scholarly journals Bone Marrow Endothelial Cells Influence Function and Phenotype of Hematopoietic Stem and Progenitor Cells after Mixed Neutron/Gamma Radiation

2019 ◽  
Vol 20 (7) ◽  
pp. 1795 ◽  
Author(s):  
Lynnette Cary ◽  
Daniel Noutai ◽  
Rudolph Salber ◽  
Opeyemi Fadiyimu ◽  
Arthur Gross ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Ionizing Radiation ◽  
Progenitor Cells ◽  
Global Analysis ◽  
Cell Types ◽  
Hematopoietic Stem ◽  
Beneficial Effects ◽  
And Migration ◽  
Cd34 Expression

The bone marrow (BM) microenvironment plays a crucial role in the maintenance and regeneration of hematopoietic stem (HSC) and progenitor cells (HSPC). In particular, the vascular niche is responsible for regulating HSC maintenance, differentiation, and migration of cells in and out of the BM. Damage to this niche upon exposure to ionizing radiation, whether accidental or as a result of therapy, can contribute to delays in HSC recovery and/or function. The ability of BM derived-endothelial cells (BMEC) to alter and/or protect HSPC after exposure to ionizing radiation was investigated. Our data show that exposure of BMEC to ionizing radiation resulted in alterations in Akt signaling, increased expression of PARP-1, IL6, and MCP-1, and decreased expression of MMP1 and MMP9. In addition, global analysis of gene expression of HSC and BMEC in response to mixed neutron/gamma field (MF) radiation identified 60 genes whose expression was altered after radiation in both cell types, suggesting that a subset of genes is commonly affected by this type of radiation. Focused gene analysis by RT-PCR revealed two categories of BMEC alterations: (a) a subset of genes whose expression was altered in response to radiation, with no additional effect observed during coculture with HSPC, and (b) a subset of genes upregulated in response to radiation, and altered when cocultured with HSPC. Coculture of BMEC with CD34+ HSPC induced HSPC proliferation, and improved BM function after MF radiation. Nonirradiated HSPC exhibited reduced CD34 expression over time, but when irradiated, they maintained higher CD34 expression. Nonirradiated HSPC cocultured with nonirradiated BMEC expressed lower levels of CD34 expression compared to nonirradiated alone. These data characterize the role of each cell type in response to MF radiation and demonstrate the interdependence of each cell’s response to ionizing radiation. The identified genes modulated by radiation and coculture provide guidance for future experiments to test hypotheses concerning specific factors mediating the beneficial effects of BMEC on HSPC. This information will prove useful in the search for medical countermeasures to radiation-induced hematopoietic injury.

STAT5 promotes multilineage hematolymphoid development in vivo through effects on early hematopoietic progenitor cells

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 95-101 ◽  
Author(s):  
Jonathan W. Snow ◽  
Ninan Abraham ◽  
Melissa C. Ma ◽  
Nancy W. Abbey ◽  
Brian Herndier ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Blood Cell ◽  
Progenitor Cells ◽  
Cell Types ◽  
Hematopoietic Stem ◽  
Signal Transducers ◽  
Adult Mice ◽  
Colony Forming Units ◽  
Proliferation Activity

The transcription factor signal transducers and activators of transcription 5 (STAT5) is activated by numerous cytokines that orchestrate blood cell development. Multilineage peripheral blood cytopenias were observed in adult mice lacking both isoforms of STAT5 (STAT5A and STAT5B) as well as accelerated rates of apoptosis in the bone marrow. Although the hematopoietic stem cell (HSC) population was preserved in a number of these mice, the post-HSC progenitor populations were diminished and a marked reduction in functional progenitors (spleen colony-forming units) was detected. Competitive bone marrow transplantation studies in vivo revealed a profound impairment of repopulation potential of STAT5-null HSCs, leading to complete lack of contribution to the myeloid, erythroid, and lymphoid lineages. These abnormalities were associated with heightened proliferation activity in the HSC fraction, suggesting the action of homeostatic mechanisms to maintain sufficient levels of diverse blood cell types for viability. Thus, STAT5 normally sustains the robust hematopoietic reserve that contributes to host viability through crucial survival effects on early progenitor cells.

3′ Distal Regulatory Elements Required for Human CD34 Expression in Transgenic Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 125-125
Author(s):  
Elena Levantini ◽  
Yutaka Okuno ◽  
Pu Zhang ◽  
Steffen Koschmieder ◽  
Hanna S. Radomska ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
Progenitor Cells ◽  
Regulatory Element ◽  
Restriction Enzymes ◽  
Regulatory Elements ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Cd34 Expression

Abstract CD34 is the best-defined human hematopoietic stem cell (HSC) marker, however the regulation of its gene expression is still largely unknown. Therefore, unraveling the elements that regulate human CD34 expression would be an invaluable tool for a broad range of studies, including the establishment of models of leukemia in mice, which require targeting of the transgene to stem and/or early progenitor cells. Moreover, identification of such regulatory elements will provide important insights into the transcriptional agenda of stem and progenitor cells and most importantly will prove useful for gene therapy protocols. Studies from our laboratory demonstrated that human CD34 transgenes are expressed in murine repopulating HSCs, which resembles the expression of the CD34 gene in human hematopoiesis, thus indicating the mouse model as an excellent way to study the expression of human CD34. Using P1 derived artificial chromosome (PAC) clones encompassing the human CD34 gene to generate transgenic mice, we showed that 90kb of upstream and 26kb of downstream flanking sequences were capable of regulating human CD34 expression in murine transgenic lines. Successive deletions of this larger construct were then performed to identify the important control regions. Deletion of the 5′ region from −90kb to −18kb did not result in any loss of activity. PAC54A19, a clone extending from −18kb to +26kb, expressed RNA in various tissues in a manner similar to that of larger fragments. In contrast, deletions creating a construct spanning from −10kb to +17kb led to complete loss of expression in transgenic animals, indicating that critical distal elements are located between −18kb to −10kb and/or +17kb to +26kb. In order to facilitate identification of important regulatory elements present in the upstream (−18kb to −10 kb) and/or downstream (+17kb to +26kb) regions of human CD34, we created further deletions of PAC54A19 using rare-cutting restriction enzymes, and studied the effects of the deletions on human CD34 expression in transgenic mice. Interestingly, we did not detect any human CD34 mRNA and protein expression in bone marrow and HSCs from transgenic mice carrying a construct spanning from −18kb to +17.4kb. In contrast, we observed expression of human CD34 transcripts in the bone marrow of transgenic mice containing a PAC spanning from −12.8kb to +26kb. Furthermore, HSCs from this latter group of mice presented the human CD34 antigen on their surface, as detected by FACS. Taken together, these data are highly suggestive that critical cis regulatory element(s) required to drive human CD34 in vivo expression are located in a 8.6kb fragment placed between +17.4kb and +26kb downstream of the human CD34 gene. Our current efforts focus on identifying the element(s) within the 8.6kb 3′ region that might be required to achieve human CD34 expression in HSCs.

Hemangiogenic Role of ELF4 in Bone Marrow Post Myeloablation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1783-1783
Author(s):  
Mariela Sivina ◽  
Takeshi Yamada ◽  
Natalie Dang ◽  
H. Daniel Lacorazza
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Hematopoietic Stem Cells ◽  
Blood Vessels ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Bone Marrow Cells ◽  
Hematopoietic Stem ◽  
Huvec Cells

Abstract Bone marrow suppression is an important cause of death in patients exposed to radiation or in cancer patients treated with conventional chemotherapeutic agents. Myeloablative treatments (i.e. 5-fluorouracil administration) lead to apoptosis of blood forming cells and to regression of blood vessels in bone marrow. It is well known that hematological recovery post-bone marrow insult depends on the capacity of hematopoietic stem cells to regenerate the entire hematopoietic system, however, the transcriptional machinery involved in the regeneration of sinusoidal blood vessels in bone marrow from endothelial progenitor cells is largely unknown. Endothelial cells express the Tie2 receptor tyrosine kinase (a.k.a. Tek), which is involved in the angiogenic remodeling and vessel stabilization. Gene targeting of Tie2 showed that it is not required for differentiation and proliferation of definitive hematopoietic lineages in the embryo although Tie2 is needed during postnatal bone marrow hematopoiesis. ELF is a subgroup of the ETS family of transcription factors composed by ELF1, ELF2 (a.k.a. NERF), ELF3, ELF4 (a.k.a. MEF) and ELF5. ELF1 and ELF2 have been shown to regulate Tie2 expression in vitro. Recently we showed that ELF4 modulates the exit of hematopoietic stem cells (HSC) from quiescence (Lacorazza et al., Cancer Cell2006, 9:175–187). Given the high homology between ELF1 and ELF4 and the same origin of HSC and endothelial progenitor cells, we hypothesize that ELF4 regulates proliferation and Tie2 expression of endothelial cells. We used a luciferase gene reporter system in COS-7 and HEK cells to examine the capacity of ELF proteins to activate Tie2. ELF4 is the strongest activator of Tie2 expression following the hierarchy ELF4>ELF1>ELF2 variant 1>ELF2 variant 2. Site directed mutagenesis of each of the five ETS-binding sites (EBS) present in the Tie2 promoter shows that ELF4 binds preferentially to EBS 1, 3 and 5. Binding of ELF4 to the Tie2 promoter was confirmed by chromatin immunoprecipitation and EMSA. Although Elf1 gene expression is essentially normal in Elf4−/− bone marrow cells collected after 5-FU treatment, we detected diminished Tie2 expression compared to Elf4+/+ bone marrow cells. The association of this effect to human endothelial cells derived from umbilical cord (HUVEC cells) was investigated. All-trans retinoic acid (ATRA) and vascular-endothelial growth factor (VEGF) induced ELF4 expression in HUVEC cells in a dose and time dependent manner which was followed by increased Tie2 expression, suggesting that expression of ELF4 is modulated by angiogenic signals. Moreover, endothelial cells treated with ATRA showed rapid wound colonization in a wound assay. Expression of the pan-endothelial marker MECA-32 was determined by immunohistochemistry to correlate Tie2 with the regeneration of blood vessels: myeloablated Elf4−/− femurs exhibited a reduction of MECA-32 positive arterioles. Finally, temporal and spatial expression of Tie2 during hematological recovery post ablation was measured in bone marrow using transgenic Tie2-LacZ mice crossed to Elf4−/− mice. Collectively, our data suggests that ELF4 regulates Tie2 expression in endothelial cells but most importantly their proliferative capacity in response to angiogenic signals.

Reversibility of CD34 expression on human hematopoietic stem cells that retain the capacity for secondary reconstitution

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 112-118 ◽  
Author(s):  
Mo A. Dao ◽  
Jesusa Arevalo ◽  
Jan A. Nolta
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cell Surface ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
Cd34 Expression

Abstract The cell surface protein CD34 is frequently used as a marker for positive selection of human hematopoietic stem/progenitor cells in research and in transplantation. However, populations of reconstituting human and murine stem cells that lack cell surface CD34 protein have been identified. In the current studies, we demonstrate that CD34 expression is reversible on human hematopoietic stem/progenitor cells. We identified and functionally characterized a population of human CD45+/CD34− cells that was recovered from the bone marrow of immunodeficient beige/nude/xid (bnx) mice 8 to 12 months after transplantation of highly purified human bone marrow–derived CD34+/CD38− stem/progenitor cells. The human CD45+ cells were devoid of CD34 protein and mRNA when isolated from the mice. However, significantly higher numbers of human colony-forming units and long-term culture-initiating cells per engrafted human CD45+ cell were recovered from the marrow of bnx mice than from the marrow of human stem cell–engrafted nonobese diabetic/severe combined immunodeficient mice, where 24% of the human graft maintained CD34 expression. In addition to their capacity for extensive in vitro generative capacity, the human CD45+/CD34− cells recovered from thebnx bone marrow were determined to have secondary reconstitution capacity and to produce CD34+ progeny following retransplantation. These studies demonstrate that the human CD34+ population can act as a reservoir for generation of CD34− cells. In the current studies we demonstrate that human CD34+/CD38− cells can generate CD45+/CD34− progeny in a long-term xenograft model and that those CD45+/CD34− cells can regenerate CD34+ progeny following secondary transplantation. Therefore, expression of CD34 can be reversible on reconstituting human hematopoietic stem cells.

Leukemic Predisposition of Mice Transplanted With Gene-Modified Hematopoietic Precursors Expressing flt3 Ligand

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 2003-2011 ◽  
Author(s):  
Teresa S. Hawley ◽  
Andrew Z.C. Fong ◽  
Henrik Griesser ◽  
Stewart D. Lyman ◽  
Robert G. Hawley
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Transmembrane Protein ◽  
Macrocytic Anemia ◽  
Leukemic Cell ◽  
Cell Types ◽  
Soluble Form ◽  
Hematopoietic Stem

Abstract flt3/flk-2 ligand (FL) is a cytokine that exhibits synergistic activities in combination with other early acting factors on subpopulations of hematopoietic stem/progenitor cells. In addition to normal hematopoietic precursors, expression of the FL receptor, flt3R, has been frequently demonstrated on the blast cells from patients with acute B-lineage lymphoblastic, myeloid, and biphenotypic (also known as hybrid or mixed) leukemias. Because many of these leukemic cell types express FL, the possibility has been raised that altered regulation of FL-mediated signaling might contribute to malignant transformation or expansion of the leukemic clone. In humans, FL is predominantly synthesized as a transmembrane protein that must undergo proteolytic cleavage to generate a soluble form. To investigate the consequences of constitutively expressing the analogous murine FL isoform in murine hematopoietic stem/progenitor cells, lethally irradiated syngeneic mice (18 total) were engrafted with post–5-fluorouracil–treated bone marrow cells transduced ex vivo with a recombinant retroviral vector (MSCV-FL) encoding murine transmembrane FL. Compared with control mice (8 total), MSCV-FL mice presented with a mild macrocytic anemia but were otherwise healthy for more than 5 months posttransplant (until 22 weeks). Subsequently, all primary MSCV-FL recipients observed for up to 1 year plus 83% (20 of 24) of secondary MSCV-FL animals that had received bone marrow from asymptomatic primary hosts reconstituted for 4 to 5 months developed transplantable hematologic malignancies (with mean latency periods of 30 and 23 weeks, respectively). Phenotypic and molecular analyses indicated that the tumor cells expressed flt3R and displayed B-cell and/or myeloid markers. These data, establishing that dysregulated expression of FL in primitive hematopoietic cells predisposes flt3R+ precursors to leukemic transformation, underscore a potential role of this cytokine/receptor combination in certain human leukemias. © 1998 by The American Society of Hematology.

Connexin-43 Expression Regulates the Migration of Hematopoietic Stem Cells and Progenitors towards and From Bone Marrow.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 562-562
Author(s):  
Daniel Gonzalez-Nieto ◽  
Kyung-Hee Chang ◽  
Anja Koehler ◽  
Jorden Arnett ◽  
Susan Dunn ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Hematopoietic Stem Cells ◽  
Connexin 43 ◽  
Cell Types ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Hematopoietic Microenvironment ◽  
Deficient Mice

Abstract Abstract 562 In the bone marrow (BM) cavity, the migratory traffic of hematopoietic stem cells and progenitors (HSC/P) from the endosteal niches to circulation and viceversa depends on their response to chemokine gradients and interaction with endothelial and mesenchymal pre-osteoblastic cells located at the endosteal niches, forming the hematopoietic microenvironment (HM). Several lines of evidence have pointed out the possible role of the gap junction-forming protein connexin-43 (Cx43) in the control of stem cell and progenitor migration. Our group previously demonstrated that Cx43 expression in the hematopoietic microenvironment (HM) is critical in the fetal liver and BM hematopoietic regeneration after administration of 5-fluorouracil (5-FU) and other investigators have shown that Cx43 is crucial controlling the migration of neural progenitors along radial glial during brain development. We hypothesized that Cx43 could regulate the bidirectional migration of HSC/P in the BM stroma. Since Cx43 is expressed by mesenchymal cells, endothelial cells and hematopoietic stem cells and progenitors, we decided to analyze the Cx43 contribution in the control of HSC/P migration in cell-specific conditional knock-out mice. To achieve this objective, we have used mice that were selectively deficient for Cx43 in the osteoblast/stromal cells (Collagen 1a-Creflox/flox; O/S-Cx43-deficient), in endothelial cells (Tek-Creflox/flox; E-Cx43-deficient) or in hematopoietic cells (Vav1-Creflox/flox; H-Cx43-deficient). O/S-Cx43-deficient mice have been shown to be a model of osteoblast loss of function (Chung DJ et al., J. Cell. Sci., 2006) and E-Cx43-deficient mice have been shown to be a model of arterial hypotension induced by both increase nitric oxide and angiotensin levels (Liao Y et al, PNAS 2001). Analysis with reporter crossings with Rosa-loxP-Stop-LoxP-LacZ mice showed anatomical specificity of the Cre recombinase expression in different cell types of BM, and western-blot and RT-PCR expression indicated practical abolishment of the expression of Cx43 in each of the specific cell types. First, we analyzed whether there were changes in the levels of circulating progenitors in O/S-, E- or H-Cx43-deficient mice. While H-Cx43-deficient mice did not show any change in the levels of circulating HSC/P, E-Cx43-deficient mice showed a 3.5-fold and 4.7-fold, respectively, increase of circulating CFU-C and competitive repopulating units while maintaining normal repopulation ability of BM HSC. O/S-Cx43-deficient mice showed a 30% reduction in basal conditions which was more accentuated when administered G-CSF (50% reduction on day +6), compared with their WT counterparts. Interestingly, while osteoblast loss-of-function was induced in O/S Cx43-deficient mice, the intramarrow expression levels of CXCL12a/b and mesenchymal progenitor content (CFU-F) were increased (4- and 2-fold, respectively). In correlation with the increased levels of CXCL12, the distance to endosteum of transplanted CFSE+/lin-/c-kit+ BM cells into non-myeloablated O/S-Cx43-deficient mice was dramatically decreased (36.1±4.3 vs 23.2±2.1 mm, p<0.01), suggesting a major change in the cellular composition and chemokinesis within the hematopoietic microenvironment “in vivo”. Interestingly, the 16-hour homing of HSC/P transplanted into lethally irradiated O/S-Cx43KO recipient mice showed a ∼60% reduction and a significantly decreased survival in a limiting-dose transplantation radioprotection assay (50% survival in WT mice vs 0% survival in O/S Cx43-deficient recipients). The homing/engraftment defect of these mice correlated with a reversal of the increased levels of CXCL12 in irradiated BM and a 50% reduction of the migration of WT HSC/P through O/S-Cx43-deficient stroma in response to CXCL12. Altogether, these data indicate that intercellular communication through Cx43 shares distinct functions between the different cell components of the hematopoietic microenvironment, and mediates CXCL12-dependent and CXCL12-independent mechanisms in control of the BM homing and retention of HSC/P. Disclosures: No relevant conflicts of interest to declare.

Abstract 369: Isolation and Characterization of Developmentally and Functionally Discrete Subsets of Cardiac Fibroblasts

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Reza Ardehali ◽  
Shah Ali ◽  
Irving Weissman
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Cardiac Fibroblasts ◽  
Cell Types ◽  
Lineage Tracing ◽  
Reporter Protein ◽  
Hematopoietic Stem ◽  
Mesenchymal Transition ◽  
Isolation And Characterization ◽  
Embryonic Origin

Although cardiac fibroblasts (CF) are the most prominent cell types in the heart, little is known about their origin and development. Fibroblasts play a key role in regulating the normal myocardial function, as well as the adverse remodeling that occurs with injury. Fundamental to understanding cardiac development is the ability to determine when and where CFs are generated, their ancestry, and how they move to reside in their final position. We used novel transgenic mouse models to lineage trace the developmental origin of CFs and their contribution to fibrosis in response to injury. Here, we show that a subset of cardiac fibroblasts is derived from Mesp1-expressing cells (multipotent cardiac progenitor cells that contribute to precursors of both heart fields). Using Mesp1-Cre;mT/mG mice, in which cells derived from Mesp1-expressing cells are indelibly marked by the GFP reporter protein, we demonstrate that approximately 65% of CFs share an embryonic origin with cardiomyocytes, vascular smooth muscle, and endothelial cells. In addition, experimental myocardial fibrosis did change this proportion. In an attempt to identify the source of the fibroblasts that are non-MesP1-derived, we evaluated contribution from: (i) the bone marrow stromal cells and hematopoietic stem cells, (ii) endothelial-to-mesenchymal transition, (iii) circulating cells, and (iv) epicardial-derived cells. Transplantation of GFP-bone marrow into irradiated wildtype mice resulted in an insignificant contribution of stromal-derived fibroblasts in the heart in response to injury. Using Tie2-Cre;mT/mG mice, we did not observe cardiac fibroblasts originating from endothelial cells in injured hearts. Finally, using a parabiotic pair of GFP and wildtype mice where blood chimerism is established, no evidence for homing of circulating fibroblasts to the heart upon injury was noted. However, we provide unequivocal evidence that epicardial-derived cells migrate to myocardium as fibroblasts to contribute to fibrosis. In summary, using lineage-tracing systems, we provide evidence for two sources of fibroblasts in the heart, one that shares an embryonic origin with the cardiovascular lineages and the other from a non-cardiac origin, which is primarily derived from the epicardium.

Spatial Analysis of Hematopoietic Stem and Progenitor Cells in the Bone Marrow

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3570-3570
Author(s):  
Cesar Nombela-Arrieta ◽  
Brendan Harley ◽  
Elena Levantini ◽  
John E Mahoney ◽  
Gregory Pivarnik ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Laser Scanning ◽  
Imaging Techniques ◽  
Cell Types ◽  
Specific Cell ◽  
Hematopoietic Stem ◽  
Lineage Differentiation ◽  
Stem And Progenitor Cells ◽  
Laser Scanning Cytometry

Abstract Sustained production of all mature blood cell types relies on the continuous proliferation and differentiation of a rare population of self-renewing, multipotent hematopoietic stem cells (HSCs). HSC maintenance and lineage differentiation are strictly regulated by distinct microenvironments, termed niches, defined by cellular components, soluble regulators, and by the extracellular matrix. Definitive identification of the location as well as cellular and extracellular characteristics of HSC niches in the bone marrow (BM) has not been completed due to limitations of conventional imaging techniques. We have employed a novel imaging technology, Laser Scanning Cytometry (LSC) to define the localization of hematopoietic stem and progenitor cells (HSPCs) within different regions of the BM. LSC allows imaging and objective quantitative analysis of the anatomical position(s), number, and frequency of specific cell populations within the native tissue microenvironment. Analysis of whole femoral longitudinal sections of Bmi-GFP mice, in which GFP is expressed at its highest levels in HSPCs, revealed that within the bone diaphysis, HSPCs (Bmi-GFPhi c-kit+) cells were highly enriched in endosteal regions (within 100nm away from inner bone surface) compared to the central medullary region. Importantly, our data show that HSPCs are found at highest frequencies in the metaphysis of long bones, suggesting that these areas, which display characteristic morphological features, are functionally distinct from the diaphyseal region and a preferential location for HSPC-specific niches. We are currently employing LSC to identify HSPC niche cellular constituents by quantifying the relative frequency at which these cells are found in association with previously proposed niche-components such as osteoblasts, BM endothelial sinusoidal cells and CXCL12-abundant reticular cells. A detailed understanding of niche-derived signals regulating unique properties of HSCs will certainly prove relevant in human HSPC transplantation and cell therapy.

Leukemic Predisposition of Mice Transplanted With Gene-Modified Hematopoietic Precursors Expressing flt3 Ligand

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 2003-2011 ◽  
Author(s):  
Teresa S. Hawley ◽  
Andrew Z.C. Fong ◽  
Henrik Griesser ◽  
Stewart D. Lyman ◽  
Robert G. Hawley
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Transmembrane Protein ◽  
Macrocytic Anemia ◽  
Leukemic Cell ◽  
Cell Types ◽  
Soluble Form ◽  
Hematopoietic Stem

flt3/flk-2 ligand (FL) is a cytokine that exhibits synergistic activities in combination with other early acting factors on subpopulations of hematopoietic stem/progenitor cells. In addition to normal hematopoietic precursors, expression of the FL receptor, flt3R, has been frequently demonstrated on the blast cells from patients with acute B-lineage lymphoblastic, myeloid, and biphenotypic (also known as hybrid or mixed) leukemias. Because many of these leukemic cell types express FL, the possibility has been raised that altered regulation of FL-mediated signaling might contribute to malignant transformation or expansion of the leukemic clone. In humans, FL is predominantly synthesized as a transmembrane protein that must undergo proteolytic cleavage to generate a soluble form. To investigate the consequences of constitutively expressing the analogous murine FL isoform in murine hematopoietic stem/progenitor cells, lethally irradiated syngeneic mice (18 total) were engrafted with post–5-fluorouracil–treated bone marrow cells transduced ex vivo with a recombinant retroviral vector (MSCV-FL) encoding murine transmembrane FL. Compared with control mice (8 total), MSCV-FL mice presented with a mild macrocytic anemia but were otherwise healthy for more than 5 months posttransplant (until 22 weeks). Subsequently, all primary MSCV-FL recipients observed for up to 1 year plus 83% (20 of 24) of secondary MSCV-FL animals that had received bone marrow from asymptomatic primary hosts reconstituted for 4 to 5 months developed transplantable hematologic malignancies (with mean latency periods of 30 and 23 weeks, respectively). Phenotypic and molecular analyses indicated that the tumor cells expressed flt3R and displayed B-cell and/or myeloid markers. These data, establishing that dysregulated expression of FL in primitive hematopoietic cells predisposes flt3R+ precursors to leukemic transformation, underscore a potential role of this cytokine/receptor combination in certain human leukemias. © 1998 by The American Society of Hematology.

scholarly journals Circulating Endothelial Progenitor Cells is a predictor in Atherosclerosis: Is it really a promising candle?

2013 ◽  
pp. 20-2
Author(s):  
Anwar Santoso
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Cd 34 ◽  
Circulating Endothelial Progenitor Cells

Circulating endothelial progenitor cells (CEPC) are supposed to be a subset of bone marrow-derived peripheral blood mononuclear cells (PBMC), revealing immature surface markers common to hematopoietic stem cells, such as CD 34 and CD 133 and endothelial lineage markers. These cells can be isolated from peripheral, umbilical cord, and bone marrow blood. CD 34 represents a marker of immature stem cells that is commonly used to characterize CEPC together with other surface antigens. Though, as CD 34 is also expressed at lower levels on mature endothelial cells, most recent studies used CD 133, a marker of more immature hematopoietic stem cells that is now considered the best surface marker to define, identify and isolate the CEPC1. CD 133 (also known as AC 133 or prominin) is highly conserved antigen with unknown biological activity. It would be expressed on hematopoietic stem cells, but not on mature endothelial cell and monocytes. In order to reflect the endothelial cells, there is general agreement for the use of at least one additional marker, such as vascular endothelial growth factor receptor-2 (VEGFR-2 or KDR), while others are platelet-endothelial cells adhesion molecules-1 (PECAM-1), von Willebrand factor, c-kit, Tie-2, vascular endothelial-cadherin and VEGFR-12.

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