Resolution of a human mast cell development conundrum

Austen, K. Frank; Gurish, Michael F.

doi:10.1182/blood-2017-09-802173

Cited by 3 publications

(2 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, recent data suggest that the human system is similar to mouse, where IL-3 induces mast cell differentiation. 57 Some results suggest that CD123 expression in human is continuously downregulated during mast cell differentiation of cord blood cultures. 54 Other studies show that CD123 is maintained during development and that IL-3 itself can induce the expression of the receptor in mature mast cells.…”

Section: Identification Of Early Progenitors With Mast Cell-forming Cmentioning

confidence: 99%

Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells

Grootens¹,

Ungerstedt²,

Nilsson³

et al. 2018

Blood Advances

View full text Add to dashboard Cite

Hematopoietic stem cells differentiate into all types of blood cells, including peripheral tissue-resident mast cells. The early mast cell differentiation takes place in the bone marrow, after which the progenitor cells enter the circulation and mature once reaching their target organ. Early results from single-cell culture experiments and colony-forming assays have produced the classic hierarchical tree model of hematopoiesis. The introduction of high-throughput, single-cell RNA sequencing is now revolutionizing our understanding of the differentiation process, questioning the classic tree-based models. By integrating the results from early cell culture experiments with single-cell transcriptomics, we present a differentiation landscape model of hematopoiesis and discuss it with focus on mast cells. The review also describes how the hematologic neoplasm systemic mastocytosis can be used to model human hematopoiesis using naturally occurring cell barcoding by means of the common D816V mutation.

show abstract

Section: Identification Of Early Progenitors With Mast Cell-forming Cmentioning

confidence: 99%

Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells

Grootens¹,

Ungerstedt²,

Nilsson³

et al. 2018

Blood Advances

View full text Add to dashboard Cite

show abstract

“…Two distinct populations of mast cells (MCs) have been described, the connective tissue mast cells (CTMCs) that are often embryonic-derived and serve as innate tissue sentinels, and the bone marrow-derived mucosal mast cells (MMCs) that are induced in response to parasitic invasion or tissue damage (1). CTMCs are independent of T-cells while MMCs are recruited into the gut as progenitors and mature in a T-cell dependent manner (2–4).…”

Section: Introductionmentioning

confidence: 99%

Cell Intrinsic Deregulated ß-Catenin Signaling Promotes Expansion of Bone Marrow Derived Connective Tissue Type Mast Cells, Systemic Inflammation, and Colon Cancer

et al. 2019

Self Cite

View full text Add to dashboard Cite

Mast cells constitutively express ß-catenin and expand in solid tumors such as colon and skin cancer. However, the role of ß-catenin signaling in mast cells and the cause or effect of mast cell expansion and tumor growth has yet to be established. In earlier studies we used mast cell depletion and protease staining approaches, to provide evidence for a causative role of mast cells in small bowel polyposis, and related specific phenotypes and distributions of tumor infiltrating mast cells to stages of tumor growth. Here we report that, stabilization of ß-catenin expands mast cells to promote high incidence of colon polyposis and infrequent small bowel polyps and skin cancer. Expression of a dominant acting ß-catenin in mast cells (5CreCAT) stimulated maturation and expression of granule stored proteases. Both mucosal and connective tissue type mast cells accumulated in colonic small bowel polyps independent of gender, and mice developed chronic systemic inflammation with splenomegaly. Reconstitution of polyposis-prone mice with bone marrow from 5CreCAT mice resulted in focal expansion of connective tissue like mast cells, which are normally rare in benign polyps and characteristically expand during adenoma-to-carcinoma transition. Our findings highlight a hitherto unknown contribution of ß-catenin signaling in mast cells to their maturation and to increased risk of colon cancer.

show abstract

JNK signaling during IL-3–mediated differentiation contributes to the c-kit–potentiated allergic inflammatory capacity of mast cells

Hicks

Crozier

MacNeil

2023

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Mast cells are leukocytes that mediate various aspects of immunity and drive allergic hypersensitivity pathologies. Mast cells differentiate from hematopoietic progenitor cells in a manner that is largely IL-3 dependent. However, molecular mechanisms, including the signaling pathways that control this process, have yet to be thoroughly investigated. Here, we examine the role of the ubiquitous and critical MAPK signaling pathway due to its position downstream of the IL-3 receptor. Hematopoietic progenitor cells were harvested from the bone marrow of C57BL/6 mice and differentiated to bone marrow-derived mast cells (BMMCs) in the presence of IL-3 and MAPK inhibitors. Inhibition of the JNK node of the MAPK pathway induced the most comprehensive changes to the mature mast cell phenotype. BMMCs differentiated during impaired JNK signaling express impaired c-kit levels on the mast cell surface, first detected at week 3 of differentiation. Following 1 week of inhibitor withdrawal and subsequent stimulation of IgE-sensitized FcεRI receptors with allergen (TNP-BSA), and c-kit receptors with SCF, JNK-inhibited BMMCs exhibit impediments in early phase mediator release through degranulation (80% of control), as well as late phase secretion of CCL1, CCL2, CCL3, TNF, and IL-6. Experiments with dual stimulation conditions (TNP-BSA + SCF or TNP-BSA alone), show impediments in mediator secretion were found to be mechanistically linked to reduced c-kit surface levels. This study is the first to implicate JNK activity in IL-3-mediated mast cell differentiation, and also identifies development as a critical and functionally determinative period.

show abstract

Resolution of a human mast cell development conundrum

Cited by 3 publications

References 10 publications

Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells

Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells

Cell Intrinsic Deregulated ß-Catenin Signaling Promotes Expansion of Bone Marrow Derived Connective Tissue Type Mast Cells, Systemic Inflammation, and Colon Cancer

JNK signaling during IL-3–mediated differentiation contributes to the c-kit–potentiated allergic inflammatory capacity of mast cells

Contact Info

Product

Resources

About