scholarly journals “Hierarchy” and “Holacracy”; A Paradigm of the Hematopoietic System

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1138 ◽  
Author(s):  
Takafumi Yokota
Keyword(s):  
Stem Cells ◽  
Network Theory ◽  
Extramedullary Hematopoiesis ◽  
Social Network Theory ◽  
New Paradigm ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Cast Doubt ◽  
Homeostatic State ◽  
Clonal Assays

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.

scholarly journals UTX maintains functional integrity of murine hematopoietic system by globally regulating aging-associated genes

Blood ◽  
2020 ◽  
Author(s):  
Yasuyuki Sera ◽  
Yuichiro Nakata ◽  
Takeshi Ueda ◽  
Norimasa Yamasaki ◽  
Shuhei Koide ◽  
...  
Keyword(s):  
Stem Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Extramedullary Hematopoiesis ◽  
Rna Seq ◽  
Dna Double Strand Breaks ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Expression Of Genes ◽  
Hematopoietic Disorders

Epigenetic regulation is essential for the maintenance of the hematopoietic system, and its deregulation is implicated in hematopoietic disorders. Here, we show that UTX, a demethylase for lysine 27 on histone H3 (H3K27) and a component of Compass-like and SWI/SNF complexes, plays an essential role in the hematopoietic system by globally regulating aging-associated genes. Utx-deficient (UtxΔ/Δ) mice exhibited myeloid skewing with dysplasia, extramedullary hematopoiesis, impaired hematopoietic reconstituting ability, and increased susceptibility to leukemia, which are the hallmarks of hematopoietic aging. RNA-sequencing (RNA-seq) analysis revealed that Utx deficiency converted the gene expression profiles of young hematopoietic stem-progenitor cells (HSPCs) to those of aged HSPCs. Utx expression in HSCs declines with age and UtxΔ/Δ HSPCs exhibited increased expression of an aging-associated marker, accumulation of reactive oxygen species, and impaired repair of DNA double-strand breaks. Pathway and chromatin immunoprecipitation (ChIP) analyses coupled with RNA-seq data indicated that UTX contributes to hematopoietic homeostasis mainly by maintaining the expression of genes downregulated with aging, via both demethylase-dependent and -independent epigenetic programming. Of note, comparison of pathway changes in UtxΔ/Δ HSPCs, aged muscle stem cells, aged fibroblasts, and aged iPS-induced neuronal cells showed substantial overlap, strongly suggesting common aging mechanisms among different tissue stem cells.

scholarly journals Deletion of PI3-Kinase Promotes Myelodysplasia Through Dysregulation of Autophagy in Hematopoietic Stem Cells

2020 ◽  
Author(s):  
Kristina Ames ◽  
Imit Kaur ◽  
Yang Shi ◽  
Meng Tong ◽  
Taneisha Sinclair ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Akt Pathway ◽  
Hematopoietic Growth Factors ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Phosphoinositide 3 Kinase

AbstractHematopoietic stem cells (HSCs) maintain the blood system through a delicate equilibrium between self-renewal and differentiation. Most hematopoietic growth factors and cytokines signal through phosphoinositide 3-kinase (PI3K) via three Class IA catalytic PI3K isoforms (P110α, β, and δ), encoded by Pik3ca, Pik3cb, and Pik3cd, respectively. The PI3K/AKT pathway is commonly activated in acute myeloid leukemia (AML), and PI3K is a common therapeutic target in cancer. However, it is not known whether PI3K is required for HSC differentiation or self-renewal. We previously demonstrated that individual PI3K isoforms are dispensable in HSCs1,2. To determine the redundant roles of PI3K isoforms in HSCs, we generated a triple knockout (TKO) mouse model with deletion of all three Class IA PI3K isoforms in the hematopoietic system. Surprisingly, we observed significant expansion of TKO HSCs after transplantation, with decreased differentiation capacity and impaired multilineage repopulation. Additionally, the bone marrow of TKO mice exhibited myelodysplastic features with chromosomal abnormalities. Interestingly, we found that macroautophagy (thereafter autophagy) is impaired in TKO HSCs, and that pharmacologic induction of autophagy improves their differentiation. Therefore, we have uncovered important roles for PI3K in autophagy regulation in HSCs to maintain the balance between self-renewal and differentiation.

Haploinsufficiency of AML1 results in a decrease in the number of LTR-HSCs while simultaneously inducing an increase in more mature progenitors

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3565-3572 ◽  
Author(s):  
Weili Sun ◽  
James R. Downing
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Normal Limits ◽  
Platelet Disorder ◽  
Familial Platelet Disorder ◽  
Transcriptional Complex

The AML1/CBFβ transcriptional complex is essential for the formation of definitive hematopoietic stem cells (HSCs). Moreover, development of the hematopoietic system is exquisitely sensitive to the level of this complex. To investigate the effect of AML1 dosage on adult hematopoiesis, we compared the hematopoietic systems of AML1+/– and AML1+/+ mice. Surprisingly, loss of a single AML1 allele resulted in a 50% reduction in long-term repopulating hematopoietic stem cells (LTR-HSCs). This decrease did not, however, extend to the next level of hematopoietic differentiation. Instead, AML1+/– mice had an increase in multilineage progenitors, an expansion that resulted in enhanced engraftment following transplantation. The expanded pool of AML1+/– progenitors remained responsive to homeostatic mechanisms and thus the number of mature cells in most lineages remained within normal limits. Two notable exceptions were a decrease in CD4+ T cells, leading to an inversion of the CD4+ to CD8+ T-cell ratio and a decrease in circulating platelets. These data demonstrate a dosage-dependent role for AML1/CBFβ in regulating the quantity of HSCs and their downstream committed progenitors, as well as a more restricted role in T cells and platelets. The latter defect mimics one of the key abnormalities in human patients with the familial platelet disorder resulting from AML1 haploinsufficiency.

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 Prdm16 is a physiologic regulator of hematopoietic stem cells

Blood ◽  
2011 ◽  
Vol 117 (19) ◽  
pp. 5057-5066 ◽  
Author(s):  
Francesca Aguilo ◽  
Serine Avagyan ◽  
Amy Labar ◽  
Ana Sevilla ◽  
Dung-Fang Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Fetal Liver ◽  
Feedback Loops ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Number Of Genes ◽  
Adult Bone ◽  
Deficient Mice

Abstract Fetal liver and adult bone marrow hematopoietic stem cells (HSCs) renew or differentiate into committed progenitors to generate all blood cells. PRDM16 is involved in human leukemic translocations and is expressed highly in some karyotypically normal acute myeloblastic leukemias. As many genes involved in leukemogenic fusions play a role in normal hematopoiesis, we analyzed the role of Prdm16 in the biology of HSCs using Prdm16-deficient mice. We show here that, within the hematopoietic system, Prdm16 is expressed very selectively in the earliest stem and progenitor compartments, and, consistent with this expression pattern, is critical for the establishment and maintenance of the HSC pool during development and after transplantation. Prdm16 deletion enhances apoptosis and cycling of HSCs. Expression analysis revealed that Prdm16 regulates a remarkable number of genes that, based on knockout models, both enhance and suppress HSC function, and affect quiescence, cell cycling, renewal, differentiation, and apoptosis to various extents. These data suggest that Prdm16 may be a critical node in a network that contains negative and positive feedback loops and integrates HSC renewal, quiescence, apoptosis, and differentiation.

Hematopoiesis in the Elderly: Age-Associated Effects in Frequency, Function, and Gene Expression of Human Hematopoietic Stem Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1505-1505
Author(s):  
Wendy W. Pang ◽  
Elizabeth A. Price ◽  
Irving L. Weissman ◽  
Stanley L. Schrier
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stem Cells ◽  
Bone Marrow ◽  
Expression Profiles ◽  
Frequency Function ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Cell Cycle Status

Abstract Abstract 1505 Poster Board I-528 Aging of the human hematopoietic system is associated with an increase in the development of anemia, myeloid malignancies, and decreased adaptive immune function. While the hematopoietic stem cell (HSC) population in mouse has been shown to change both quantitatively as well as functionally with age, age-associated alterations in the human HSC and progenitor cell populations have not been characterized. In order to elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated and compared HSC and other hematopoietic progenitor populations prospectively isolated via fluorescence activated cell sorting (FACS) from 10 healthy young (20-35 years of age) and 8 healthy elderly (65+ years of age) human bone marrow samples. Bone marrow was obtained from hematologically normal young and old volunteers, under a protocol approved by the Stanford Institutional Review Board. We determined by flow cytometry the distribution frequencies and cell cycle status of HSC and progenitor populations. We also analyzed the in vitro function and generated gene expression profiles of the sorted HSC and progenitor populations. We found that bone marrow samples obtained from normal elderly adults contain ∼2-3 times the frequency of immunophenotypic HSC (Lin-CD34+CD38-CD90+) compared to bone marrow obtained from normal young adults (p < 0.02). Furthermore, upon evaluation of cell cycle status using RNA (Pyronin-Y) and DNA (Hoechst 33342) dyes, we observed that a greater percentage of HSC from young bone marrow are in the quiescent G0- phase of the cell cycle compared to elderly HSC, of which there is a greater percentage in G1-, S-, G2-, or M-phases of the cell cycle (2.5-fold difference; p < 0.03). In contrast to the increase in HSC frequency, we did not detect any significant differences in the frequency of the earliest immunophenotypic common myeloid progenitors (CMP; Lin-CD34+CD38+CD123+CD45RA-), granulocyte-macrophage progenitors (GMP; Lin-CD34+CD38+CD123+CD45RA+), and megakaryocytic-erythroid progenitors (MEP; Lin-CD34+CD38+CD123-CD45RA-) from young and elderly bone marrow. We next analyzed the ability of young and elderly HSC to differentiate into myeloid and lymphoid lineages in vitro. We found that elderly HSC exhibit diminished capacity to differentiate into lymphoid B-lineage cells in the AC6.21 culture environment. We did not, however, observe significant differences in the ability of young and elderly HSC to form myeloid and erythroid colonies in methylcellulose culture, indicating that myelo-erythroid differentiation capacity is preserved in elderly HSC. Correspondingly, gene expression profiling of young and elderly human HSC indicate that elderly HSC have up-regulation of genes that specify myelo-erythroid fate and function and down-regulation of genes associated with lymphopoiesis. Additionally, elderly HSC exhibit increased levels of transcripts associated with transcription, active cell-cycle, cell growth and proliferation, and cell death. These data suggest that hematopoietic aging is associated with intrinsic changes in the gene expression of human HSC that reflect the quantitative and functional alterations of HSC seen in elderly bone marrow. In aged individuals, HSC are more numerous and, as a population, are more myeloid biased than young HSC, which are more balanced in lymphoid and myeloid potential. We are currently investigating the causes of and mechanisms behind these highly specific age-associated changes in human HSC. Disclosures: Weissman: Amgen: Equity Ownership; Cellerant Inc.: ; Stem Cells Inc.: ; U.S. Patent Application 11/528,890 entitled “Methods for Diagnosing and Evaluating Treatment of Blood Disorders.”: Patents & Royalties.

Periostin Acts As An Important Cell Cycle Regulator Of Adult Hematopoietic Stem Cells Via Binding To Integrin-αvβ3

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 341-341 ◽  
Author(s):  
Satish Khurana ◽  
Catherine M. Verfaillie
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Conflicts Of Interest ◽  
Integrin Αvβ3 ◽  
Brdu Incorporation ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Cell Cycle Regulator ◽  
Blocking Antibodies

Osteoblasts are one of the important cellular components of the niche for hematopoietic stem cells (HSCs) in mammalian bone marrow (BM). Integrin receptors not only play a key role in HSC adhesion within the BM niche but also transfer regulatory signals from the microenvironment to HSCs. Periostin (Postn or osteoblast specific factor-1; OSF-1) is expressed in osteoblasts in addition to many other tissues, and acts as a ligand for Integrin-αvβ3 (ITGAV-B3). We identified POSTN as an important regulator of the cell cycle in adult murine HSCs. POSTN inhibited culture induced proliferation of HSCs thereby decreasing the total number of cells following 2-5 day culture of primitive HSCs, identified as CD150+CD48-Lin-Sca-1+c-kit+ (CD150 KLS) cells with SCF and TPO, while increasing the proportion of long-term (LT-) HSCs. Culture for 5 days with POSTN decreased the short-term (ST-) engraftment of progeny of 200 CD150 KLS cells, while significantly increasing LT- engraftment of the donor derived cells. A significant fraction of CD150 KLS cells expressed ITGAV as well as ITGB3. POSTN did not affect proliferation of HSCs in vitro following blocking of ITGAV with neutralizing antibodies. Among the important cell cycle regulators, we found an increase in p27kip1 expression in HSCs. Preliminary studies on possible signaling mechanisms involved, showed that POSTN inhibits Akt phosphorylation, known to mediate inhibition of both expression and activation of p27Kip1. Intravenous infusion of recombinant POSTN protein significantly decreased proliferation of hematopoietic progenitors as shown by Brdu incorporation and Hoechst/Pyronin staining. Interestingly, POSTN infusion also led to an increase in the number of KLS as well as CD150 KLS cells in the BM. Studies on characterization of the hematopoietic system of Postn-/- mice are underway. To further determine the role of ITGAV in HSCs, we used blocking antibodies against ITGAV and performed homing and engraftment studies. No effect on either homing potential or engraftment of ST- and LT- engraftment was seen. However, the competitive repopulation of ITGAV- CD150 KLS cells was significantly lower that that of ITGAV+ CD150 KLS cells (isolated using non-blocking antibodies). Therefore, our studies confirm the importance of ITGAV expression on primitive HSCs as well as presents POSTN as an important cell cycle regulator in the hematopoietic system. Disclosures: No relevant conflicts of interest to declare.

Role of the WT1 tumor suppressor in murine hematopoiesis

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2570-2574 ◽  
Author(s):  
Julia A. Alberta ◽  
Gregory M. Springett ◽  
Helen Rayburn ◽  
Thomas A. Natoli ◽  
Janet Loring ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tumor Suppressor ◽  
Fetal Liver ◽  
Hematopoietic Cells ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Colony Forming Unit ◽  
Organ Systems

The WT1 tumor-suppressor gene is expressed by many forms of acute myeloid leukemia. Inhibition of this expression can lead to the differentiation and reduced growth of leukemia cells and cell lines, suggesting that WT1 participates in regulating the proliferation of leukemic cells. However, the role of WT1 in normal hematopoiesis is not well understood. To investigate this question, we have used murine cells in which the WT1 gene has been inactivated by homologous recombination. We have found that cells lacking WT1 show deficits in hematopoietic stem cell function. Embryonic stem cells lacking WT1, although contributing efficiently to other organ systems, make only a minimal contribution to the hematopoietic system in chimeras, indicating that hematopoietic stem cells lacking WT1 compete poorly with healthy stem cells. In addition, fetal liver cells lacking WT1 have an approximately 75% reduction in erythroid blast-forming unit (BFU-E), erythroid colony-forming unit (CFU-E), and colony-forming unit–granulocyte macrophage–erythroid–megakaryocyte (CFU-GEMM). However, transplantation of fetal liver hematopoietic cells lackingWT1 will repopulate the hematopoietic system of an irradiated adult recipient in the absence of competition. We conclude that the absence of WT1 in hematopoietic cells leads to functional defects in growth potential that may be of consequence to leukemic cells that have alterations in the expression of WT1.

scholarly journals Stem Cell Fate Analysis Revisited: Interpretation of Individual Clone Dynamics in the Light of a New Paradigm of Stem Cell Organization

2007 ◽  
Vol 2007 ◽  
pp. 1-9 ◽  
Author(s):  
Ingo Roeder ◽  
Katrin Braesel ◽  
Ronny Lorenz ◽  
Markus Loeffler
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Hematopoietic Stem Cell ◽  
Cell System ◽  
New Paradigm ◽  
Hematopoietic Stem ◽  
Cell Organization ◽  
Experimental Findings ◽  
Self Organizing

Many experimental findings on heterogeneity, flexibility, and plasticity of tissue stem cells are currently challenging stem cell concepts that assume a cell intrinsically predefined, unidirectional differentiation program. In contrast to these classical concepts, nonhierarchical self-organizing systems provide an elegant and comprehensive alternative to explain the experimental data. Here we present the application of such a self-organizing concept to quantitatively describe the hematopoietic stem cell system. Focusing on the analysis of individual-stem-cell fates and clonal dynamics, we particularly discuss implications of the theoretical results on the interpretation of experimental findings. We demonstrate that it is possible to understand hematopoietic stem cell organization without assumptions on unidirectional developmental hierarchies, preprogrammed asymmetric division events or other assumptions implying the existence of a predetermined stem cell entity. The proposed perspective, therefore, changes the general paradigm of thinking about stem cells.

Analysis of the hematopoietic potential of muscle-derived cells in mice

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 721-723 ◽  
Author(s):  
Hartmut Geiger ◽  
Jarrod M. True ◽  
Barry Grimes ◽  
Elizabeth J. Carroll ◽  
Roger A. Fleischman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Muscle Tissue ◽  
Cell Sorting ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Muscle Stem Cells ◽  
Antibody Staining ◽  
Stem And Progenitor Cells

Abstract Cells in murine muscle have been reported to differentiate into hematopoietic stem and progenitor cells and thus repopulate the hematopoietic system of an irradiated animal. This activity was attributed to muscle stem cells. We used an in vitro and in vivo approach to identify the hematopoietic repopulating activity found in muscle tissue of mice by antibody staining and cell sorting. We confirmed existence of a hematopoietic repopulating cell in muscle tissue, but the data strongly suggest that repopulation is due not to muscle stem cells but to hematopoietic cells present in muscle tissue. Unexpectedly, the blood-forming cells were enriched in muscle relative to their frequency in peripheral blood.

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