The human stem cell hierarchy is defined by a functional dependence on Mcl-1 for self-renewal capacity

Blood ◽  
2010 ◽  
Vol 116 (9) ◽  
pp. 1433-1442 ◽  
Author(s):  
Clinton J. V. Campbell ◽  
Jung Bok Lee ◽  
Marilyne Levadoux-Martin ◽  
Tracy Wynder ◽  
Anargyros Xenocostas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Functional Dependence ◽  
Family Members ◽  
Human Stem Cell ◽  
Human Stem Cells ◽  
Renewal Function ◽  
Self Renewal ◽  
Stem Cell Hierarchy

The molecular basis for the unique proliferative and self-renewal properties that hierarchically distinguish human stem cells from progenitors and terminally differentiated cells remains largely unknown. We report a role for the Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) as an indispensable regulator of self-renewal in human stem cells and show that a functional dependence on Mcl-1 defines the human stem cell hierarchy. In vivo pharmacologic targeting of the Bcl-2 family members in human hematopoietic stem cells (HSCs) and human leukemic stem cells reduced stem cell regenerative and self-renewal function. Subsequent protein expression studies showed that, among the Bcl-2 family members, only Mcl-1 was up-regulated exclusively in the human HSC fraction on in vivo regeneration of hematopoiesis. Short hairpin RNA–knockdown of Mcl-1 in human cord blood cells did not affect survival in the HSC or hematopoietic progenitor cell fractions in vitro but specifically reduced the in vivo self-renewal function of human HSCs. Moreover, knockdown of Mcl-1 in ontogenetically primitive human pluripotent stem cells resulted in almost complete ablation of stem cell self-renewal function. Our findings show that Mcl-1 is an essential regulator of stem cell self-renewal in humans and therefore represents an axis for therapeutic interventions.

scholarly journals Functional Properties of Human Stem Cell-Derived Neurons in Health and Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Jason P. Weick
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Functional Properties ◽  
New Technologies ◽  
Synaptic Activity ◽  
Model Systems ◽  
Phenotypic Characterization ◽  
Human Stem Cell ◽  
Human Stem Cells

Stem cell-derived neurons from various source materials present unique model systems to examine the fundamental properties of central nervous system (CNS) development as well as the molecular underpinnings of disease phenotypes. In order to more accurately assess potential therapies for neurological disorders, multiple strategies have been employed in recent years to produce neuronal populations that accurately representin vivoregional and transmitter phenotypes. These include new technologies such as direct conversion of somatic cell types into neurons and glia which may accelerate maturation and retain genetic hallmarks of aging. In addition, novel forms of genetic manipulations have brought human stem cells nearly on par with those of rodent with respect to gene targeting. For neurons of the CNS, the ultimate phenotypic characterization lies with their ability to recapitulate functional properties such as passive and active membrane characteristics, synaptic activity, and plasticity. These features critically depend on the coordinated expression and localization of hundreds of ion channels and receptors, as well as scaffolding and signaling molecules. In this review I will highlight the current state of knowledge regarding functional properties of human stem cell-derived neurons, with a primary focus on pluripotent stem cells. While significant advances have been made, critical hurdles must be overcome in order for this technology to support progression toward clinical applications.

scholarly journals Silencing of long noncoding RNA HOXA11-AS inhibits the Wnt signaling pathway via the upregulation of HOXA11 and thereby inhibits the proliferation, invasion, and self-renewal of hepatocellular carcinoma stem cells

2019 ◽  
Vol 51 (11) ◽  
pp. 1-20 ◽  
Author(s):  
Jun-Cheng Guo ◽  
Yi-Jun Yang ◽  
Jin-Fang Zheng ◽  
Jian-Quan Zhang ◽  
Min Guo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Methylation Level ◽  
Wnt Signaling Pathway ◽  
The Self ◽  
Self Renewal

AbstractHepatocellular carcinoma (HCC) is a major cause of cancer-related deaths, but its molecular mechanisms are not yet well characterized. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis, including that of HCC. However, the role of homeobox A11 antisense (HOXA11-AS) in determining HCC stem cell characteristics remains to be explained; hence, this study aimed to investigate the effects of HOXA11-AS on HCC stem cell characteristics. Initially, the expression patterns of HOXA11-AS and HOXA11 in HCC tissues, cells, and stem cells were determined. HCC stem cells, successfully sorted from Hep3B and Huh7 cells, were transfected with short hairpin or overexpression plasmids for HOXA11-AS or HOXA11 overexpression and depletion, with an aim to study the influences of these mediators on the self-renewal, proliferation, migration, and tumorigenicity of HCC stem cells in vivo. Additionally, the potential relationship and the regulatory mechanisms that link HOXA11-AS, HOXA11, and the Wnt signaling pathway were explored through treatment with Dickkopf-1 (a Wnt signaling pathway inhibitor). HCC stem cells showed high expression of HOXA11-AS and low expression of HOXA11. Both HOXA11-AS silencing and HOXA11 overexpression suppressed the self-renewal, proliferation, migration, and tumorigenicity of HCC stem cells in vivo, as evidenced by the decreased expression of cancer stem cell surface markers (CD133 and CD44) and stemness-related transcription factors (Nanog, Sox2, and Oct4). Moreover, silencing HOXA11-AS inactivated the Wnt signaling pathway by decreasing the methylation level of the HOXA11 promoter, thereby inhibiting HCC stem cell characteristics. Collectively, this study suggested that HOXA11-AS silencing exerts an antitumor effect, suppressing HCC development via Wnt signaling pathway inactivation by decreasing the methylation level of the HOXA11 promoter.

scholarly journals Clonal-level lineage commitment pathways of hematopoietic stem cells in vivo

2019 ◽  
Vol 116 (4) ◽  
pp. 1447-1456 ◽  
Author(s):  
Rong Lu ◽  
Agnieszka Czechowicz ◽  
Jun Seita ◽  
Du Jiang ◽  
Irving L. Weissman
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Lineage Commitment ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Different Levels

While the aggregate differentiation of the hematopoietic stem cell (HSC) population has been extensively studied, little is known about the lineage commitment process of individual HSC clones. Here, we provide lineage commitment maps of HSC clones under homeostasis and after perturbations of the endogenous hematopoietic system. Under homeostasis, all donor-derived HSC clones regenerate blood homogeneously throughout all measured stages and lineages of hematopoiesis. In contrast, after the hematopoietic system has been perturbed by irradiation or by an antagonistic anti-ckit antibody, only a small fraction of donor-derived HSC clones differentiate. Some of these clones dominantly expand and exhibit lineage bias. We identified the cellular origins of clonal dominance and lineage bias and uncovered the lineage commitment pathways that lead HSC clones to different levels of self-renewal and blood production under various transplantation conditions. This study reveals surprising alterations in HSC fate decisions directed by conditioning and identifies the key hematopoiesis stages that may be manipulated to control blood production and balance.

scholarly journals Spatial Distributions, Characteristics, and Applications of Craniofacial Stem Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Geru Zhang ◽  
Qiwen Li ◽  
Quan Yuan ◽  
Shiwen Zhang
Keyword(s):  
Stem Cells ◽  
Spatial Distribution ◽  
Stem Cell ◽  
Cranial Sutures ◽  
Stem Cell Markers ◽  
Spatial Distributions ◽  
Self Renewal ◽  
Stem Cell Niches ◽  
Multidirectional Differentiation

Stem cells play an irreplaceable role in the development, homeostasis, and regeneration of the craniofacial bone. Multiple populations of tissue-resident craniofacial skeletal stem cells have been identified in different stem cell niches, including the cranial periosteum, jawbone marrow, temporomandibular joint, cranial sutures, and periodontium. These cells exhibit self-renewal and multidirectional differentiation abilities. Here, we summarized the properties of craniofacial skeletal stem cells, based on their spatial distribution. Specifically, we focused on the in vivo genetic fate mapping of stem cells, by exploring specific stem cell markers and observing their lineage commitment in both the homeostatic and regenerative states. Finally, we discussed their application in regenerative medicine.

Inhibition of Chronic Myelogenous Leukemia Stem Cells with Novel Wnt Antagonists.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 238-238 ◽  
Author(s):  
Edward Kavalerchik ◽  
Jason Gotlib ◽  
Ifat Geron ◽  
Annelie Abrahamsson ◽  
Wolfgang Wrasidlo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Chronic Myelogenous Leukemia ◽  
Reporter Gene ◽  
Myelogenous Leukemia ◽  
Beta Catenin ◽  
Self Renewal ◽  
Leukemia Stem Cell ◽  
Wnt Inhibitors

Abstract Introduction A growing proportion of chronic myelogenous leukemia (CML) patients show evidence of disease progression. Recent research suggests that leukemia stem cells (LSC) that share phenotypic characteristics with granulocyte-macrophage progenitors (GMP) are involved in CML progression. These LSC have aberrantly gained self-renewal capacity as a result of enhanced Wnt/beta-catenin signaling. We assayed the capacity of novel Wnt/beta-catenin antagonists to inhibit CML LSC. Methods To assay the efficacy of a novel Wnt inhibitor, MC-001, HEK293 cells were transfected with a Wnt-dependent reporter gene and expression plasmid for Dsh. After 16h, the cells were treated for 24 h with MCC-001, a novel marine sponge derived inhibitor, at varying concentrations and the reporter gene activity was measured. All cells were also transfected with a b-gal reporter gene to control for transfection efficiency. To assess the effects of MCC-001 and other Wnt inhibitors on Wnt/beta-catenin induced self-renewal, hematopoietic stem cells (HSC), GMP and lineage positive cells from normal (n=8) and advanced phase CML (n=8) peripheral blood and marrow (n=8) were clone sorted with the aid of a FACS Aria into methocult media (Stem Cell Technologies) with or without Wnt inhibitors including recombinant Dkk1, lentiviral axin or MCC-001. On day 10, individual colonies were plucked and replated in new methylcellulose and the replating efficiency determined at day 10. To establish an in vivo CML LSC model, HSC, GMP and lineage positive cells were transduced with a lentiviral luciferase GFP for 48 hours and transplanted intrahepatically into newborn immunocompromised mice (RAG2−/−gamma−/−) mice that facilitate high levels of human hematopoietic progenitor engraftment. Results The HEK293 beta-catenin reporter assay revealed that the MC-001 IC50 was 2.1 microM. In comparative Wnt inhibitor replating assays (n=8), recombinant Dkk1 did not inhibit CML HSC (n=8) while lentiviral axin and MCC-001 (at 2 and 10 microM) inhibited both CML HSC and CML GMP at doses that spared normal HSC replating (Figure 1). Transplantation of CML HSC, GMP and lineage positive cells into RAG2−/−gamma−/− mice demonstrated that only CML GMP provided serial transplantation potential and thus, were enriched for the LSC population (Figure 2). Conclusions Selective Wnt/beta-catenin inhibition with a marine sponge derived beta-catenin antagonist, MCC-001, blocks in vitro replating capacity of CML LSC at doses that spare normal HSC. Current experiments focus on in vivo inhibition of LSC self-renewal with novel Wnt inhibitors in a robust CML LSC bioluminescent imaging model (Figure 2). Figure 1. Chronic Myelogenous Leukemia Stem Cell Inhibition with MCC-001: A novel β-catenin Inhibitor Figure 1. Chronic Myelogenous Leukemia Stem Cell Inhibition with MCC-001: A novel β-catenin Inhibitor Figure 2. Bioluminescent Chronic Myelogenous Leukemia Stem Cell Transplantation Model. Figure 2. Bioluminescent Chronic Myelogenous Leukemia Stem Cell Transplantation Model.

Hematopoietic Stem Cell Cycling Dynamics In Steady State and Upon Hematopoietic Challenge

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 572-572
Author(s):  
Hitoshi Takizawa ◽  
Chandra S Boddupalli ◽  
Roland R Regoes ◽  
Sebastian Bonhoeffer ◽  
Markus G Manz
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Steady State ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Naturally Occurring ◽  
Blood Formation ◽  
Serial Transplantation ◽  
Limiting Dilution

Abstract Abstract 572 Life-long blood production is maintained by a small fraction of hematopoietic stem cells (HSCs). Steady-state HSC cycling kinetics have been evaluated by in vivo labeling assays with 5-bromo-2-deoxyuridine (BrdU) (Cheshier et. al., PNAS 1999; Kiel et al., Nature 2007), biotin (Nygren et. al., 2008) and histon 2B-green fluorescent protein (H2B-GFP) transgenic mouse models (Wilson et. al., 2008; Foudi et. al., 2009). While the former studies showed that all HSCs equally divide and likely contribute to blood formation (clonal maintenance), the latter suggested that some HSCs divide frequently and contribute to blood formation until cell death or full differentiation, while some HSCs are quiescent and then get activated to follow the same fate as frequently dividing ones (clonal succession). However, due to low resolution, none of the labeling techniques used were able to track single cell divisions. Furthermore, methods used might have direct influence on cycling activity of HSCs. Thus it remains to be determined a) if HSC divide continuously, sequentially or repetitively and contribute to steady-state hematopoiesis, b) what is a relationship between divisional history and repopulating ability, and c) how self-renewal and differentiation capacity of HSC is impacted by naturally-occurring severe hematopoietic challenges as infections. To address this directly, we set up a high resolution non-invasive in vivo HSC divisional tracking assay with CFSE (carboxyfluorescein diacetate succinimidyl ester). We here show that i.v. transfer of CFSE-labeled HSCs into non-conditioned congenic recipient mice allows evaluation of steady-state HSC cycling-dynamics as CFSE is equally distributed to daughter cells upon cellular division. Transfer of Lin-c-kit+Sca-1+ cells (LKS) into non-irradiated mice revealed non- and 1–7x divided LKS in recipient bone marrow over 20 weeks. To test in vivo limiting dilution and single cell HSC potential, non- or ≥5x divided cells were sorted based on divisional history from primary recipients at different weeks after transplantation, and transplanted into lethally irradiated secondary recipients. Single non-divided LKS at 3 weeks post primary transfer was able to multi-lineage repopulate 24% of recipients long-term, while 50 of ≥5x divided LKS did not engraft. Interestingly, both non- and ≥5x divided LKS at 7 or 12–14 weeks after primary transfer engrafted and showed fluctuating contribution to multi-lineage hematopoiesis over serial transplantation. Mathematical modeling based on limiting dilution transplantation, revealed no evidence for a dichotomy of biologically defined HSCs in different groups. Instead, steady-state serial transplantation with temporary fast-cycling cells revealed that they can slow down over time, suggesting dynamically changing cycling activity of HSC. We next tested the effects of hemato-immunological challenge on HSC proliferation. Mice transplanted with CFSE-labeled LKS cells were repetitively treated with LPS. Analysis 8 days after final LPS injection, i.e. three weeks after steady-state transplantation revealed that all LKS entered cell cycle and the number of ≥5x divided LKS was increased. Secondary transplantation showed that 2–4 time and ≥5x divided LKS from LPS-treated mice reconstituted multi-lineage hematopoiesis whereas both fractions from control mice failed to engraft. This data clearly indicate that HSCs are activated from quiescence upon LPS challenge and provide evidence, that naturally-occurring hemato-immunological challenges, such as gram-negative bacterial infection induces proliferation and self-renewal of HSCs. Our data suggest in contrast to previously proposed concepts, a novel “dynamic repetition” model for HSC cycling activity and blood formation where some HSCs participate in hematopoiesis for a while, subsequently enter a resting phase and get reactivated again to contribute to blood formation in repetitive cycles, leading to homogenous total divisional history of all HSCs at end of life. These findings might represent a biological principle that could hold true for other somatic stem cell-sustained organ-systems and might have developed during evolution to ensure equal distribution of work-load, efficient recruitment of stem cells during demand, and reduction of risk to acquire genetic alterations or fatal damage to the whole HSC population at any given time. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Are MSCs Stem Cells? Demonstration of in Vitro and in Vivo Stem Cell Properties of Highly Enriched linneg/CD45neg/CD271pos/CD140alow/Neg Mesenchymal Stromal Cells from Adult Human Bone Marrow

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4374-4374
Author(s):  
Roshanak Ghazanfari ◽  
Hongzhe Li ◽  
Dimitra Zacharaki ◽  
Simón Méndez-Ferrer ◽  
Stefan Scheding
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Adult Human

Abstract Human bone marrow contains a rare population of non-hematopoietic mesenchymal stromal cells (BM-MSC) with multilineage differentiation capacity, which are essential constituents of the hematopoietic microenvironment. Self-renewal and differentiation are the two key properties of somatic stem cells, however, stem cell properties of human adult BM-MSC have not been demonstrated conclusively yet. We have previously shown that low/negative expression of PDGFRα on linneg/CD45neg/CD271pos cells identified a highly enriched population of primary BM-MSC in adult human bone marrow (Li et al. Blood, 2013, 122:3699). Based on this work, the current study aimed to investigate the in-vitro and in-vivo stem cell properties of this putative stromal stem cell population. The in-vitro clonogenic potential of freshly sorted human linneg/CD45neg/CD271pos/PDGFRlow/neg cells was evaluated by utilizing the CFU-F assay as well as the recently-developed mesensphere assay, which enables MSC amplification while preserving an immature phenotype (Isern et al, Cell Reports 2013, 30: 1714-24). Comparable colony frequencies were obtained with both assays (19.3 ± 2 and 17.5 ± 2.3 CFU-F and spheres per 100 plated cells, respectively, n=6, p=0.19). In order to test whether both assays identified the same population of clonogenic cells, colonies and spheres were replated under both conditions for up to three generations. The results showed comparable capacities of CFU-F and mesenspheres to form secondary and tertiary CFU-F and spheres. In-vitro self-renewal as indicated by increasing numbers of CFU-F and spheres (416.6 ± 431.7-fold and 49.5 ± 65.7-fold, respectively, n=3) was observed up to the third generation and decreased thereafter. The total number of generations was five (CFU-F) and six (spheres). In-vitro differentiation assays with both, CFU-F- and sphere-derived cells (tested until passage three) demonstrated tri-lineage differentiation potential (adipocytes, osteoblasts, chondrocytes). In addition, CFU-Fs and spheres had comparable surface marker profiles (CD73, CD90, CD105, and HLA-ABC positive; CD31, CD34 and HLA-DR negative), except for CD90, which was higher expressed on CFU-Fs. To investigate in-vivo self-renewal and differentiation potential of the putative stromal stem cells, linneg/CD45neg/CD271pos/PDGFRlow/neg -derived CFU-F and spheres were serially transplanted s.c into NSG mice. After 8 weeks, implants were harvested, human cells were FACS-isolated (CD90 and CD105 expression), and re-assayed under CFU-F and sphere conditions. Whereas in-vivo self-renewal of CFU-F could not be shown (111.5 ± 36 –fold decrease in total CFU-F numbers after primary transplantation, n=3), sphere self-renewal was clearly demonstrated by increased numbers of spheres after primary as well as secondary transplantation (1.13 ± 0.05 and 2.06 ± 0.26 –fold, respectively, n=3), which is remarkable given the fact that the number of recovered human cells is underestimated due to the isolation approach. Here, confirming GFP-marking experiments are ongoing. Finally, preliminary data indicate that linneg/CD45neg/CD271pos/PDGFRlow/neg –derived spheres display full in-vivo differentiation capacity in primary and secondary transplantations. Taken together, our data demonstrate - for the first time - that primary human linneg/CD45neg/CD271pos/PDGFRlow/neg cells meet stringent stem cell criteria, i.e. in-vitro and in-vivo self-renewal and differentiation. These findings answer the long-open question of the potential stem cell properties of adult human MSC and will enable to better understand the properties of native BM-MSC and their biological role in the bone marrow. Disclosures No relevant conflicts of interest to declare.

Inactivation of p38 MAPK Extends Self-Renewal Capacity of Haematopoietic Stem Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 265-265
Author(s):  
Keisuke Ito ◽  
Atsushi Hirao ◽  
Fumio Arai ◽  
Sahoko Matsuoka ◽  
Keiyo Takubo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
P38 Mapk ◽  
Cell Population ◽  
Critical Role ◽  
Dependent Manner ◽  
Self Renewal ◽  
Haematopoietic Stem Cells ◽  
P38 Inhibitor

Abstract Haematopoietic stem cells (HSCs) undergo self-renewing cell divisions and maintain blood production for their lifetime. Appropriate control of HSC self-renewal is critical for maintenance of haematopoietic homeostasis. Here we show that activation of p38 MAPK limits lifespan of HSCs in response to increasing levels of reactive oxygen species (ROS) in vivo. Although normal quiescent HSCs maintain a low level of oxidative stress, an increase in ROS was observed in HSCs after transplantation as well as in aged mice. In vitro treatment with BSO (Buthionine sulfoximine), which depletes intra-cellular glutathion, increased ROS (H2O2) level in immature hematopoietic cell population, c-kit+Sca1+Lin- (KSL) cells, in a dose-dependent manner. Low dose concentration of BSO suppressed reconstitution capacity of HSCs, whereas higher concentration did not affect progenitors. These data indicate that HSCs are much more sensitive to increased ROS than progenitors and are consistent with our previous results from Atm−/− mice in which ROS level is elevated in vivo. Here we focused on MAPKs for the stem cell dysfunction since it has been shown that several MAPKs are activated in response to ROS. We evaluated effects of MAPK inhibitors for p38, JNK or ERK in incubation of KSL cell with BSO. p38 inhibitor (SB203580), neither JNK nor ERK inhibitor, restored reconstitution capacity of HSCs after transplantation, suggesting that activation of p38 may contributes to defect of stem cell function in vivo. To address the question, we evaluated p38 activation in Atm−/− BM cells by immunohistochemistry. Surprisingly, p38 protein was phosphorylated only in KSL cells, but not other more differentiated cell populations, despite that the ROS levels were comparable among the cell population of mice. In response to activation of p38, p16INK4a was up-regulated only in KSL cells. The data indicates a possibility that stem cell-specific p38 activation negatively regulates self-renewal of HSCs. We then investigated a role of p38 activation on self-renewal of HSCs in vivo. When p38 inhibitor was intraperitoneally administered both before and after BMT, the level of repopulation achieved was comparable to that of the wild-type. Furthermore, Atm−/− mice that received long-term p38 inhibitor treatment did not show either anemia, a decrease in progenitor colony-forming capacity, or reduced frequencies of stem cell subsets. These data demonstrate that the activation of p38 present in HSCs promotes the exhaustion of stem cell pool in response to elevation of ROS. It has been proposed that aging is driven in part by a gradual depletion of stem cell functional capacity. There are evidences that inappropriate production of oxidants is connected to aging and life span. We propose a possibility that p38 activation in response to ROS plays a critical role for limit of stem cell capacity.

Cellular and molecular basis of haematopoiesis

2020 ◽  
pp. 5172-5181
Author(s):  
Paresh Vyas ◽  
N. Asger Jakobsen
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Cell Number ◽  
Stages Of Development ◽  
Self Renewal ◽  
Haematopoietic System

Haematopoiesis involves a regulated set of developmental stages from haematopoietic stem cells (HSCs) that produce haematopoietic progenitor cells that then differentiate into more mature haematopoietic lineages, which provide all the key functions of the haematopoietic system. Definitive HSCs first develop within the embryo in specialized regions of the dorsal aorta and umbilical arteries and then seed the fetal liver and bone marrow. At the single-cell level, HSCs have the ability to reconstitute and maintain a functional haematopoietic system over extended periods of time in vivo. They (1) have a self-renewing capacity during the life of an organism, or even after transplantation; (2) are multipotent, with the ability to make all types of blood cells; and (3) are relatively quiescent, with the ability to serve as a deep reserve of cells to replenish short-lived, rapidly proliferation progenitors. Haematopoietic progenitor cells are unable to maintain long-term haematopoiesis in vivo due to limited or absent self-renewal. Rapid proliferation and cytokine responsiveness enables increased blood cell production under conditions of stress. Lineage commitment means limited cell type production. The haematopoietic stem cell niche is an anatomically and functionally defined regulatory environment for stem cells modulates self-renewal, differentiation, and proliferative activity of stem cells, thereby regulating stem cell number. Haematopoietic reconstitution during bone marrow transplantation is mediated by a succession of cells at various stages of development. More mature cells contribute to repopulation immediately following transplantation. With time, cells at progressively earlier stages of development are involved, with the final stable repopulation being provided by long-lived, multipotent HSCs. Long-term haematopoiesis is sustained by a relatively small number of HSCs.

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