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Intrinsic and extrinsic control of hemopoietic stem cell numbers: mapping of a stem cell gene.

de Haan G, Van Zant G - J. Exp. Med. (1997)

Bottom Line: The population size of primitive stem cells (CAFC day 35) varied widely (up to sevenfold) among strains, unlike total CAFC day 7 numbers (cycling and quiescent), which were similar.Administration of the early acting cytokine flt-3 ligand to these strains resulted in activation of quiescent primitive stem cells exclusively in strains with high endogenous stem cell numbers (DBA and AKR), but was unrelated to strain-specific progenitor cell cycling.Linkage with this genomic interval was associated with a likelihood of odds score of 3.3, surpassing the level required for significance.

View Article: PubMed Central - PubMed

Affiliation: Blood and Marrow Transplant Program, Division of Hematology/Oncology, University of Kentucky Medical Center, Lexington, Kentucky 40536-0093, USA.

ABSTRACT
We evaluated in vivo interactions between extrinsic (growth factor induced) and intrinsic (genetically determined) effectors of mouse primitive hemopoietic stem cell proliferation and numbers. Accordingly, stem cell frequency and cell cycle kinetics were assessed in eight strains of inbred mice using the cobblestone area-forming cell (CAFC) assay. A strong inverse correlation was observed between mouse lifespan and the number of autonomously cycling progenitors (CAFC day 7) in the femur. The population size of primitive stem cells (CAFC day 35) varied widely (up to sevenfold) among strains, unlike total CAFC day 7 numbers (cycling and quiescent), which were similar. Administration of the early acting cytokine flt-3 ligand to these strains resulted in activation of quiescent primitive stem cells exclusively in strains with high endogenous stem cell numbers (DBA and AKR), but was unrelated to strain-specific progenitor cell cycling. To map loci affecting stem cell frequency, we quantified stem cells in BXD recombinant inbred mice (offspring of C57BL/6 and DBA/2). The resulting strain distribution pattern showed high concordance with a marker that mapped to chromosome 18 (19 cM). Linkage with this genomic interval was associated with a likelihood of odds score of 3.3, surpassing the level required for significance. Interestingly, this segment, containing the EGR-1 gene, shows synteny with human chromosome 5q, a region strongly associated with various hematological malignancies. Our findings indicate that a gene mapping to this region is mutated in either C57BL/6 or DBA/2 (and possibly AKR) mice. These studies in apparently healthy mice may facilitate the identification of a gene implicated in human 5q-syndromes.

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Different strains of mice have largely varying primitive stem  cell numbers. CAFC subsets were quantified in eight inbred strains of  mice for five consecutive weeks. Each point represents data obtained from  6 to 15 mice in a minimum of two independent experiments. CAFC frequency is shown on a logarithmic scale.
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Figure 3: Different strains of mice have largely varying primitive stem cell numbers. CAFC subsets were quantified in eight inbred strains of mice for five consecutive weeks. Each point represents data obtained from 6 to 15 mice in a minimum of two independent experiments. CAFC frequency is shown on a logarithmic scale.

Mentions: In all eight strains of mice the absolute number of the various CAFC subsets was determined weekly for five consecutive weeks (Fig. 3). When the frequency of progenitors (CAFC day 7) was assessed, no significant differences could be detected between strains, a result identical to that obtained when blood cell counts or cells forming colonies in semisolid medium (23) were compared among the strains. All strains had ∼2 × 104 CAFC day 7/femur. However, significant differences were observed when more primitive subsets were evaluated. Starting at day 14, the variation in cell frequency between strains increased steadily, indicating a distinct, genetically determined, control mechanism for primitive stem cells. At days 28 and 35, two strains (AKR and DBA/2), had significantly more stem cells than other strains; conversely, three strains (CBA, BALB/c, and C3H/He), had far fewer stem cells. CBA, the strain with the smallest stem cell pool, had fourfold fewer CAFC day 35 than C57BL/6, and eightfold fewer than AKR. These data suggest that the progenitor population is most likely linked to peripheral blood cell counts, which are equal in all strains, but that another mechanism(s) controls more primitive stem cells.


Intrinsic and extrinsic control of hemopoietic stem cell numbers: mapping of a stem cell gene.

de Haan G, Van Zant G - J. Exp. Med. (1997)

Different strains of mice have largely varying primitive stem  cell numbers. CAFC subsets were quantified in eight inbred strains of  mice for five consecutive weeks. Each point represents data obtained from  6 to 15 mice in a minimum of two independent experiments. CAFC frequency is shown on a logarithmic scale.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199035&req=5

Figure 3: Different strains of mice have largely varying primitive stem cell numbers. CAFC subsets were quantified in eight inbred strains of mice for five consecutive weeks. Each point represents data obtained from 6 to 15 mice in a minimum of two independent experiments. CAFC frequency is shown on a logarithmic scale.
Mentions: In all eight strains of mice the absolute number of the various CAFC subsets was determined weekly for five consecutive weeks (Fig. 3). When the frequency of progenitors (CAFC day 7) was assessed, no significant differences could be detected between strains, a result identical to that obtained when blood cell counts or cells forming colonies in semisolid medium (23) were compared among the strains. All strains had ∼2 × 104 CAFC day 7/femur. However, significant differences were observed when more primitive subsets were evaluated. Starting at day 14, the variation in cell frequency between strains increased steadily, indicating a distinct, genetically determined, control mechanism for primitive stem cells. At days 28 and 35, two strains (AKR and DBA/2), had significantly more stem cells than other strains; conversely, three strains (CBA, BALB/c, and C3H/He), had far fewer stem cells. CBA, the strain with the smallest stem cell pool, had fourfold fewer CAFC day 35 than C57BL/6, and eightfold fewer than AKR. These data suggest that the progenitor population is most likely linked to peripheral blood cell counts, which are equal in all strains, but that another mechanism(s) controls more primitive stem cells.

Bottom Line: The population size of primitive stem cells (CAFC day 35) varied widely (up to sevenfold) among strains, unlike total CAFC day 7 numbers (cycling and quiescent), which were similar.Administration of the early acting cytokine flt-3 ligand to these strains resulted in activation of quiescent primitive stem cells exclusively in strains with high endogenous stem cell numbers (DBA and AKR), but was unrelated to strain-specific progenitor cell cycling.Linkage with this genomic interval was associated with a likelihood of odds score of 3.3, surpassing the level required for significance.

View Article: PubMed Central - PubMed

Affiliation: Blood and Marrow Transplant Program, Division of Hematology/Oncology, University of Kentucky Medical Center, Lexington, Kentucky 40536-0093, USA.

ABSTRACT
We evaluated in vivo interactions between extrinsic (growth factor induced) and intrinsic (genetically determined) effectors of mouse primitive hemopoietic stem cell proliferation and numbers. Accordingly, stem cell frequency and cell cycle kinetics were assessed in eight strains of inbred mice using the cobblestone area-forming cell (CAFC) assay. A strong inverse correlation was observed between mouse lifespan and the number of autonomously cycling progenitors (CAFC day 7) in the femur. The population size of primitive stem cells (CAFC day 35) varied widely (up to sevenfold) among strains, unlike total CAFC day 7 numbers (cycling and quiescent), which were similar. Administration of the early acting cytokine flt-3 ligand to these strains resulted in activation of quiescent primitive stem cells exclusively in strains with high endogenous stem cell numbers (DBA and AKR), but was unrelated to strain-specific progenitor cell cycling. To map loci affecting stem cell frequency, we quantified stem cells in BXD recombinant inbred mice (offspring of C57BL/6 and DBA/2). The resulting strain distribution pattern showed high concordance with a marker that mapped to chromosome 18 (19 cM). Linkage with this genomic interval was associated with a likelihood of odds score of 3.3, surpassing the level required for significance. Interestingly, this segment, containing the EGR-1 gene, shows synteny with human chromosome 5q, a region strongly associated with various hematological malignancies. Our findings indicate that a gene mapping to this region is mutated in either C57BL/6 or DBA/2 (and possibly AKR) mice. These studies in apparently healthy mice may facilitate the identification of a gene implicated in human 5q-syndromes.

Show MeSH
Related in: MedlinePlus