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Cited by 60Mast cells and histamineFood Allergy and Anaphylaxis ResearchImmune cells in cancer

The DOI matches its Crossref record; 251 of the 252 references it cites were found in a registry or an index; none of the 278 sources its claims cite is checked for support yet.

Mast cell ontogeny: From fetal development to life‐long health and disease

Open access
Chia, Shin Li, Kapoor, Simran, Carvalho, Cyril, Bajénoff, Marc, Gentek, Rebecca·2023·Immunological Reviews
DOI 10.1111/imr.13191PMC PMC10952628
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Abstract

Summary: Mast cells (MCs) are evolutionarily ancient innate immune cells with important roles in protective immunity against bacteria, parasites, and venomous animals. They can be found in most organs of the body, where they also contribute to normal tissue functioning, for example by engaging in crosstalk with nerves. Despite this, they are most widely known for their detrimental roles in allergy, anaphylaxis, and atopic disease. Just like macrophages, mast cells were conventionally thought to originate from the bone marrow. However, they are already present in fetal tissues before the onset of bone marrow hematopoiesis, questioning this dogma. In recent years, our view of myeloid cell ontogeny has been revised. We now know that the first mast cells originate from progenitors made in the extra‐embryonic yolk sac, and later get supplemented with mast cells produced from subsequent waves of hematopoiesis. In most connective tissues, sizeable populations of fetal‐derived mast cells persist into adulthood, where they self‐maintain largely independently from the bone marrow. These developmental origins are highly reminiscent of macrophages, which are known to have critical functions in development. Mast cells too may thus support healthy development. Their fetal origins and longevity also make mast cells susceptible to genetic and environmental perturbations, which may render them pathological. Here, we review our current understanding of mast cell biology from a developmental perspective. We first summarize how mast cell populations are established from distinct hematopoietic progenitor waves, and how they are subsequently maintained throughout life. We then discuss what functions mast cells may normally have at early life stages, and how they may be co‐opted to cause, worsen, or increase susceptibility to disease.

Overview

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TL;DR

This review argues that mast cells are not solely bone-marrow-derived: the first mast cells arise from yolk-sac erythro-myeloid progenitors (EMPs), are later supplemented by fetal-restricted hematopoietic stem cells, and persist into adulthood with tissue-specific replacement. It proposes that these layered origins shape mast cell functions in development, allergy, mastocytosis, and cancer.

Key findings

  • Mast cell ontogeny is layered: the first mast cell progenitors arise from extraembryonic yolk-sac EMPs starting at E8.25 in mice, followed by a second wave predominantly from fetal-restricted HSCs, with possible perinatal contribution from adult-type HSCs. Adult connective-tissue mast cells, such as in skin and adipose tissue, remain largely fetal-derived and self-maintain, whereas mucosal mast cells receive more bone-marrow input.
  • Bone-marrow contribution to mast cells is limited at steady state: after bone-marrow transfer into lethally irradiated mice, approximately 50% of resident mast cells in cecum and stomach were donor-derived after 8 months, while over 4.5 months of parabiosis only cecum, stomach, and spleen received sizeable input from the parabiotic partner.
  • Fetal mast cells appear functionally mature early: granule-containing mast cells are detected in mouse cornea at E12.5 and skin at E14.5, and human fetal mast cells express tryptase (TPSAB1) and carry granules. The review links fetal mast cells to potential developmental roles in corneal vascular/nerve branching, brain sexual differentiation, mammary gland branching, and uterine spiral artery remodeling.
  • Ontogeny may explain disease heterogeneity: pediatric- and adult-onset mastocytosis may have distinct cells of origin, with activating KIT mutations described in HSCs and downstream progenitors of adult systemic disease but not pediatric patients; the paper also notes D186V in 80% of adult patients and almost 40% of pediatric cases, with another 40% of pediatric patients carrying other activating mutations.

Methods

  • Narrative review; no new primary data are reported. The authors synthesize mouse genetic fate-mapping models (Cdh5-CreERT2, Runx1-CreERT2, Csf1r-based), adoptive transfer, parabiosis, bone-marrow transplantation, Kit-mutant and Cre/LoxP mast cell depletion models, single-cell transcriptomics, and human fetal tissue studies.
  • The main analysis is conceptual: the authors reconcile conflicting fate-mapping interpretations into an updated model of mast cell origins and discuss implications for development, allergy, mastocytosis, mast cell activation syndrome, and cancer.

Limitations

  • The paper states that current fate-mapping models cannot spatially distinguish yolk-sac from intraembryonic hematopoiesis and rely on temporal distinctions; 4-hydroxy-tamoxifen remains bioavailable for at least 24 hours, causing overlap between labeled progenitor waves, and no single model is specific to each wave.
  • The paper states that Kit-dependent mast cell-deficient models are not mast-cell-specific because Kit has pleiotropic effects, and that many Cre-based models also target basophils, can show off-target effects or Cre leakiness, and vary in depletion efficiency; it recommends using complementary models.
  • Evident from the text: as a review, it does not perform a systematic search or meta-analysis, and several proposed developmental and pathological roles for mast cells remain speculative or based largely on mouse studies, with limited direct human evidence.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

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Crossref · 10.1111/imr.13191

Cites

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Figures

FIGURE 1 Mast cell development in the mouse. (Top) Different progenitors generating mast cells. The first mast cell progenitors arise from the erythro‐myeloid progenitors (EMPs) produced in the extra‐embryonic yolk sac starting at embryonic day 8.25 (E8.25). EMPs differentiate into mast cells via committed progenitors that may seed peripheral tissues directly from the yolk sac and/or through fetal liver intermediates. The intra‐embryonic aorta‐gonad‐mesonephros (AGM) region generates fetal‐restricted hematopoietic stem cells (HSCs) between E9.0 and E10.0 and adult‐type HSCs from E10.5 onwards. Both migrate to the fetal liver and may produce mast cells that supplement the first wave of EMP‐derived mast cells. Around birth, adult‐type HSCs colonize the bone marrow where they persist lifelong. Throughout life, bone marrow‐derived progenitors further complement mast cells notably at mucosal sites and in conditions of environmental perturbations. Mast cell‐committed progenitors express integrin α4β7, Cx3cr1, and Kit and undergo terminal maturation following recruitment into tissues. (Bottom) Origins of mast cells in adult tissues. In connective tissues like the skin and adipose tissues like the ones harboring the mammary glands, mast cells remain predominantly of fetal origins, with contribution from yolk sac EMPs and fetal‐restricted HSCs. In the lung and gut mucosa, fetal‐derived mast cells are largely replaced by bone marrow HSCs.
FIGURE 1 Mast cell development in the mouse. (Top) Different progenitors generating mast cells. The first mast cell progenitors arise from the erythro‐myeloid progenitors (EMPs) produced in the extra‐embryonic yolk sac starting at embryonic day 8.25 (E8.25). EMPs differentiate into mast cells via committed progenitors that may seed peripheral tissues directly from the yolk sac and/or through fetal liver intermediates. The intra‐embryonic aorta‐gonad‐mesonephros (AGM) region generates fetal‐restricted hematopoietic stem cells (HSCs) between E9.0 and E10.0 and adult‐type HSCs from E10.5 onwards. Both migrate to the fetal liver and may produce mast cells that supplement the first wave of EMP‐derived mast cells. Around birth, adult‐type HSCs colonize the bone marrow where they persist lifelong. Throughout life, bone marrow‐derived progenitors further complement mast cells notably at mucosal sites and in conditions of environmental perturbations. Mast cell‐committed progenitors express integrin α4β7, Cx3cr1, and Kit and undergo terminal maturation following recruitment into tissues. (Bottom) Origins of mast cells in adult tissues. In connective tissues like the skin and adipose tissues like the ones harboring the mammary glands, mast cells remain predominantly of fetal origins, with contribution from yolk sac EMPs and fetal‐restricted HSCs. In the lung and gut mucosa, fetal‐derived mast cells are largely replaced by bone marrow HSCs.CC BY · PubMed Central
FIGURE 2 Waves of fetal hematopoiesis and their labeling using genetic fate mapping in mice. (Top) Overlapping waves of hematopoiesis during fetal development. Fetal hematopoiesis occurs in a rapid succession of several waves that partially overlap in space and time. The extra‐embryonic yolk sac first produces primitive progenitors that do not contribute to mast cells. This is followed by single, continuous wave of erythro‐myeloid progenitors (EMPs) that produce the first mast cells. At the time that EMPs production ceases, hematopoiesis commences intra‐embryonically in the aorta‐gonad‐mesonephros region. The first hematopoietic stem cells (HSCs) are fetal‐restricted but remain poorly defined. This is followed by the production of adult‐type HSCs that colonize the bone marrow perinatally. (Bottom) Labeling of distinct and overlapping progenitor waves using genetic fate mapping. Key models that have been used to study mast cell ontogeny are shown. They depend on label induction in either endothelial cells with hemogenic activity (Cdh5, encoding vascular E‐Cadherin), pan‐hematopoietic progenitors (Runx1, encoding a transcription factor essential for hematopoiesis), or myeloid‐committed progenitors (Csf1r, which encodes a growth factor receptor expressed by EMPs). Labeling is achieved through Cre‐mediated recombination resulting in expression of a fluorescent protein. Recombination is induced at specific developmental time points matching hematopoietic waves through administration of 4‐hydroxy‐tamoxifen (4OHT). Double quoted annotations indicate what each labeling approach has been interpreted as in the literature on mast cell ontogeny. However, as discussed in the main text and Box 1, EMPs likely constitute a continuous wave (see main text and labeling partially overlaps between waves and fate‐mapping models). This is illustrated by color‐coded bars. Since there is currently no single fate‐mapping model specific to either wave, data obtained in the different approaches should be interpreted in a complementary manner.
FIGURE 2 Waves of fetal hematopoiesis and their labeling using genetic fate mapping in mice. (Top) Overlapping waves of hematopoiesis during fetal development. Fetal hematopoiesis occurs in a rapid succession of several waves that partially overlap in space and time. The extra‐embryonic yolk sac first produces primitive progenitors that do not contribute to mast cells. This is followed by single, continuous wave of erythro‐myeloid progenitors (EMPs) that produce the first mast cells. At the time that EMPs production ceases, hematopoiesis commences intra‐embryonically in the aorta‐gonad‐mesonephros region. The first hematopoietic stem cells (HSCs) are fetal‐restricted but remain poorly defined. This is followed by the production of adult‐type HSCs that colonize the bone marrow perinatally. (Bottom) Labeling of distinct and overlapping progenitor waves using genetic fate mapping. Key models that have been used to study mast cell ontogeny are shown. They depend on label induction in either endothelial cells with hemogenic activity (Cdh5, encoding vascular E‐Cadherin), pan‐hematopoietic progenitors (Runx1, encoding a transcription factor essential for hematopoiesis), or myeloid‐committed progenitors (Csf1r, which encodes a growth factor receptor expressed by EMPs). Labeling is achieved through Cre‐mediated recombination resulting in expression of a fluorescent protein. Recombination is induced at specific developmental time points matching hematopoietic waves through administration of 4‐hydroxy‐tamoxifen (4OHT). Double quoted annotations indicate what each labeling approach has been interpreted as in the literature on mast cell ontogeny. However, as discussed in the main text and Box 1, EMPs likely constitute a continuous wave (see main text and labeling partially overlaps between waves and fate‐mapping models). This is illustrated by color‐coded bars. Since there is currently no single fate‐mapping model specific to either wave, data obtained in the different approaches should be interpreted in a complementary manner.CC BY · PubMed Central
FIGURE 3 Functional implications of mast cell ontogeny for health and disease. (Centre) Mast cells may be generated from available progenitors to meet stage‐specific tissue demands. During normal development, they may support tissue remodeling processes. These physiological functions may be pathologically co‐opted by exposure to adverse stimuli during development, or for example by the tumor microenvironment. In disease, additional mast cells may be generated from the bone marrow and aberrantly imprinted. (Top) Mast cells support developmental processes taking place before, around, and after birth. In the developing cornea, they mediate fine‐tuning of vascular and neuronal networks. In the pre‐optic region of the brain of male mice, mast cells responding to hormones mediate synaptic patterning. During puberty and pregnancy, mast cells also support branching morphogenesis in the mammary gland and spiral artery remodeling in the uterus. (Bottom) Fetal mast cells are primed in utero by maternal allergy. This renders them hyperactivated, resulting in heightened offspring susceptibility to allergic disease. Mast cells with different developmental origins and microenvironmental imprinting could mediate their pro‐ and anti‐tumorigenic effects in cancer. Further explanations in the main text.
FIGURE 3 Functional implications of mast cell ontogeny for health and disease. (Centre) Mast cells may be generated from available progenitors to meet stage‐specific tissue demands. During normal development, they may support tissue remodeling processes. These physiological functions may be pathologically co‐opted by exposure to adverse stimuli during development, or for example by the tumor microenvironment. In disease, additional mast cells may be generated from the bone marrow and aberrantly imprinted. (Top) Mast cells support developmental processes taking place before, around, and after birth. In the developing cornea, they mediate fine‐tuning of vascular and neuronal networks. In the pre‐optic region of the brain of male mice, mast cells responding to hormones mediate synaptic patterning. During puberty and pregnancy, mast cells also support branching morphogenesis in the mammary gland and spiral artery remodeling in the uterus. (Bottom) Fetal mast cells are primed in utero by maternal allergy. This renders them hyperactivated, resulting in heightened offspring susceptibility to allergic disease. Mast cells with different developmental origins and microenvironmental imprinting could mediate their pro‐ and anti‐tumorigenic effects in cancer. Further explanations in the main text.CC BY · PubMed Central

Verification

Claims the paper makes

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  • It may state two separate claims as one. 113
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129 of 129

  • The paper relies on this without support.

    Mouse models of mast cell development and mast cell deficiency are informative for human mast cell biology and disease.

    “With such carefully designed approaches, we may ultimately be able to assess the relevance of findings obtained in mouse models for human development.”

  • The paper relies on this without support.

    The normal developmental kinetics of mast cells in mice, in which YS EMP-derived mast cells are gradually replaced by later progenitor waves, are similar enough in humans to explain pediatric- versus adult-onset mastocytosis.

    “Indeed, persistence of adult‐ and spontaneous regression of pediatric‐onset disease resemble the normal kinetics of mast cell development that we have outlined above: In mice, the first, YS EMP‐derived mast cells are gradually replaced by mast cells originating from later progenitor waves. 53 , 54”

  • The paper relies on this without support.

    If mast cells were essential for development, human mast cell deficiencies would be symptomatic or detectable.

    “mice that lack mast cells develop normally without obvious defects, and mast cell deficiencies have not been reported in humans.”

  • The paper relies on this without support.

    Mast cells are long-lived.

    “They are long‐lived, and most mast cell populations found in healthy connective tissues are established in the pre‐ or early postnatal periods and subsequently self‐maintain with site‐specific, but overall low input from the BM.”

  • The paper relies on this without support.

    Most mast cell populations in healthy connective tissues are established in the pre- or early postnatal periods and subsequently self-maintain with site-specific, but overall low input from the BM.

    “They are long‐lived, and most mast cell populations found in healthy connective tissues are established in the pre‐ or early postnatal periods and subsequently self‐maintain with site‐specific, but overall low input from the BM.”

  • The paper relies on this without support.

    Mast cells are already present in the fetus and appear functionally mature.

    “Mast cells are already present in the fetus, where they can sense and respond to environmental signals and thus, appear functionally mature.”

  • The paper relies on this without support.

    The first mast cells originate from EMPs produced in the extra-embryonic YS.

    “While it is now firmly established that the first mast cells originate from EMPs produced in the extra‐embryonic YS, it is less clear to what extent these and subsequent progenitor waves contribute to the various mast cell compartments throughout life.”

  • The paper relies on this without support.

    Progenitors with mast cell potential are present in mouse and human BM.

    “Progenitors with mast cell potential are also present in mouse and human BM, but their contribution is tissue‐ and potentially environment‐specific.”

  • The paper relies on this without support.

    At steady state, most mast cell populations in mouse connective tissue are only minimally supplemented from the BM.

    “At steady state, most mast cell populations in mouse connective tissue are only minimally supplemented from the BM.”

  • The paper relies on this without support.

    Skin-resident mast cells are largely self-maintained with negligible BM input.

    “On the other hand, skin‐resident mast cells are largely self‐maintained with neglectable BM input.”

  • The paper relies on this without support.

    Mast cells can first be detected in humans from the 8th gestational week onwards.

    “Mast cells can first be detected in humans from the 8th gestational week onwards.”

  • The paper relies on this without support.

    The first granule-containing mast cells in rodents have been identified at E12.5, more than halfway through fetal development.

    “Relative to the length of gestation, this is earlier than in rodents, where the first granule‐containing mast cells have been identified at E12.5, more than halfway through fetal development.”

  • The paper relies on this without support.

    Mast cell progenitors appear in peripheral tissues before mature mast cells, indicating that fetal progenitors commit to the mast cell lineage prior to entering tissues and undergo further maturation there.

    “Mast cell progenitors appear in peripheral tissues before mature mast cells, indicating that fetal progenitors commit to the mast cell lineage prior to entering tissues and undergo further maturation there, much like what has been shown for adult progenitors.”

  • The paper relies on this without support.

    There is evidence that mast cells contribute to tissue remodeling processes in the fetal cornea and pubertal mammary gland.

    “Although they are currently thought to be dispensable for normal development, there is evidence that they do contribute to tissue remodeling processes in the fetal cornea and pubertal mammary gland.”

  • The paper relies on this without support.

    Data obtained in Kit-independent mouse models found a role for mast cells in artery remodeling in the pregnant uterus.

    “However, in keeping with this idea, data obtained in Kit‐independent mouse models also found a role for mast cells in artery remodeling in the pregnant uterus.”

  • The paper relies on this without support.

    Sensitization of fetal mast cells by maternal IgE results in increased allergen sensitivity postnatally.

    “For example, sensitization of fetal mast cells by maternal IgE results in an increased allergen sensitivity postnatally.”

  • The paper relies on this without support.

    The abundance of BM-derived mast cells is highest in the gut and lung mucosa.

    “Considering that the abundance of BM‐derived mast cells is highest in the gut and lung mucosa, the microbiome may be a factor.”

  • The paper relies on this without support.

    Macrophages are recruited either de novo from BM-derived monocytes or as pre-existing mature cells from surrounding tissues, which can have different origins.

    “Macrophages are recruited either de novo from BM‐derived monocytes or as pre‐existing mature cells from surrounding tissues, which again can have different origins.”

  • The paper relies on this without support.

    Cellular senescence limits tumor progression.

    “Of note, cleavage of histone H3 and loss of lamin B1 also occur during cellular senescence, 237 , 238 , 239 a process known to limit tumor progression.”

  • The paper relies on this without support.

    Mast cells are enriched in (peri)tumoral areas.

    “This interpretation remains difficult to reconcile with their (peri)tumoral enrichment, however, which suggests active recruitment.”
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Citations

Cites

Show all 252 references

Research works printed but not linked: 25

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Metadata

Authors
Chia, S. L., Kapoor, S., Carvalho, C., Bajénoff, M., & Gentek, R.
Affiliations
  • MRC Centre for Reproductive Health (GB)
  • Centre d’Immunologie de Marseille-Luminy (FR)
Corresponding author
Gentek, Rebecca
ORCID
Venue
Immunological Reviews
Publisher
Wiley
Published
2023-02-08
Volume
315
Issue
1
Pages
31-53
ISSN
  • 0105-2896 (ISSN-L)
  • 1600-065X
DOI
10.1111/imr.13191
PMC
PMC10952628
OpenAlex
W4319461430
Cited by
60
References
252
Citations by year
2026: 13 · 2025: 24 · 2024: 15 · 2023: 8
FWCI
1.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunological Reviews (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL AMU (submittedVersion, other-oa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
  • Agence Nationale de la Recherche
  • Cancer Research UK
  • Fondation pour la Recherche Médicale
  • Kennedy Trust for Rheumatology Research
  • University of Edinburgh
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
  • Health Sciences › Medicine › Immunology and Allergy › Food Allergy and Anaphylaxis Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
mast cells, fetal development, yolk sac hematopoiesis, hematopoietic progenitor cells, innate immunity, allergy, anaphylaxis, atopic diseases, histogenesis
MeSH terms
Animals, Bone Marrow, Cell Differentiation, Hematopoiesis, Hematopoietic Stem Cells, Humans, Macrophages, Mast Cells, Fetal Development

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