scholarly journals Molecular Mechanisms Underlying Bone Marrow Homing of Hematopoietic Stem Cells

10.5772/31554 ◽  
2012 ◽  
Author(s):  
Aysegul Ocal ◽  
Miranda Buitenhuis
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Molecular Mechanisms ◽  
Hematopoietic Stem

Reversible Expansion of Hematopoietic Stem Cells (HSC) and CML-Like Disease in Transgenic Mice Expressing BCR-ABL under the Control of the SCL 3′ Enhancer.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 715-715
Author(s):  
Steffen Koschmieder ◽  
Berthold Goettgens ◽  
Pu Zhang ◽  
Tajhal Dayaram ◽  
Kristin Geary ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Transgenic Mice ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Molecular Mechanisms ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Double Transgenic Mice

Abstract Chronic myeloid leukemia (CML) is a malignant disorder originating from the transformation of hematopoietic stem cells (HSC) by the BCR-ABL oncogene. Using the tet-off system, we have generated double-transgenic mice in which BCR-ABL is expressed under the control of the murine SCL 3′ enhancer, which targets expression to the vast majority of HSC and progenitors. After induction of BCR-ABL, all mice developed progressive chronic neutrophilia and leukocytosis (20–40 K/ul), and the animals died or were sacrificed in moribund condition within 58+/−28 days. Upon necropsy, bone marrow granulocytic hyperplasia, splenomegaly as well as organ infiltration by leukemic cells (liver, kidney, lung, small intestine, skin) were found. In addition, 31% of the mice subsequently developed ALL or lymphomas. BCR-ABL mRNA and protein expression were demonstrated in the affected organs. Expression of the transactivating transgene tTA was high in HSC, CMP, and CLP, but low in GMP and MEP, as assessed by real-time PCR, suggesting that the SCL 3′ enhancer indeed directed BCR-ABL expression to the most primitive hematopoietic cells within the bone marrow. The percentage of HSC in the bone marrow was expanded 7- and 26-fold in double-transgenic as compared to single-transgenic or wild-type control mice within 12 and 21 days, respectively, after BCR-ABL induction. GMP were increased 2- and 3-fold while the number of CMP was decreased 2-fold after 12 days but was increased 1.5-fold after 21 days. MEP were decreased 3-fold at both time points. In keeping with these results, the percentage of Ter-119 positive erythroid cells was decreased while the percentage of Gr-1 positive granulocytic cells was increased in the bone marrow. To assess reversibility of the phenotype, we readministered tetracycline to abrogate BCR-ABL expression. Double-transgenic mice showed rapid clinical improvement, reversion of neutrophilia and leukocytosis, normalization of Gr-1/Mac-1 positive cells in the peripheral blood and spleen, and reversion of splenomegaly. In addition, in mice that had developed lymphoblastic disease, readministration of tetracycline led to disappearance of lymphomas and of B220/BP-1 positive lymphoblastic cells in the peripheral blood. Furthermore, expansion of the HSC compartment in the bone marrow was also reversible, and the percentage of HSC decreased to levels observed in control mice. Repeated induction of BCR-ABL expression by removal of tetracycline led to reappearance of the myeloid and lymphoid phenotype. Again, the disease was reversible, and none of the animals relapsed while on tetracycline, suggesting that the phenotype remained completely dependent on the expression of the oncogene. In conclusion, we present a model of BCR-ABL mediated CML-like disease with expansion of phenotypic hematopoietic stem cells and myeloid progenitor cells in the bone marrow. The target cell population in this model closely resembles the origin of transformation in patients with CML, allowing for in vivo monitoring of early molecular mechanisms of BCR-ABL transformation. We are currently studying the function of the expanded HSC and progenitor cells in transplantation experiments.

The Balance of Gfi-1 and Gfi-1b Maintains the Undifferentiated, Multipotent State of Hematopoietic Stem Cells and Regulates Lineage-Commitment

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1210-1210
Author(s):  
Adlen Foudi ◽  
Hanno Hock
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Global Gene Expression ◽  
Family Factors ◽  
Lineage Commitment ◽  
Hematopoietic Stem ◽  
Global Gene Expression Profiling

Abstract Abstract 1210 Gfi-1 and Gfi-1b are homologous transcriptional repressors that are expressed in hematopoietic stem cells (HSCs). Gfi-1 is crucial for the terminal maturation of neutrophils, and Gfi-1b is critical for erythropoiesis and thrombopoiesis. HSCs give rise to all mature blood lineages through a tightly regulated multistep differentiation process, but the mechanism of their early lineage specification remains largely elusive. Here, we have dissected the role of the Gfi-family factors in HSC maintenance and early lineage-commitment. To this end, we generated conditional targeted alleles for Gfi-1 and Gfi-1b that allowed for time controlled induced disruption of their genes. Acute disruption of Gfi-1 resulted in a rapid, severe decrease of HSCs numbers in the bone marrow and ablated their function in competitive repopulation assays. Surprisingly, and sharply contradicting recent claims to the opposite, acute disruption of Gfi-1b also led to decreased numbers of long-term repopulating HSCs in the bone marrow and decreased fitness in competitive transplantation. After induced, combined disruption of both factors, no HSC and progenitor cells were maintained in the bone marrow for more than 2 weeks. To elucidate the molecular mechanisms of the Gfi-family mediated HSC maintenance we performed global gene expression profiling of Gfi-1−/− and Gfi-1b−/− HSCs. Unexpectedly, both factors regulate highly distinct gene sets involved in differentiation of alternative lineages. Thus, surprisingly, their action in HSCs is not redundant but synergistic. Consistent with this, disruption of individual Gfi-family factors renders HSCs prone to differentiation to specific alternative lineages, while combined disruption is entirely incompatible with HSCs maintenance, in large part due to unchecked differentiation. Together, our data reveal that balanced expression of Gfi-1 and Gfi-1b is required for maintaining the undifferentiated, multipotent state of HSCs, while altering the balance is sufficient for inducing commitment to specific lineages. Disclosures: No relevant conflicts of interest to declare.

Phenotype, Function, and Regulation of Migrating Hematopoietic Stem Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2680-2680
Author(s):  
Amy J. Wagers ◽  
Susan S. Prohaska ◽  
Emmanuelle Passegue ◽  
Jessica Price ◽  
Irving L. Weissman
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Cell Transplantation ◽  
Molecular Mechanisms ◽  
Hematopoietic Cell Transplantation ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Cycle Regulators ◽  
Hematopoietic Stem

Abstract Hematopoiesis in adult animals is maintained by a small population of clonogenic, multipotent hematopoietic stem cells (HSC), which maintain throughout life the capacity to self-renew and to differentiate to give rise to progeny cells that ultimately generate all lineages of mature blood cells. In adult mice and humans, the majority of HSC are found in the bone marrow (BM); however, HSC are also constitutively present at low levels in the circulation. The frequency of HSC in the blood can be significantly increased through the use of “mobilizing” agents, including cytotoxic drugs and/or cytokines, which often act both to drive HSC proliferation and to induce HSC migration from the BM into the bloodstream. Yet despite the increasingly common clinical exploitation of HSC in bone marrow and mobilized peripheral blood progenitor cell transplantation, both the evolutionary rationale and the molecular mechanisms that underlie the remarkable migratory capacity of HSC remain largely unknown. Therefore, to begin to elucidate the mechanisms and regulators of these events, we have used parabiotic and transplantation models to characterize normal blood-borne HSC. Our data clearly demonstrate that HSC are constitutively present in the blood of untreated mice and maintain a cell surface phenotype in the blood highly similar to their BM counterparts. Blood-borne HSC in normal mice can engraft both irradiated and non-irradiated BM niches, and subsequently are phenotypically and functionally indistinguishable from endogenous, host-type cells. These data suggest that BM homing of transplanted HSC in irradiated recipients and HSC mobilization in cytokine-treated animals likely makes use of pre-existing pathways that support the constitutive recirculation of these cells in normal animals. Finally, to extend these data and begin to uncover factors likely to play a role in stimulating HSC migration in both normal and mobilized mice, we have employed cDNA microarray technology to compare global gene expression profiles of normal and pre-migratory BM HSC, and have thus identified multiple candidate genes, including cell cycle regulators, signaling molecules, and transcription factors, that may be involved in HSC expansion or in HSC retention in and/or egress from the BM. Taken together, these findings provide significant insight into the dynamic nature and function of HSC, and may ultimately suggest novel and improved strategies for clinical hematopoietic cell transplantation.

Ang1 Functions as An Autocrine Activating Factor of Tie2 Signaling In Hematopoietic Stem Cells.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1548-1548
Author(s):  
Haruka Momose ◽  
Kazuya Takizawa ◽  
Madoka Kuramitsu ◽  
Takuo Mizukami ◽  
Atsuko Masumi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Molecular Mechanisms ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Lentiviral Vector ◽  
Down Regulation ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Abstract 1548 Hematopoietic stem cells (HSCs) are clonogenic cells that possess the self-renewal capacity to produce more HSCs, as well as the multilineage potential that gives rise to a defined set of mature differentiated progeny for maintenance or repair of the whole blood system. HSCs lie in the hematopoietic niches located along the inner surface of the bone or the sinusoidal endothelium, and are in contact with niche cells. The cell-cell interactions with niche cells are believed to be an important prerequisite to trigger signaling events in HSCs, thereby controlling the balance between HSC self-renewal and differentiation. However, the precise molecular mechanisms regulating niche cell-HSC interactions are not well understood. One of the key molecules for those interactions is Angiopoietin-1 (Ang1). Ang1 is expressed by the niche cells and has been identified as an activating ligand for Tie2 (tyrosine kinase with Ig-like loops and epidermal growth factor homology domains 2). The expression of Tie2 is dominant in HSCs, and Tie2 in HSCs is supposed to be stimulated by Ang1 derived from niche cells. However, Ang1 is also expressed in HSCs. Detailed analysis has shown that Ang1 expression was found to be restricted in long-term HSCs (CD34-lineage-Sca-1+c-Kit+), indicating that Ang1 derived from HSCs plays a role in regulating HSCs. We attempted to elucidate a novel regulating system for HSCs through Ang1-Tie2 signaling by utilizing a hematopoietic cell line in which Tie2 was stably expressed (Ba/F3-Tie2). In Ba/F3-Tie2 cells, Tie2 was found to be phosphorylated on tyrosine residues, even without exogenous addition of Ang1. In the same cells, the expression level of endogenous Ang1 was increased four-fold. When Ang1 expression was down-regulated by transduction with a lentiviral vector expressing short hairpin RNA (shRNA) for Ang1 (shAng1), the phosphorylation of Tie2 was suppressed, suggesting that Tie2 expressed in Ba/F3-Tie2 cells could be stimulated by endogenous Ang1. To mimic the physiological circumstances of the bone marrow, Ba/F3-Tie2 cells were cultured on OP9 stromal cells. Under these culture conditions, the effect of endogenous Ang1 was investigated. Down-regulation of Ang1 by shAng1 demonstrated an approximate 50% reduction in the proliferation of Ba/F3-Tie2 cells on the OP9 cell layer. A HSC-rich population of cells prepared from bone marrow (lineage-Sca-1+c-Kit+; LSK) was also analyzed on OP9 cell layers. Similar to the results obtained from the analysis of Ba/F3-Tie2 cells, down-regulation of Ang1 by shAng1 resulted in an approximately 70% decrease in the proliferation of LSK cells cultured on OP9 monolayers. We confirmed that the suppressive effect on HSC proliferation was due to the lack of Ang1 from HSCs by culturing on Ang1-defective OP9 cells. Finally, we performed in vivo analysis to confirm the importance of endogenous Ang1 to HSCs. Ly5.2 LSK cells transduced with the shAng1 expressing vector were transplanted along with Ly5.1xLy5.2 bone marrow cells into lethally irradiated Ly5.1 mice. The Ly5.2 donor-derived cells in the recipient's peripheral blood were monitored every 2 weeks. As expected, shAng1-introduced donor cells were at decreased ratios at week four (mean ratios, 31.5% for control vs. 17.5% for shAng1), and were reduced to an even lower level at week 12 (mean ratios, 27.1% for control vs. 6.79% for shAng1). This phenomenon was also confirmed by histochemical results, where statistically fewer HSCs existed in the bone marrow of recipient mice in which shAng1-introduced HSCs were transplanted, as compared to the control. Altogether, our data suggested that Tie2 in HSCs could be stimulated by the Ang1 produced by the surrounding HSCs, and this possible autocrine regulation might control the functions of HSCs. Disclosures: No relevant conflicts of interest to declare.

The Impact of Age and Gender on Hematopoietic Stem Cells and Immune Contexture of the Bone Marrow Microenvironment

2020 ◽  
pp. 1-6
Author(s):  
Rebar N. Mohammed
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Immune Cells ◽  
Absolute Number ◽  
Cell Number ◽  
Hematopoietic Stem ◽  
The Absolute ◽  
And Gender ◽  
The Impact

Hematopoietic stem cells (HSCs) are a rare population of cells that reside mainly in the bone marrow and are capable of generating and fulfilling the entire hematopoietic system upon differentiation. Thirty-six healthy donors, attending the HSCT center to donate their bone marrow, were categorized according to their age into child (0–12 years), adolescence (13–18 years), and adult (19–59 years) groups, and gender into male and female groups. Then, the absolute number of HSCs and mature immune cells in their harvested bone marrow was investigated. Here, we report that the absolute cell number can vary considerably based on the age of the healthy donor, and the number of both HSCs and immune cells declines with advancing age. The gender of the donor (male or female) did not have any impact on the number of the HSCs and immune cells in the bone marrow. In conclusion, since the number of HSCs plays a pivotal role in the clinical outcome of allogeneic HSC transplantations, identifying a younger donor regardless the gender is critical.

scholarly journals Influence of height on endothelial maintenance activity: a narrative review

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Yuji Shimizu ◽  
Takahiro Maeda
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Inverse Association ◽  
Hematopoietic Stem ◽  
Genetic Characteristics ◽  
Maintenance Activity ◽  
Marrow Activity

AbstractRecent studies have revealed an inverse association between height and cardiovascular disease. However, the background mechanism of this association has not yet been clarified. Height has also been reported to be positively associated with cancer. Therefore, well-known cardiovascular risk factors, such as increased oxidative stress and chronic inflammation, are not the best explanations for this inverse association because these risk factors are also related to cancer. However, impaired blood flow is the main pathological problem in cardiovascular disease, while glowing feeding vessels (angiogenesis) are the main characteristic of cancer pathologies. Therefore, endothelial maintenance activity, especially for the productivity of hematopoietic stem cells such as CD34-positive cells, could be associated with the height of an individual because this cell contributes not only to the progression of atherosclerosis but also to the development of angiogenesis. In addition, recent studies have also revealed a close connection between bone marrow activity and endothelial maintenance; bone marrow-derived hematopoietic stem cells contribute towards endothelial maintenance. Since the absolute volume of bone marrow is positively associated with height, height could influence endothelial maintenance activity. Based on these hypotheses, we performed several studies. The aim of this review is not only to discuss the association between height and bone marrow activity, but also to describe the potential mechanism underlying endothelial maintenance. In addition, this review also aims to explain some of the reasons that implicate hypertension as a major risk factor for stroke among the Japanese population. The review also aims to clarify the anthropological reasons behind the high risk of atherosclerosis progression in Japanese individuals with acquired genetic characteristics.

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