Mast cell transcriptional networks

Abstract

Unregulated activation of mast cells can contribute to the pathogenesis of inflammatory and allergic diseases, including asthma, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis (1;2). Absence of mast cells in animal models can lead to impairment in the innate immune response to parasites and bacterial infections (3)(4)(5). Aberrant clonal accumulation and proliferation of mast cells can result in a variety of diseases ranging from benign cutaneous mastocytosis to systemic mastocytosis or mast cell leukemia(6). Understanding mast cell differentiation provides important insights into mechanisms of lineage selection during hematopoiesis and can provide targets for new drug development to treat mast cell disorders,. In this review, we discuss controversies related to development, sites of origin,, and the transcriptional program of mast cells. KeywordsMast cells; transcription factors; GATA; PU.1; Mitf Origins of Mast CellsLike other granulocytes (neutrophils, eosinophils and basophils), mast cells are derived from hematopoietic stem cells in the marrow; however, they are unique with regard to the tissue compartments in which they traffic and reside. The gastrointestinal mucosa is the major compartment occupied by committed mast cell precursors in the mouse (7). Trafficking to these compartments is dependent on the expression of the alpha4 beta7 integrin and the chemokine receptor CXCR2.(8;9) Mast cell progenitors migrate to the connective tissue of the skin, lung, and the mucosa of other gastrointestinal tissues where they mature under the influence local 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. Transplantation studies in mice indicate that mast cells are derived from hematopoietic stem cells of marrow (or spleen)(10;11). Studies using prospectively identified hematopoietic precursors have reported different precursor cells that give rise to the committed mast cell progenitor One study found that the committed mast cell progenitor (MCP) arose from an early multipotential progenitor (MPP) that is distinct from the common myeloid progenitor (12). However, using a similar strategy to prospectively isolate hematopoietic precursors from mouse marrow, another study found that the MCP was derived from either the common myeloid progenitor or the granulocyte-monocyte progenitor(13) (Figure 1). Plasticity may permit other committed progenitor cell populations to be "reprogrammed" into the mast cell lineage by altering the expression of selected transcription factors. Isolated common lymphoid precursors that are retrovirally-tranduced with the tr...

The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor

“…To identify the mechanism behind this alteration, we analyzed the expression of transcription factors that are important for the maturation and generation of BMMCs and Gr-1/Mac-1-positive myeloid cells, including Mitf, Gata-2, and PU.1. 22 As seen in Figure 3B, p85␣-deficient cells showed reduced expression of Mitf relative to WT cells. In contrast, increased expression of Gata-2 was observed in p85␣-deficient cells compared with controls ( Figure 3B).…”

Increased Differentiation of Dermal Mast Cells in Mice Lacking the Mpl Gene

“…Under normal circumstances, MCP do not differentiate in the marrow, as indicated by the fact that the frequency of mast cell precursors (c-Kit high CD34 pos ) in this tissue remains limited (0.02%) throughout adult life [10]. Instead, MCP circulate in the blood to colonize extramedullary sites where they differentiate into tissue-restricted mast cells, each with a specifi c mast cell protease (MMCP) (for a review on mast cell-specifi c MMCP, see [11,12]) expression profi le [13,14], giving rise to dermal, mucosal, and serosal mast cell populations. The molecular mechanism in normal mice that restricts the mastocytopoietic potential of stem/progenitor cells to extramedullary sites, as well as the factors that guide their differentiation along different lineages is unknown.…”

PU.1 Positively Regulates GATA-1 Expression in Mast Cells

“…The mechanisms of this potential cooperativity between GATA-1 and PU.1 require further investigation. We have previously shown that, in fetal liver and yolk sac, the chromatin in both the IE and IB regions is open (4). Other investigators have also identified open chromatin that is sensitive to DNase I close to the IB start site in a multipotential hematopoietic progenitor cell line FDCP-mix (45).…”

“…Mature mast cells in the connective and mucosal tissues differentiate from uncommitted hematopoietic stem cells in the bone marrow; this process of lineage selection is orchestrated by a network of tightly regulated transcription factors (4). Current models of hematopoiesis suggest that multiple lineage-specific transcription factors are expressed at low levels in early, pluripotent progenitor cells.…”