high incidence of thymic lymphoma, which prevents long-term studies (Shultz et al., 1995Shultz L. Schweitzer P. Christianson S. Gott B. Schweitzer I. Tennent B. McKenna S. Mobraaten L. Rajan T. Greiner D. et al.Multiple defects in innate and adaptive immunological function in NOD/LtSz-scid mice.J. Immunol. 1995; 154: 180-191PubMed Google Scholar), and the fact that NK cells remain active and able to resist engraftment. To circumvent this problem, NOD-scid mice with either truncation (NOG) or a deletion in the IL-2R common γ chain (NSG), a critical component for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 signaling, were developed (Ito et al., 2002Ito M. Hiramatsu H. Kobayashi K. Suzue K. Kawahata M. Hioki K. Ueyama Y. Koyanagi Y. Sugamura K. Tsuji K. et al.NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells.Blood. 2002; 100: 3175-3182Crossref PubMed Scopus (493) Google Scholar, Shultz et al., 2005Shultz L.D. Lyons B.L. Burzenski L.M. Gott B. Chen X. Chaleff S. Kotb M. Gillies S.D. King M. Mangada J. et al.Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells.J. Immunol. 2005; 174: 6477-6489Crossref PubMed Google Scholar). The deletion of this gene in mice results in a complete loss of B, T, and NK cells. NSG mice support 5-fold higher CD34+ cell engraftment compared with NOD-scid mice. Defects in cytokine signaling also prevent lymphomagenesis, permitting long-term analysis of human HSCs after transplant. Newer generations of mice are now being developed to better humanize the mice through the expression of human cytokines, such as thrombopoietin (TPO), IL-3, GM-CSF, and others that are not cross-reactive (Rongvaux et al., 2011Rongvaux A. Willinger T. Takizawa H. Rathinam C. Auerbach W. Murphy A.J. Valenzuela D.M. Yancopoulos G.D. Eynon E.E. Stevens S. et al.Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo.Proc. Natl. Acad. Sci. USA. 2011; 108: 2378-2383Crossref PubMed Scopus (48) Google Scholar, Willinger et al., 2011Willinger T. Rongvaux A. Strowig T. Manz M.G. Flavell R.A. Improving human hemato-lymphoid-system mice by cytokine knock-in gene replacement.Trends Immunol. 2011; 32: 321-327Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). Interestingly, sex-specific factors also affect human engraftment. Female NSG mice are 6-fold more sensitive at detecting single human HSCs (Notta et al., 2010Notta F. Doulatov S. Dick J.E. Engraftment of human hematopoietic stem cells is more efficient in female NOD/SCID/IL-2Rgc-null recipients.Blood. 2010; 115: 3704-3707Crossref PubMed Scopus (35) Google Scholar). This observation suggests that yet undefined sex-specific factors, such as steroid hormones, can regulate human HSCs. The development of more and more robust xenograft models has enabled isolation and better characterization of human HSCs over the past 2 decades (Figure 1). A major obstacle to studying HSC biology is that the cells are extremely rare. Only 1 in 106 cells in human BM is a transplantable HSC (Wang et al., 1997Wang J.C. Doedens M. Dick J.E. Primitive human hematopoietic cells are enriched in cord blood compared with adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell assay.Blood. 1997; 89: 3919-3924PubMed Google Scholar), requiring purification from the bulk of differentiated cells. Just as HSCs were discovered in the context of rescuing the effects of lethal doses of radiation, the activity of prospectively purified stem cell fractions can only be assayed by transplantation into conditioned hosts. To be defined as a stem cell, a cell must demonstrate durable self-renewal and differentiation into all cell types that compose the tissue. It should also do so at a clonal or single-cell level to exclude the possibility that a population that is homogeneous in terms of cell surface marker expression is still functionally heterogeneous and composed of multiple single-lineage precursors. These requirements present particular difficulties when testing human cells in xenografts. For example, in syngenic mouse experiments, long-term HSCs (LT-HSCs) have been historically defined as enabling repopulation beyond 12 weeks. Cells that generate all lineages but are only capable of transient engraftment are defined as short-term HSCs (ST-HSCs) or multipotent progenitors (MPPs). Even so, extended tracking for 6–8 months reveals so-called intermediate HSCs that extinguish between 3 and 6 months and are separable from both ST-HSCs and LT-HSCs (Benveniste et al., 2010Benveniste P. Frelin C. Janmohamed S. Barbara M. Herrington R. Hyam D. Iscove N.N. Intermediate-term hematopoietic stem cells with extended but time-limited reconstitution potential.Cell Stem Cell. 2010; 6: 48-58Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). Defining the appropriate end-points for human cells in xenografts is more difficult. A 12-week period has been adopted by most investigators in the past. However, a longer period may be needed to distinguish between human transient and durable-reconstituting cells (Glimm et al., 2001Glimm H. Eisterer W. Lee K. Cashman J. Holyoake T.L. Nicolini F. Shultz L.D. von Kalle C. Eaves C.J. Previously undetected human hematopoietic cell populations with short-term repopulating activity selectively engraft NOD/SCID-beta2 microglobulin-null mice.J. Clin. Invest. 2001; 107: 199-206Crossref PubMed Google Scholar, Notta et al., 2011Notta F. Doulatov S. Laurenti E. Poeppl A. Jurisica I. Dick J.E. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment.Science. 2011; 333: 218-221Crossref PubMed Scopus (157) Google Scholar). In addition, production of different cell types in xenografts is temporally restricted. For instance, nucleated erythrocytes are found in the marrow 2–4 weeks after transplant, but they typically do not persist. On the other hand, thymic engraftment is not observed until 12 weeks after transplant, and peripheral T cells appear even later. At any given time point, not all lineages may be readily assayed, requiring careful kinetic assessment. These caveats notwithstanding, xenograft models can now be used to track self-renewal and multilineage output of single human cells over 8 months, fulfilling stringent criteria for HSCs (Notta et al., 2011Notta F. Doulatov S. Laurenti E. Poeppl A. Jurisica I. Dick J.E. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment.Science. 2011; 333: 218-221Crossref PubMed Scopus (157) Google Scholar). Formative studies in stem cell biology have been carried out in mice. Mouse HSCs were first isolated as a lineage-negative (Lin–), c-Kit+, Sca-1+ (LSK) population (Ikuta and Weissman, 1992Ikuta K. Weissman I.L. Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation.Proc. Natl. Acad. Sci. USA. 1992; 89: 1502-1506Crossref PubMed Google Scholar, Spangrude et al., 1988Spangrude G.J. Heimfeld S. Weissman I.L. Purification and characterization of mouse hematopoietic stem cells.Science. 1988; 241: 58-62Crossref PubMed Google Scholar). Within this subset, CD34– cells possess the unique capacity for long-term multilineage reconstitution and self-renewal (Osawa et al., 1996Osawa M. Hanada K. Hamada H. Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell.Science. 1996; 273: 242-245Crossref PubMed Google Scholar). About one in two or three CD34– LSK cells, alternatively defined by the CD150+CD48– SLAM phenotype, possess LT-HSC activity (Kiel et al., 2005Kiel M.J. Yilmaz O.H. Iwashita T. Terhorst C. Morrison S.J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells.Cell. 2005; 121: 1109-1121Abstract Full Text Full Text PDF PubMed Scopus (1341) Google Scholar, Osawa et al., 1996Osawa M. Hanada K. Hamada H. Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell.Science. 1996; 273: 242-245Crossref PubMed Google Scholar). The ability to isolate purified HSCs has led to the detailed analysis of their transcriptional and epigenetic status (Ji et al., 2010Ji H. Ehrlich L.I. Seita J. Murakami P. Doi A. Lindau P. Lee H. Aryee M.J. Irizarry R.A. Kim K. et al.Comprehensive methylome map of lineage commitment from haematopoietic progenitors.Nature. 2010; 467: 338-342Crossref PubMed Scopus (204) Google Scholar, Ivanova et al., 2002Ivanova N.B. Dimos J.T. Schaniel C. Hackney J.A. Moore K.A. Lemischka I.R. A stem cell molecular signature.Science. 2002; 298: 601-604Crossref PubMed Scopus (969) Google Scholar, Ramalho-Santos et al., 2002Ramalho-Santos M. Yoon S. Matsuzaki Y. Mulligan R.C. Melton D.A. “Stemness”: transcriptional profiling of embryonic and adult stem cells.Science. 2002; 298: 597-600Crossref PubMed Scopus (1132) Google Scholar). This detailed cellular picture of murine hematopoietic development (Figure 2A ) combined with robust genetic approaches is beginning to unlock the molecular and biochemical pathways that underlie HSC function (Orkin and Zon, 2008Orkin S.H. Zon L.I. Hematopoiesis: an evolving paradigm for stem cell biology.Cell. 2008; 132: 631-644Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar). The major classes of stem and progenitor cells described in the text are defined by cell surface phenotypes, which are listed next to each population and in the gray bars below each schematic. Terminally" @default.
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• W1982202983 date "2012-02-01" @default.
• W1982202983 modified "2023-10-16" @default.
• W1982202983 title "Hematopoiesis: A Human Perspective" @default.
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