Hematopoietic Stem Cells “Stemness” Genes Contain Many Genes Mutated or Abnormally Expressed in Hematopoietic Malignancies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4125-4125
Author(s):  
Amos Toren ◽  
Bella Bielorai ◽  
Jasmine Jacob-Hirsch ◽  
Tamar Fisher ◽  
Sharon Zelikovsky ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Underlying Mechanism ◽  
Stem Cell Population ◽  
Human Stem Cells ◽  
Acute Leukemias ◽  
Oligonucleotide Arrays ◽  
Hematopoietic Stem ◽  
Hematopoietic Malignancies

Abstract Umbilical cord blood (CB) and mobilized peripheral blood (PB) are relatively new sources of hematopoietic stem cells (HSC) that have been increasingly used in clinical transplantations. The genetic basis of the underlying mechanism of HSC self- renewal and differentiation has not been elucidated yet. Several groups have recently used microarray technology to study the common characteristics of stem cells from different tissues (“stemness”) and the typical features of each source of stem cell (“specificity”). Most groups focused their study on mice, used relatively small cDNA microarrays, and used CD34 as the cell surface marker for stem cells isolation. We studied human stem cells characterized by expression of the more primitive CD133 antigen, and used the Affymetrix Human Hu133A oligonucleotide arrays containing 22,215 probe sets to study the expression profile of these cells. An unsupervised hierarchical clustering of 14,025 “valid” probe sets showed a clear distinction between the CD133 + cells representing the stem cell population, and CD133 − cells that represent various stages of cell differentiation. CD133+ cells isolated from CB were compared to CD133− cells identifying 304 genes that were up regulated by at least two folds and the comparison between PB CD133+ cells and CD133− cells identified 218 genes which were up regulated by at least two-folds. These genes were considered as source specific and maybe relevant to the unique properties of CB and PB derived HSC. We were concentrated in the 244 genes that were found to be up regulated by at least two folds in the CD133 positive cells as compared to the CD133 negative cells and were common to both CB and PB. Comparison of these “stemness” genes, to the lists of “stemness” genes that were identified by 2 recent studies that analyzed mainly murine HSC identified 39 (Ramalho et al.) and 83 (Ivanova et al.) common genes. Twenty-four genes were common to another study that analyzed human HSC (Georgantas et al.). Among these common “stemness” genes we identified 4 groups of genes that have an important role in hematopoiesis: Growth factor receptors (Receptor thyrosine kinases (RTK) and c-mpl), a group of transcription factors which includes several homeobox genes and TGF-β targeted genes, genes that have an important role in the process of development and genes involved in cell growth. Among these 4 groups we identified 16 “stemness” genes (MPL, FLT3, HOXA9, MEIS 1, MLLT3, KIT, TIE, GATA-2, HOXA5, BAALC, HLF, MYCN, EVI1, MYB, FHL1, and HMGA2) that are known to be mutated or abnormally regulated in acute leukemias. It can be suggested that perturbation of expression of key hematopoietic stemness machinery genes may lead to abnormal proliferation and leukemia.]

scholarly journals Life span of multipotential hematopoietic stem cells in vivo.

1990 ◽  
Vol 171 (5) ◽  
pp. 1407-1418 ◽  
Author(s):  
G Keller ◽  
R Snodgrass
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Strong Evidence ◽  
Stem Cell Population ◽  
Hematopoietic Stem ◽  
Somatic Tissues ◽  
Exogenous Factors

The findings reported in this study highlight several important features of the development of hematopoietic stem cells after transplantation into irradiated recipients. First, they demonstrate the existence of a class of primitive multipotential stem cells that can function for a significant portion of the lifetime of a mouse (15 mo). In addition, they clearly show that these primitive stem cells can be infected with recombinant retroviruses and thus would be appropriate targets for gene therapy in somatic tissues. Second, our data indicate that the progeny of some, but not all, of the primitive stem cells have fully expanded into the various hematopoietic lineages by 2 mo after reconstitution. Finally, our analysis of the secondary recipients provides strong evidence suggesting that the primitive stem cell population can actually clonally expand. Our current experiments are aimed at determining the extent to which this expansion can occur and whether or not this expansion can be influenced by exogenous factors.

Differential Expression of SLAM Family Receptor Markers in Normal Human Hematopoietic Stem Cells and Their Malignant Counterpart in MDS and AML.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1897-1897
Author(s):  
Ramon V. Tiu ◽  
Jennifer J. Powers ◽  
Abdo Haddad ◽  
Ying Jiang ◽  
Jaroslaw P. Maciejewski
Keyword(s):  
Stem Cells ◽  
Flow Cytometry ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Cell Population ◽  
Stem Cell Population ◽  
Leukemic Stem Cell ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Slam Family

Abstract Members of the signaling lymphocytic activation molecule (SLAM) family, including CD150, CD48 and CD244, were shown to precisely distinguish more committed lineage restricted progenitor cells from pluripotent and multipotent murine hematopoietic stem cells (HSC; Kiel et al; 2005 Cell). Similar SLAM profiles may also be present on HSC subsets in humans. We hypothesized that these SLAM markers may be indicators not only of stem cell potential in normal hematopoiesis but also distinguish a subset of the most immature malignant precursors of leukemia. In agreement with the concept of a “cancer stem cell,” the presence of leukemic stem cell population may be an indicator of important clinical and biological properties. We first tested the distribution of CD150, CD48 and CD244 antigens on human CD34+ cells derived from 7 control individuals using 4-color flow cytometry. CD34+ cells were measured in the blast gate based on side scatter and CD45 expression. Within CD34+ blasts, expression of CD48, CD150, and CD244 was detected on 16.71%±9.69, 6.53%±2.93, and 26.92%±6.95 of cells respectively. Subsequently, we investigated SLAM expression in 9 immature leukemic cell lines, including KG-1, K562, U937, HEL, HL60, MKN-95, NB-4, Kasumi and UT7, and found increased expression of SLAM markers in KG-1 (CD48+, CD150+, CD244+) and Kasumi (CD48−, CD150−, CD244+). Consequently, none of the leukemic cells showed pluripotent/multipotent SLAM profiles. We then compared the SLAM marker expression on blasts from patients with AML and MDS with that of CD34+ cells from normal controls. We studied a total of 28 patients: 11 MDS (2 low grade, 5 advanced MDS, 3 MDS/MPD overlap) and 10 AML (FAB: 3 M1, 2 M2, 1 M3, 2 M4/M4E0 and 2 M6). In our cohort, 8/10 AML patients expressed one of the three SLAM markers; 6/10 were CD150−CD48−CD244+ (63.57%±6.96) and 2/10 were CD150+CD48−CD244−(46%±10.96) suggestive of the presence of either pluripotent or multipotent leukemic stem cell phenotype. In the MDS cohort, 8/11 patients expressed one of three SLAM markers, 7/11 were CD150−CD48−CD244+ (41.21% ± 8.9) and 1/11 were CD150+CD48−CD244− (1.26%±0.59) again consistent with a profile derived from either pluripotent or multipotent stem cells. None of the MDS and AML patients had either co-expression of CD244 and CD48 or increased expression of CD48 alone. Two of the M1 type AML patients with CD150−CD48−CD244+ phenotype received prior chemotherapy and achieved complete remission on bone marrow biopsy and flow cytometry using traditional blast markers. In some, we conclude that the SLAM receptor markers may be associated with certain types of leukemic blasts and may be useful in the identification of leukemic stem cell population in both MDS and AML.

scholarly journals Albumin-expressing hepatocyte-like cells develop in the livers of immune-deficient mice that received transplants of highly purified human hematopoietic stem cells

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 4201-4208 ◽  
Author(s):  
Xiuli Wang ◽  
Shundi Ge ◽  
George McNamara ◽  
Qian-Lin Hao ◽  
Gay M. Crooks ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Liver Damage ◽  
Human Albumin ◽  
Cell Populations ◽  
Human Stem Cells ◽  
Hematopoietic Stem ◽  
Stem Cell Populations

AbstractRodent bone marrow cells can contribute to liver. If these findings are applicable to humans, marrow stem cells could theoretically be harvested from a patient and used to repair his/her damaged liver. To explore this potential, CD34+ or highly purified CD34+CD38−CD7− human hematopoietic stem cells from umbilical cord blood and bone marrow were transplanted into immunodeficient mice. One month after transplantation, carbon tetrachloride (CCl4) was administered into the mice to induce liver damage and hepatocyte proliferation. Mice were analyzed in comparison with CCl4-injured mice that did not receive transplants and noninjured controls that received transplants with the same stem cell populations, one month after liver damage. Human-specific albumin mRNA and protein were expressed in the mouse liver and human albumin was detected in the serum of mice that had received CCl4 injury. Human alpha-fetoprotein was never expressed, but in some mice, human cytokeratin 19 was expressed, which may indicate bile duct development in addition to the albumin-secreting hepatocyte-like cells. Human albumin was not expressed in the starting stem cell populations in injured mice that did not receive transplants nor in noninjured mice that had received transplants of human stem cells. Human albumin expression was detected only in CCl4-treated mice that received transplants of human stem cells, and recovery was increased by administration of human hepatocyte growth factor 48 hours after the CCl4-mediated liver injury. Our studies provide evidence that human “hematopoietic” stem/progenitor cell populations have the capacity to respond to the injured liver microenvironment by inducing albumin expression.

System for Rapid and Reproducible Identification of MLL-AF9 Translocations Induced by Dietary Compounds and Nutritional Supplements

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1275-1275
Author(s):  
Carol Greer Vestal ◽  
Bhawana Bariar ◽  
Christine Richardson
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Acute Leukemia ◽  
Hematopoietic Stem Cells ◽  
Nutritional Supplements ◽  
Model System ◽  
Genetically Engineered ◽  
Inverse Pcr ◽  
Acute Leukemias ◽  
Hematopoietic Stem

Abstract Abstract 1275 Infant acute leukemias account for ∼30% of all malignancy seen in childhood across the Western world. They are aggressive and characterized by rapid onset shortly after birth. The majority of these (∼80% ALL and ∼60% AML) have rearrangements involving the MLL gene. Although MLL fusion to more than 75 genes have been identified, AF9 is one of its most common translocation partners. MLL breakpoint sequences associated with infant acute leukemia are similar to those in secondary AML following exposure to the topoisomerase II (topoII) poison etoposide. This similarity led to the hypothesis that exposure during preganancy to biochemically similar compounds may promote infant acute leukemia. Some studies have shown an epidemiological link between bioflavonoid intake and increased incidence of MLL-rearranged infant leukemias. These bioflavonoids have also been shown to inhibit topoII in in vitro DNA cleavage assays and produce MLL rearrangements by inverse PCR in mice. Hundreds of unregulated nutritional supplements are widely available and perceived to prevent cardiovascular disease, inflammation, and cancer; however, their potential to promote leukemic translocations should be determined. Our goal was to create a model system that allows for rapid quantifiable screening of a large number of compounds to determine their potential to promote MLL-AF9 bcr translocations, and does not rely on inverse PCR that requires elimination of artifacts or less physiologically relevant internal deletions or intronic alterations from analysis. Thus, we developed reporter stem cell lines that contain two transgene constructs—(1) the MLL bcr fragment containing a genetically-engineered GFP 5' exon, and (2) the AF9 bcr containing a genetically-engineered GFP 3' exon. A translocation between the two bcrs reconstitutes the full-length GFP transcript resulting in quantifiable green fluorescence. Cells were treated with etoposide, quercetin, genestein, luteolin, dipyrone, or benzoquinone for 1 hour at 25mM – 200mM concentrations then allowed to repair and proliferate in culture. GFP+ fluorescent colonies as a result of MLL-AF9 translocations were readily scorable by 96 hours in a dose-dependent manner. As previously demonstrated, totipotent stem cell viability was extremely impaired by multiple concentrations of etoposide, but the surviving fraction of hematopoietic stem cells that differentiated into multiple lineage sub-types exhibited a significant number of MLL-AF9 translocations (frequency of 1.5×10−4). Bioflavonoids genistein and quercetin (75mM) were also potent promoters of MLL-AF9 translocations in totipotent stem cells and hematopoietic stem cells at roughly similar frequencies as etoposide. By contrast, more differentiated hematopoietic progenitor cells had a significantly decreased (3-log) number of colonies with MLL-AF9 translocations following exposure to multiple compounds. This decrease is likely due to differences in DNA damage and repair responses or the potential of cells carrying translocations to proliferate in culture. The accuracy and significance of this model system is apparent from treatment of stem cells with benzoquinone that was not sufficient to produce MLL-AF9 translocations following exposure to concentrations up to 125mM (frequency < 0.1×10−6). Benzoquinone is a non-bioflavonoid thought to have a distinct mechanism of action and clinically associated with multiple leukemias. This system is a direct measure of the sensitivity of the MLL and AF9 bcrs to topoII poisons and bioflavonoids independent of their normal chromatin context and independent of formation of a leukemic fusion protein. In addition, the system allows for rapid and reproducible screening of hundreds of compounds that may have the potential to promote leukemogenic translocations in early stem cell and more differentiated cell subpopulations analogous to the events observed in infant acute leukemias. Disclosures: No relevant conflicts of interest to declare.

The Distinct Stem Cell Population Derived From Chorionic Plate Of Human Placenta Which Has Differentiation Potential Into Erythroid Lineage Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4843-4843
Author(s):  
Yong Park ◽  
Ji Hye Kim ◽  
Ji Hye Jung ◽  
Ga-won Kang ◽  
Dae Sik Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Stem Cell Population ◽  
In Vitro Differentiation ◽  
High Concentration ◽  
Culture Dish ◽  
Differentiation Potential ◽  
Hematopoietic Stem

Abstract Background/Aims Placenta is a specialized organ which has a property of fetal and adult tissues simultaneously. Mesenchymal stem cell and hematopoietic stem cells have been founded in the parenchyma of placenta tissue contributed by fetal side. Recently, it was reported that placenta is a major hematopoietic organ contributing to both generation and expansion of multipotent hematopoietic stem and progenitor cells. We hypothesized that hematopoietic stem cells in placenta might be originated from another placental stem cells which has been so-called “placenta mesenchymal stem cells”. To prove this hypothesis, this study is designed to induce in vitro differentiation of placental stem cells into the hematopoietic stem cells without genetic transduction. Methods Placental stem cells was obtained from surgically isolated placental chorionic plates from healthy women who had undergone abortion at 6-8 weeks of gestation. To prevent the contamination of hematopoietic stem cells, CD34-CD44+ cells were purified by flowcytometric isolation. After mesenchymal differentiation potential was identified in these cells by induction of adipogenic and osteogenic differentiation, they were cultured in vitro with serum-free media including cytokine cocktail which was known to induce differentiation of embryonic stem cells into hematopoietic lineage (erythropoietin, Flt-3/Flk-2 ligand, G-CSF, GM-CSF, IL-6/7/15, stem cell factor, and thrombopoietin). In vitro differentiation was performed in conventional cell culture dish (group 1) and Ultra-low attachment dish (group2) for 3 weeks, respectively (Figure 1). Expression of hematopoietic stem and progenitor cell markers were analyzed at every 1 week. Results In group 1 (conventional cell culture dish), no hematopoietic differentiation was identified regardless of the concentrations of cytokine cocktail. In group 2 (Ultra-low attachment dish), expression of pan-hematopoietic markers, CD34 and CD45 was also not observed. However, after 2 weeks of differentiation induction, red cells aggregates and expression of erythroid-lineage markers (CD235a and CD38) were detected in cells cultured using high concentration cytokines (Media 3 in Figure 1). The proportion of cells expressing erythroid-lineage markers became increased during in vitro differentiation (Figure 2). Conclusion Although this study failed to show the differentiation of placenta-derived stem cells into hematopoietic stem cells, the results demonstrated that placenta-derived stem cells could be differentiated into the erythroid lineage under certain condition (i.e. liquid culture + high concentration cytokines). Therefore, placenta-derived stem cells which have been so-called “placenta mesenchymal stem cells” is considered to be a distinct stem cell population including property of erythroid progenitor cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals LKB1 Coordinates Metabolic Pathways to Maintain Homeostasis of Haematopoietic Stem Cells and Regulate Erythropoiesis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 920-920
Author(s):  
Shijie Zhang ◽  
Yuanlin Xu ◽  
Mingming Zhang ◽  
Jingxin Zhang ◽  
Peijun Jia ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Energy Metabolism ◽  
Golgi Apparatus ◽  
Hematopoietic Stem Cells ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Underlying Mechanism ◽  
Haematopoietic Stem Cells ◽  
Hematopoietic Stem

Abstract Erythropoiesis is a highly regulated multistage process by which hematopoietic stem cells (HSCs) proliferate, differentiate and eventually form mature erythrocytes. Stem-cell maintenance and cell differentiation require homeostasis and coordination of multiple metabolisms. However, underlying mechanism of this coordination is poorly identified. Liver kinase B1 (LKB1) acts as evolutionarily conserved regulator to control cellular metabolism, cell polarity and proliferation during development and stress response. Considering that all the fundamental cellular processes regulated by LKB1 are present in erythropoiesis, we hypothesize that LKB1 may involve in orchestrating this coordination. To explore the role of LKB1 in entire erythropoiesis, we firstly crossed mice carrying loxP-flanked LKB1 alleles with EpoR-tdTomato-Cre mice, which can lead to cleavage in from HSCs to erythroblasts. LKB1fl/fl EPORcre mice developed exhaustion of HSCs, progressive severe anemia and ultimately lethality. Intriguingly, HSCs of LKB1fl/fl EPORcre mice exhibited a swiftly skewness toward the erythoid lineage when LKB1 is deleted. Nevertheless, erythroblasts of LKB1fl/fl EPORcre mice were significantly reduced. Further analysis showed that the colony forming ability of the colony-forming unit-erythroid (CFU-E) cells and subsequent terminal erythoid differentiation in LKB1fl/fl EPORcre mice were seriously impaired. In order to study erythropoiesis more specifically without the influence of stem cells, we next assessed the impact of deletion of LKB1 in the mouse erythropoietic system using GYPA-eGFP-Cre mice. LKB1fl/flGYPAcre mice showed mild anemia but had the normal lifespan.The Ter119 + cells were decreased while CFU-E cells were significantly increased. However, the colony forming ability of sorted CFU-E cells from LKB1fl/flGYPAcre mice were drastically reduced. In addition, LKB1fl/flGYPAcre mice exhibited disordered terminal erythropoiesis. Taken together, these results indicate that LKB1 may play multinomial roles in regulating stem-cell homeostasis and effective erythoid differentiation. Previous studies have shown that LKB1 controls energy metabolism via phosphorylating AMPK and regulating PGC-1 transcription to maintain homeostasis of HSCs. We found that both of p-AMPK and PGC-1 of LKB1fl/fl EPORcre mice were down-regulated in Lin - cells while Ter119 + cells have comparable p-AMPK and PGC-1. In this regard, LKB1fl/flGYPAcre mice, whether in Lin - cells or in Ter119 + cells, exhibited similar p-AMPK and PGC-1 level. Moreover, administration of ZLN005, an activator of PGC-1, partly rescued the anemia in LKB1fl/fl EPORcre mice but not in LKB1fl/flGYPAcre mice. These data imply that there is other underlying mechanism of LKB1 in erythropoiesis. To gain further mechanistic insight, we carried out proteomics analysis. Gene ontology analysis of differentially expressed proteins revealed that cholesterol metabolism related genes were significantly altered under LKB1 deficiency. We then found that LKB1 ablation led to a reduction of cholesterol level and diminishment of expression levels of primary cholesterol biosynthesis related genes. Moreover, the mature active form of SREBP2, the master transcriptional regulator of cholesterol biosynthesis, was prominently reduced. Golgi apparatus, in which SREBP2 is cleaved for activation, is intumescent or dispersed in erythroid cells of LKB1fl/fl EPORcre mice and LKB1fl/flGYPAcre mice. These results supported that loss of LKB1 impaired the cholesterol metabolism in erythropoiesis. To demonstrate Golgi apparatus-dependent cholesterol metabolism is essential for erythropoiesis, we treated LKB1fl/flGYPAcre mice with 2,3-oxidosqualene, the important intermediate in cholesterol synthesis and found that the phenotypes of LKB1fl/flGYPAcre mice were effectively restored. In parallel, 2,3-oxidosqualene treatment just slightly alleviated the anemia of LKB1fl/fl EPORcre mice. However, combination treatment with 2,3-oxidosqualene and ZLN005 was more effective in restoring phenotypes in LKB1fl/fl EPORcre mice, in contrast to ZLN005 alone. Thus, LKB1 serves as an essential metabolic regulator to coordinate energy metabolism in hematopoietic stem cells and lipid metabolism in erythoid cells, thereby maintaining homeostasis of haematopoietic stem cells and functional fitness of erythropoiesis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Murine hematopoietic stem cells change their surface phenotype during ex vivo expansion

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4314-4320 ◽  
Author(s):  
Cheng Cheng Zhang ◽  
Harvey F. Lodish
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Growth Factor ◽  
Hematopoietic Stem Cells ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Stem Cell Population ◽  
Stem Cell Markers ◽  
Hematopoietic Stem ◽  
Surface Phenotype

Abstract Ex vivo expansion of hematopoietic stem cells (HSCs) is important for many clinical applications, and knowledge of the surface phenotype of ex vivo–expanded HSCs will be critical to their purification and analysis. Here, we developed a simple culture system for bone marrow (BM) HSCs using low levels of stem cell factor (SCF), thrombopoietin (TPO), insulin-like growth factor 2 (IGF-2), and fibroblast growth factor-1 (FGF-1) in serum-free medium. As measured by competitive repopulation analyses, there was a more than 20-fold increase in numbers of long-term (LT)–HSCs after a 10-day culture of total BM cells. Culture of BM “side population” (SP) cells, a highly enriched stem cell population, for 10 days resulted in an approximate 8-fold expansion of repopulating HSCs. Similar to freshly isolated HSCs, repopulating HSCs after culture were positive for the stem cell markers Sca-1, Kit, and CD31 and receptors for IGF-2. Surprisingly, prion protein and Tie-2, which are present on freshly isolated HSCs, were not on cultured HSCs. Two other HSC markers, Endoglin and Mpl, were expressed only on a portion of cultured HSCs. Therefore, the surface phenotype of ex vivo–expanded HSCs is different from that of freshly isolated HSCs, but this plasticity of surface phenotype does not significantly alter their repopulation capability.

scholarly journals Genetic control of the frequency of hematopoietic stem cells in mice: mapping of a candidate locus to chromosome 1.

1996 ◽  
Vol 183 (3) ◽  
pp. 1141-1150 ◽  
Author(s):  
C E Müller-Sieburg ◽  
R Riblet
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Inbred Strains ◽  
Cell Number ◽  
Chromosome 1 ◽  
Cell Frequency ◽  
Candidate Locus ◽  
Hematopoietic Stem ◽  
Differentiation And Proliferation

The genetic elements that govern the differentiation and proliferation of hematopoietic stem cells remain to be defined. We describe here marked strain-specific differences in the frequency of long-term culture-initiating cells (LTC-IC) in the bone marrow of different strains of mice. Mice of C57Bl/6 background showed the lowest levels of stem cells in marrow, averaging 2.4 +/- .06 LTC-IC/10(5) cells, BALB/c is intermediate (9.1 +/- 4.2/10(5) cells), and DBA/2 mice contained a 11-fold higher frequency of LTC-IC (28.1 +/- 16.5/10(5) cells) than C57Bl/6 mice. The genetic factors affecting the size of the stem cell pool were analyzed in the C57Bl/6 X DBA/2 recombinant inbred strains; LTC-IC frequencies ranged widely, indicating that stem cell frequencies are controlled by multiple genes. Quantitative trait linkage analysis suggested that two loci that have major quantitative effects are located on chromosome 1 near Adprp and Acrg, respectively. The mapping of the locus near Adprp was confirmed by finding an elevated stem cell frequency in B6.C-H25, a C57Bl/6 congenic strain that carries a portion of chromosome 1 derived from BALB/c mice. We have named this gene Scfr1 (stem cell frequency regulator 1). The allelic forms of this gene may be an important predictor of stem cell number and thus would be useful for evaluating cell sources in clinical stem cell transplantation.

scholarly journals Cellular and molecular characterization of the role of the flk-2/flt-3 receptor tyrosine kinase in hematopoietic stem cells

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2422-2430 ◽  
Author(s):  
FC Zeigler ◽  
BD Bennett ◽  
CT Jordan ◽  
SD Spencer ◽  
S Baumhueter ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Tyrosine Kinase ◽  
Hematopoietic Stem Cell ◽  
Receptor Tyrosine Kinase ◽  
Lymphoid Cells ◽  
Stem Cell Population ◽  
Cell Populations ◽  
Hematopoietic Stem ◽  
Stem Cell Populations

The flk-2/flt-3 receptor tyrosine kinase was cloned from a hematopoietic stem cell population and is considered to play a potential role in the developmental fate of the stem cell. Using antibodies derived against the extracellular domain of the receptor, we show that stem cells from both murine fetal liver and bone marrow can express flk-2/flt-3. However, in both these tissues, there are stem cell populations that do not express the receptor. Cell cycle analysis shows that stem cells that do not express the receptor have a greater percentage of the population in G0 when compared with the flk-2/flt-3- positive population. Development of agonist antibodies to the receptor shows a proliferative role for the receptor in stem cell populations. Stimulation with an agonist antibody gives rise to an expansion of both myeloid and lymphoid cells and this effect is enhanced by the addition of kit ligand. These studies serve to further illustrate the importance of the flk-2/flt-3 receptor in the regulation of the hematopoietic stem cell.

Sign in / Sign up

Export Citation Format

Share Document