A clonogenic common myeloid progenitor that gives rise to all myeloid lineages

Akashi, Koichi; Traver, David; Miyamoto, Toshihiro; Weissman, Irving L.

doi:10.1038/35004599

Cited by 2,252 publications

(2,217 citation statements)

References 29 publications

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“…Stem/progenitor cells present in the marrow of normal mice expresses CD117 50 and are further divided by the CD34 marker, into specific cell subpopulations 51,52 . CD117 expression identifies also stem/progenitor cells in the marrow of mice with the Gata1 low mutation 11,44 .…”

Section: Stem/progenitor Cells From the Marrow And The Blood Of Gata1mentioning

confidence: 99%

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Migliaccio

Martelli

Verrucci

et al. 2008

Experimental Hematology

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Objective-To assess whether alterations in the SDF-1/CXCR4 occur in patients with primary myelofibrosis (PMF) and in Gata1 low mice, an animal model for myelofibrosis, and whether these abnormalities might account for increased stem/progenitor cell trafficking.Materials and Methods-In the mouse, SDF-1 mRNA levels were assayed in liver, spleen and marrow. SDF-1 protein levels were quantified in plasma and marrow and CXCR4 mRNA and protein levels were evaluated on stem/progenitor cells and megakaryocytes purified from the marrow. SDF-1 protein levels were also evaluated in plasma and in marrow biopsy specimens obtained from normal donors and PMF patients.Results-In Gata1 low mice, the plasma SDF-1 protein was 5-times higher than normal in younger animals. Furthermore, SDF-1 immuno-staining of marrow sections progressively increased with age. Similar abnormalities were observed in PMF patients. In fact, the plasma SDF-1 levels in PMF patients were significantly higher (by 2-fold) than normal (p<0.01) and SDF-1 immuno-staining of marrow biopsiy specimens demonstrated increased SDF-1 deposition in specific areas. In two of the patients, SDF-1 deposition was normalized by curative therapy with allogenic stem cell transplantation. Similarly to what already has been reported for PMF patients, the marrow from Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Gata1 low mice contained fewer CXCR4 pos CD117 pos cells and these cells expressed low levels of CXCR4 mRNA and protein. NIH Public AccessConclusion-Similar abnormalities in the SDF-1/CXCR4 axis are observed in PMF patients and in the Gata1 low mice model of myelofibrosis. We suggest that these abnormalities contribute to the increased stem/progenitor cell trafficking observed in this mouse model as well as patients with PMF.

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Section: Stem/progenitor Cells From the Marrow And The Blood Of Gata1mentioning

confidence: 99%

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Migliaccio

Martelli

Verrucci

et al. 2008

Experimental Hematology

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“…they repress the production of each other [7-9]. In the erythrocyte/megakaryocite lineage high expression levels of gene GATA-1 and low levels of PU.1 were detected [6,10]; conversely, in the granulocyte/macrophage lineage higher expression levels of PU.1 and low levels of GATA-1 were measured [5,11]. However, the initial progenitor cells stay in the third state that has low-level activation of both genes PU.1 and GATA-1 .…”

Section: Introductionmentioning

confidence: 99%

“…GATA-2 is one of the six members of the hematopoietic GATA factor family and is most abundantly expressed in HSCs as well as in immature progenitors in hematopoietic lineages [10]. Previous studies demonstrated a critical role of GATA-2 in the emergence and maintenance of HSCs [19].…”

Section: Introductionmentioning

confidence: 99%

Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell

Tian

Smith‐Miles

2014

BMC Systems Biology

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BackgroundHematopoiesis is a highly orchestrated developmental process that comprises various developmental stages of the hematopoietic stem cells (HSCs). During development, the decision to leave the self-renewing state and selection of a differentiation pathway is regulated by a number of transcription factors. Among them, genes GATA-1 and PU.1 form a core negative feedback module to regulate the genetic switching between the cell fate choices of HSCs. Although extensive experimental studies have revealed the mechanisms to regulate the expression of these two genes, it is still unclear how this simple module regulates the genetic switching.MethodsIn this work we proposed a mathematical model to study the mechanisms of the GATA-PU.1 gene network in the determination of HSC differentiation pathways. We incorporated the mechanisms of GATA switch into the module, and developed a mathematical model that comprises three genes GATA-1, GATA-2 and PU.1. In addition, a novel multiple-objective optimization method was designed to infer unknown parameters in the proposed model by realizing different experimental observations. A stochastic model was also designed to describe the critical function of noise, due to the small copy numbers of molecular species, in determining the differentiation pathways.ResultsThe proposed deterministic model has successfully realized three stable steady states representing the priming and different progenitor cells as well as genetic switching between the genetic states under various experimental conditions. Using different values of GATA-1 synthesis rate for the GATA-1 protein availability in the chromatin sites during the time period of GATA switch, stochastic simulations for the first time have realized different proportions of cells leading to different developmental pathways under various experimental conditions.ConclusionsMathematical models provide testable predictions regarding the mechanisms and conditions for realizing different differentiation pathways of hematopoietic stem cells. This work represents the first attempt at using a discrete stochastic model to realize the decision of HSC differentiation pathways showing a multimodal distribution.

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“…Multi-lineage development from single hematopoietic stem/progenitor cell raises the possibility that multi-or bi-potential lineage cells may exist at various branches of lineage development and that these cells may be able to respond under local conditions to determine their fate. Previous studies have suggested that erythroid and myeloid lineages share common precursor cells (common myeloid progenitors) giving rise to all types of myeloid cells and erythroid cells without lymphocytes [2,3]. A recent report has shown that common myeloid progenitors can be isolated from normal bone marrow using antibodies to cell surface markers, including CD19, CD34, CD45RA, IL-3Rα, and thrombopoietin receptor [4].…”

Section: Introductionmentioning

confidence: 99%

Identification of CD13+CD36+ cells as a common progenitor for erythroid and myeloid lineages in human bone marrow

Chen

Gao

Zhu

et al. 2007

Experimental Hematology

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Objective-To identify bi-potential precursor cells of erythroid and myeloid development in human bone marrow.Materials and Methods-Cells co-expressing CD13 and CD36 (CD13 + CD36 + ) were investigated by analyzing cell surface marker expression during erythroid development (induced with a combination of cytokines plus erythropoietin [EPO]), or myeloid development (induced with the same cocktail of cytokines plus granulocyte-colony stimulating factor [G-CSF]) of bone marrow derived CD133 cells in liquid cultures. CD13 + CD36 + subsets were also isolated on the 14 th day of cultures and further evaluated for their hematopoietic clonogenic capacity in methylcellulose.Results-Colony-forming analysis of sorted CD13 + CD36 + cells of committed erythroid and myeloid lineages demonstrated that these cells were able to generate erythroid, granulocyte, and mixed erythroid -granulocyte colonies. In contrast, CD13 + CD36 − or CD13 − CD36 + cells exclusively committed to granulocyte/monocyte or erythroid colonies, respectively, but failed to form mixed erythroid -granulocyte colonies; no colonies were detected in CD13 − CD36 − cells with lineagesupporting cytokines. In addition, our data confirmed that EPO induced both erythroid and myeloid commitment, while G-CSF only supported the differentiation of the myeloid lineage.Conclusions-The present data identify some CD13 + CD36 + cells as bi-potential precursors of erythroid and myeloid commitment in normal hematopoiesis. They provide a physiological explanation for the cell identification of myeloid and erythroid lineages observed in hematopoietic diseases. This unique fraction of CD13 + CD36 + cells may be useful for further studies on regulating erythroid and myeloid differentiation during normal and malignant hematopoiesis.

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A clonogenic common myeloid progenitor that gives rise to all myeloid lineages

Cited by 2,252 publications

References 29 publications

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell

Identification of CD13+CD36+ cells as a common progenitor for erythroid and myeloid lineages in human bone marrow

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