scholarly journals Remodeling of Bone Marrow Niches and Roles of Exosomes in Leukemia

2021 ◽  
Vol 22 (4) ◽  
pp. 1881
Author(s):  
Takanori Yamaguchi ◽  
Eiji Kawamoto ◽  
Arong Gaowa ◽  
Eun Jeong Park ◽  
Motomu Shimaoka
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Chemotherapy Resistance ◽  
Leukemia Cell ◽  
Cell Communication ◽  
Leukemia Cells ◽  
Hematopoietic Stem ◽  
Functional Changes ◽  
Bone Marrow Niches

Leukemia is a hematological malignancy that originates from hematopoietic stem cells in the bone marrow. Significant progress has made in understanding its pathogensis and in establishing chemotherapy and hematopoietic stem cell transplantation therapy (HSCT). However, while the successive development of new therapies, such as molecular-targeted therapy and immunotherapy, have resulted in remarkable advances, the fact remains that some patients still cannot be saved, and resistance to treatment and relapse are still problems that need to be solved in leukemia patients. The bone marrow (BM) niche is a microenvironment that includes hematopoietic stem cells and their supporting cells. Leukemia cells interact with bone marrow niches and modulate them, not only inducing molecular and functional changes but also switching to niches favored by leukemia cells. The latter are closely associated with leukemia progression, suppression of normal hematopoiesis, and chemotherapy resistance, which is precisely the area of ongoing study. Exosomes play an important role in cell-to-cell communication, not only with cells in close proximity but also with those more distant due to the nature of exosomal circulation via body fluids. In leukemia, exosomes play important roles in leukemogenesis, disease progression, and organ invasion, and their usefulness in the diagnosis and treatment of leukemia has recently been reported. The interaction between leukemia cell-derived exosomes and the BM microenvironment has received particular attention. Their interaction is believed to play a very important role; in addition to their diagnostic value, exosomes could serve as a marker for monitoring treatment efficacy and as an aid in overcoming drug resistance, among the many problems in leukemia patients that have yet to be overcome. In this paper, we will review bone marrow niches in leukemia, findings on leukemia-derived exosomes, and exosome-induced changes in bone marrow niches.

scholarly journals Quiescent Human Hematopoietic Stem Cells in the Bone Marrow Niches Organize the Hierarchical Structure of Hematopoiesis

Stem Cells ◽  
2008 ◽  
Vol 26 (12) ◽  
pp. 3228-3236 ◽  
Author(s):  
Takashi Yahata ◽  
Yukari Muguruma ◽  
Shizu Yumino ◽  
Yin Sheng ◽  
Tomoko Uno ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Hierarchical Structure ◽  
Hematopoietic Stem ◽  
The Hierarchical Structure ◽  
Bone Marrow Niches

Human Hematopoietic Stem Cells and Leukemic Cells Form Cadherin-Catenin Based Junctional Complexes with Mesenchymal Stromal Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1367-1367 ◽  
Author(s):  
Patrick Wuchter ◽  
Rainer Saffrich ◽  
Wolfgang Wagner ◽  
Frederik Wein ◽  
Mario Stephan Schubert ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Leukemia Cells ◽  
Feeder Layer ◽  
Hematopoietic Stem ◽  
Knock Down ◽  
Junctional Complexes

Abstract The interaction between human hematopoietic stem cells (HSC) and their niche plays a key role in regulating maintenance of “stemness” and differentiation. We have demonstrated that a feeder layer of human mesenchymal stromal cells (MSC) can serve as a surrogate model for the niche for human HSC. We could also show, MSC are intimately connected to one another by a novel kind of adhering junction, consisting of villiformto-vermiform cell projections (processus adhaerentes). With this background, we have analyzed the intercellular junctional complexes between HSC and MSC. In comparison, we also studied the cell-cell contacts between leukemia cells (LC) and MSC. MSC were derived from bone marrow aspirates from healthy voluntary donors. HSC were isolated from umbilical cord blood. Leukemia cells that were CD34+ were obtained from bone marrow aspirates from patients suffering from acute myeloid leukemia at the time point of initial diagnosis. After 24–48 hours of co-cultivation, we stained the cellular contacts with a panel of antibodies specific for various components of tight, gap and adherens junctions. Using advanced confocal laser scanning microscopy in combination with deconvolution and volume rendering software, we were able to produce 3D-images of intercellular junctions between HSC/MSC as well as between LC/MSC. To examine the specific function of N-cadherin, we analyzed the effect of siRNA knock down of N-cadherin in MSC upon co-cultures of HSC and MSC. Intercellular connections between HSC and MSC are mainly characterized by podia formation of the HSC linking to the adjacent MSC. At the intimate contact zone to the MSC, we have identified the cytoplasmic plaque proteins alpha- and beta-catenin, co-localized with the transmembrane glycoprotein N-cadherin. Additionally, we compared these findings with a similar setting consisting of human LC co-cultured with feeder-layer of MSC. Our results demonstrated that in comparison to HSC, the proportion of leukemia cells adherent to the feeder-layer is significantly lower and podia formation is less frequent (ratio 1:3). However, the mechanism of adhesion through cadherin-catenin-complex has remained the same. At a functional level, we found that siRNA knock down of N-cadherin in MSC resulted in decreased adhesion of HSC to MSC and in a reduction of cell divisions of HSC. These results confirm that direct cellular contact via N-cadherin-based junctions is essential for homing and adhesion of HSC to the cellular niche and subsequently for the regulation of self-renewal versus differentiation in HSC.

Thrombopoietin Administration Alleviates Hematopoietic Stem Cells Intrinsic Long Term Ionizing Radiation Damages. Identification of Preferential Cellular Expansion Sites

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2441-2441
Author(s):  
Diana Tronik-Le Roux ◽  
Johnny Nehme ◽  
Arthur Simonnet ◽  
Pierre Vaigot ◽  
Marie Anne Nicola ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Ionizing Radiation ◽  
Hematopoietic Stem Cells ◽  
Cellular Response ◽  
Side Population ◽  
Hematopoietic Stem ◽  
Functional Changes ◽  
Progenitor Compartment

Abstract Hematopoietic stem cells (HSC) are indispensable for the integrity of complex and long-lived organisms since they can reconstitute the hematopoietic system for life and achieve long term repopulation of lethally irradiated mice. Exposure of an organism to ionizing radiation (IR) causes dose dependant bone marrow suppression and challenge the replenishment capacity of HSC. Yet, the precise damages that are generated remain largely unexplored. To better understand these effects, phenotypic and functional changes in the stem/progenitor compartments of sublethally irradiated mice were monitored over a ten week period after radiation exposure. We report that shortly after sublethal IR-exposure, HSC, defined by their repopulating ability, still segregate in the Hoechst dye excluding side population (SP); yet, their Sca-1 (S) and c-Kit (K) expression levels are increased and severely reduced, respectively, with a concurrent increase in the proportion of SPSK cells positive for established indicators of HSC presence: CD150+/CD105+ and Tie2+. Virtually all HSCs quickly but transiently mobilize to replenish the bone marrow of myelo-ablated mice. Ten weeks after, whereas bone marrow cellularity has recovered and hematopoietic homeostasis is restored, major phenotypic modifications can be observed within the c-Kit+ Sca-1+ Lin−/low (KSL) stem/progenitor compartment: CD150+/Flk2− and Flk2+ KSL cell frequencies are increased and dramatically reduced, respectively. CD150+ KSL cells also show impaired reconstitution capacity, accrued γ-H2AX foci and increased tendency to apoptosis. This demonstrates that the KSL compartment is not properly restored 10 weeks after sublethal exposure, and that long-term IR-induced injury to the bone marrow proceeds, at least partially, through direct damage to the stem cell pool. Since thrombopoietin (TPO) has been shown to reduce haematopoietic injury when administered immediately after exposure to radiations, we asked whether TPO could restore the permanent IR-induced damage we observed in the HSC compartment. We first found in competitive transplant experiments that a single TPO administration rescued the impaired reconstitution capacity of HSC’s from animals exposed to sublethal IR. In addition, we observed that TPO injection right after irradiation considerably attenuates IR-induced long-term injury to the stem/progenitor compartment. Finally, the use of marrow cells from transgenic ubiquitous luciferase-expressing donors combined with bioluminescence imaging technology provided a valuable strategy that allowed visualizing HSC homing improvements of TPO-treated compared to untreated irradiated donors, and enabled the identification of a preferential cellular expansion sites which were inaccessible to investigation in most studies. Electronic microscopy analysis revealed that these sites show also differential activity of megakaryocytopoiesis with marked differences in the proplatelets reaching the vascular sinus. Altogether, our data provide novel insights in the cellular response of HSC to IR and the beneficial effects of TPO administration to these cells.

TIM-3 Is a Promising Target to Eradicate Acute Myeloid Leukemia Stem Cells Sparing Normal Hematopoietic Stem Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 559-559
Author(s):  
Toshihiro Miyamoto ◽  
Yoshikane Kikushige ◽  
Takahiro Shima ◽  
Koichi Akashi
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Hematopoietic Stem Cells ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Cytotoxic Activities ◽  
Antibody Treatment ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 559 Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for permanent cure. To selectively kill AML LSCs sparing normal hematopoietic stem cells (HSCs), one of the most practical approaches is to target the AML LSCs-specific surface or functionally indispensable molecules. Based on differential transcriptome analysis of prospectively-purified CD34+CD38− LSCs from AML patient samples and normal HSCs, we found that T-cell immunoglobulin mucin-3 (TIM-3) was highly expressed in AML LSCs but not in normal HSCs (Kikushige et al., Cell Stem Cell, 2010). In normal hematopoiesis, TIM-3 is mainly expressed in mature monocytes and a fraction of NK cells, but not in granulocytes, T cells or B cells. In the bone marrow, TIM-3 is expressed only in a fraction of granulocyte/macrophage progenitors (GMPs) at a low level, but not in HSCs, common myeloid progenitors, or megakaryocyte/erythrocyte progenitors. In contrast, in human AML, TIM-3 was expressed on cell surface of the vast majority of CD34+CD38− LSCs and CD34+CD38+ leukemic progenitors in AML of most FAB types, except for acute promyelocytic leukemia (M3). FACS-sorted TIM-3+ but not TIM-3− AML cells reconstituted human AML in the immunodeficient mice, indicating that the TIM-3+ population contains most of functional LSCs. To selectively eradicate TIM-3-expressing AML LSCs, we established an anti-human TIM-3 mouse IgG2a antibody, ATIK2a, possessing antibody-dependent cellular cytotoxic and complement-dependent cytotoxic activities in leukemia cell lines transfected with TIM-3. We first tested the effect of ATIK2a treatment on reconstitution of normal HSCs in a xenograft model. ATIK2a was intraperitoneally injected to the mice once a week after 12 hours of transplantation of human CD34+ cells. Injection of ATIK2a did not affect reconstitution of normal human hematopoiesis except removing TIM-3-expressing mature monocytes. In contrast, injection of TIM-3 to the mice transplanted with human AML samples markedly reduced leukemic repopulation. In some mice transplanted with AML bone marrow, only normal hematopoiesis was reconstituted after anti-TIM-3 antibody treatment, suggesting that the antibody selectively killed AML cells, sparing residual normal HSCs. To further test the inhibitory effect of ATIK2a on established human AML, eight weeks after transplantation of human AML cells, engraftment of human AML cells was confirmed by blood sampling and thereafter ATIK2a was injected to these mice. In all cases tested, ATIK2a treatment significantly reduced human TIM-3+ AML fraction as well as the CD34+CD38− LSCs fraction. In addition, to verify the anti-AML LSCs effect of ATIK2a treatment, human CD45+AML cells from the primary recipients were re-transplanted into secondary recipients. All mice transplanted from primary recipients treated with control IgG developed AML, whereas none of mice transplanted with cells from ATIK2a-treated primary recipients developed AML, suggesting that functional LSCs were effectively eliminated by ATIK2a treatment in primary recipients. Thus, TIM-3 is a promising surface molecule to target AML LSCs. Our experiments strongly suggest that targeting this molecule by monoclonal antibody treatment is a practical approach to eradicate human AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Age-Associated Characteristics of Murine Hematopoietic Stem Cells

2000 ◽  
Vol 192 (9) ◽  
pp. 1273-1280 ◽  
Author(s):  
Kazuhiro Sudo ◽  
Hideo Ema ◽  
Yohei Morita ◽  
Hiromitsu Nakauchi
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Cells ◽  
Lymphoid Cells ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Functional Changes

Little is known of age-associated functional changes in hematopoietic stem cells (HSCs). We studied aging HSCs at the clonal level by isolating CD34−/lowc-Kit+Sca-1+ lineage marker–negative (CD34−KSL) cells from the bone marrow of C57BL/6 mice. A population of CD34−KSL cells gradually expanded as age increased. Regardless of age, these cells formed in vitro colonies with stem cell factor and interleukin (IL)-3 but not with IL-3 alone. They did not form day 12 colony-forming unit (CFU)-S, indicating that they are primitive cells with myeloid differentiation potential. An in vivo limiting dilution assay revealed that numbers of multilineage repopulating cells increased twofold from 2 to 18 mo of age within a population of CD34−KSL cells as well as among unseparated bone marrow cells. In addition, we detected another compartment of repopulating cells, which differed from HSCs, among CD34−KSL cells of 18-mo-old mice. These repopulating cells showed less differentiation potential toward lymphoid cells but retained self-renewal potential, as suggested by secondary transplantation. We propose that HSCs gradually accumulate with age, accompanied by cells with less lymphoid differentiation potential, as a result of repeated self-renewal of HSCs.

scholarly journals Impaired Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation: Its Pathogenesis and Potential Treatments

Hemato ◽  
2021 ◽  
Vol 2 (1) ◽  
pp. 43-63
Author(s):  
Masahiro Imamura
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Hematopoietic Stem Cells ◽  
Graft Failure ◽  
Graft Function ◽  
Hematopoietic Stem ◽  
Poor Graft Function ◽  
Bone Marrow Niches

Impaired hematopoiesis is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Bone marrow aplasia and peripheral cytopenias arise from primary and secondary graft failure or primary and secondary poor graft function. Chimerism analysis is useful to discriminate these conditions. By determining the pathogenesis of impaired hematopoiesis, a timely and appropriate treatment can be performed. Hematopoietic system principally consists of hematopoietic stem cells and bone marrow microenvironment termed niches. Abnormality in hematopoietic stem and progenitor cells and/or abnormality in the relevant niches give rise to hematological diseases. Allo-HSCT is intended to cure each hematological disease, replacing abnormal hematopoietic stem cells and bone marrow niches with hematopoietic stem cells and bone marrow niches derived from normal donors. Therefore, treatment for graft failure and poor graft function after allo-HSCT is required to proceed based on determining the pathogenesis of impaired hematopoiesis. Recent progress in this area suggests promising treatment manipulations for graft failure and poor graft function.

scholarly journals Profiling of Metabolic Differences between Hematopoietic Stem Cells and Acute/Chronic Myeloid Leukemia

Metabolites ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 427
Author(s):  
Byung Hoo Song ◽  
Su Young Son ◽  
Hyun Kyu Kim ◽  
Tae Won Ha ◽  
Jeong Suk Im ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Leukemia Cell ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Gas Chromatography Mass Spectrometry ◽  
Multivariate Statistical ◽  
Hematopoietic Stem ◽  
Metabolic Characteristics

Although many studies have been conducted on leukemia, only a few have analyzed the metabolomic profiles of various leukemic cells. In this study, the metabolomes of THP-1, U937, KG-1 (acute myelogenous leukemia, AML), K562 (chronic myelogenous leukemia, CML), and cord blood-derived CD34-positive hematopoietic stem cells (HSC) were analyzed using gas chromatography-mass spectrometry, and specific metabolic alterations were found using multivariate statistical analysis. Compared to HSCs, leukemia cell metabolomes were found to have significant alterations, among which three were related to amino acids, three to sugars, and five to fatty acids. Compared to CML, four metabolomes were observed specifically in AML. Given that overall more metabolites are present in leukemia cells than in HSCs, we observed that the activation of glycolysis and oxidative phosphorylation (OXPHOS) metabolism facilitated the incidence of leukemia and the proliferation of leukemic cells. Analysis of metabolome profiles specifically present in HSCs and leukemia cells greatly increases our basic understanding of cellular metabolic characteristics, which is valuable fundamental knowledge for developing novel anticancer drugs targeting leukemia metabolism.

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