Aberrant mast-cell differentiation in mice lacking the stem-cell leukemia gene (original) (raw)
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Journal of Experimental Medicine, 2003
Here it is shown that the phenotype of adult mice lacking the first enhancer (DNA hypersensitive site I) and the distal promoter of the GATA-1 gene (neo ⌬ HS or GATA-1 low mutants) reveals defects in mast cell development. These include the presence of morphologically abnormal alcian blue ϩ mast cells and apoptotic metachromatic Ϫ mast cell precursors in connective tissues and peritoneal lavage and numerous (60-70% of all the progenitors) "unique" trilineage cells committed to erythroid, megakaryocytic, and mast pathways in the bone marrow and spleen. These abnormalities, which were mirrored by impaired mast differentiation in vitro, were reversed by retroviral-mediated expression of GATA-1 cDNA. These data indicate an essential role for GATA-1 in mast cell differentiation.
The International Journal of Cell Cloning, 1987
Mast cells * Connective tissue-type mast cells Mucosal mast Interleukin 4 * Mutant mouse-Hematopoietic stem cell cells * Interleukin 3 Abstract. Information about the differentiation of mast cells has increased remarkably in the past ten years. This progress has resulted from the introduction of techniques which developed in other fields of experimental hematology. Once mast cells were recognized as a progeny of multipotential hematopoietic stem cells, their unique differentiation processes were clarified. Although most of the progeny of stem cells leave the hematopoietic tissue after maturation, undifferentiated precursors of mast cells leave the hematopoietic tissue. Morphologically, unidentifiable precursors migrate in the bloodstream, invade the connective tissues or the mucosa of the alimentary canal, proliferate, and differentiate into mast cells. Even after their morphological differentiation, some mast cells retain an extensive proliferative potential. There are at least two subpopulations of mast cells: a connective-tissue type and a mucosal type. Connective tissue-type and mucosal mast cells can be distinguished by histochemical, electron microscopical, biochemical and immunological criteria; however, these two types can interchange, and their phenotypes are determined by the anatomical microenvironment in which their final differentiation occurs. Although biochemical natures of the anatomical microenvironment are unknown, molecules that support proliferation and differentiation of mast cells in vitro have been characterized, i.e., interleukin 3 and interleukin 4. In the next ten years, increased information about the differentiation processes will probably induce further understanding of mast cell functions.
Increased Differentiation of Dermal Mast Cells in Mice Lacking the Mpl Gene
Stem Cells and Development, 2009
Thrombopoietin interactions with its receptor, Mpl, play an important role in the regulation of hematopoietic stem/progenitor cell proliferation and differentiation. In this study, we report that the mast cell restricted progenitor cells (MCP) and the mast cell precursors in the bone marrow of wild-type mice express Mpl on their surface. Furthermore, targeted deletion of the Mpl gene in mice decreases the number of MCP while increasing the number of mast cell precursors present in the marrow and spleen. It also increases the number of mast cells present in the dermis, in the peritoneal cavity, and in the gut of the mice. In addition, serosal mast cells from Mpl null mice have a distinctive differentiation profi le similar to that expressed by wild-type dermal mast cells. These results suggest that not only does ligation of thrombopoietin with the Mpl receptor exert an effect at the mast cell restricted progenitor cell level, but also plays an unexpected yet important role in mast cell maturation.
Differentiation of mast cell subpopulations from mouse embryonic stem cells
Journal of Immunological Methods, 2012
Mast cells can generally be divided into two major groups, connective tissue mast cells and mucosal mast cells. We and others have previously shown that these mast cell populations can be developed in vitro from mouse bone marrow stem cells using a combination of specific growth factors and cytokines. Mast cell differentiation from mouse embryonic stem (ES) cells is an important alternative method when developing mast cells from an embryonic lethal genetic deficiency or to reduce the use and handling of experimental animals. In this study, we have used protocols prior known to induce connective tissue like mast cells (CTLMC) (SCF and IL-4) and mucosal like mast cells (MLMC) (SCF, IL-3, IL-9 and TGF-β) from mouse bone marrow progenitor cells and employed these protocols to study if phenotype specific mast cells can be developed from ES cells. We here demonstrate that mast cells of the different phenotypes, CTLMC and MLMC, can be derived from mouse ES cells. The mast cell populations were characterized by chymase expression, receptor expression and their difference in activation pattern and in activationinduced survival.
Blood, 2003
The transplantation of primitive human cells into sublethally irradiated immune-deficient mice is the well-established in vivo system for the investigation of human hematopoietic stem cell function. Although mast cells are the progeny of hematopoietic stem cells, human mast cell development in mice that underwent human hematopoietic stem cell transplantation has not been reported. Here we report on human mast cell development after xenotransplantation of human hematopoietic stem cells into nonobese diabetic severe combined immunodeficient \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \((\mathrm{NOD{/}SCID}){/}{\gamma}_{\mathrm{c}}^{null}\) \end{document} (NOG) mice with severe combined immunodeficiency and interleukin 2 (IL-2) receptor γ-chain allelic mutation. Supported by the murine environment, human mast cell clusters developed in mouse dermis, but they required more ti...
The Journal of Immunology, 2013
Mast cell-deficient Kit W-sh ''sash'' mice are widely used to investigate mast cell functions. However, mutations of c-Kit also affect additional cells of hematopoietic and nonimmune origin. In this study, we demonstrate that Kit W-sh causes aberrant extramedullary myelopoiesis characterized by the expansion of immature lineage-negative cells, common myeloid progenitors, and granulocyte/macrophage progenitors in the spleen. A consistent feature shared by these cell types is the reduced expression of c-Kit. Populations expressing intermediate and high levels of Ly6G, a component of the myeloid differentiation Ag Gr-1, are also highly expanded in the spleen of sash mice. These cells are able to suppress T cell responses in vitro and phenotypically and functionally resemble myeloid-derived suppressor cells (MDSC). MDSC typically accumulate in tumor-bearing hosts and are able to dampen immune responses. Consequently, transfer of MDSC from naive sash mice into line 1 alveolar cell carcinoma tumorbearing wild-type littermates leads to enhanced tumor progression. However, although it can also be observed in sash mice, accelerated growth of transplanted line 1 alveolar cell carcinoma tumors is a mast cell-independent phenomenon. Thus, the Kit W-sh mutation broadly affects key steps in myelopoiesis that may have an impact on mast cell research.
Inactivating Mast Cell Function Promotes Steady-State and Regenerative Hematopoiesis
bioRxiv, 2022
Deeper understanding of the cellular and molecular pathways regulating hematopoiesis is critical to maximize the therapeutic potential of hematopoietic stem cells (HSCs) in curative procedures including hematopoietic stem cell transplantation (HST). We have recently identified mast cells (MCs) as therapeutically-targetable components of the HSC niche. Here, we demonstrate that mice lacking MCs display peripheral neutrophilia, expansion of bone marrow (BM) HSC populations, resistance to repeated 5-fluorouracil (5-FU) administration, and a BM genetic signature primed for hematopoietic proliferation. MC deficiency functionally altered both the hematopoietic and the stromal compartment of the BM as hematopoietic reconstitution was accelerated in wildtype mice that received MC deficient BM and in MC deficient recipients that received wildtype BM. Finally, we demonstrate that mice treated at steady state with the MC stabilizing agent ketotifen exhibit increased BM cellularity as well as e...