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Commitment of hematopoietic stem cells to erythroid, megakaryocyte and mast cell lineages is accelerated by IL-33 in humans

ABSTRACT: The understanding of human haematopoiesis has much improved in the last decade. It is now accepted that lineage commitment decisions already occur at the level of single haematopoietic stem cells (HSCs). It is also thought that the balance of such decisions is highly influenced by stress, inflammation, age or disease. However, a lack of tractable models that recapitulate human HSC function and blood formation hampers insights into mechanistic understanding. To address this, we developed an in vitro model of the earliest differentiation trajectories of human HSCs to study perturbations at single-cell resolution. Within 5 days, long-term (LT) HSCs (defined by CD19−CD34+CD38−CD45RA−CD49f+CD90+) plated in this model produced progenitors committed to all major blood lineages: myeloid, erythroid (Ery), lymphoid, megakaryocytes (Meg) and mast cells (MC). We uncovered a common cultured Ery, Meg and MC progenitor (cMEMP), marked by high expression of IL1RL1, encoding the receptor for IL-33, ST2. When exposed to IL-33, LT-HSCs show accelerated production of cMEMP and further enhanced differentiation towards the Meg, MC and Ery lineages (in vitro and Ery in vivo). This effect is dependent on MAPK signalling downstream of ST2. In summary our study: i) presents a novel model to study the earliest divisions of human haematopoiesis, ii) reports a common progenitor for Ery, Meg and MC and iii) identifies IL-33 as a novel mediator of the Ery, Meg and MC lineages through cMEMP. This dataset contains LT-HSCs cultured for 5 days then 10x scRNA-seq.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317286 | GEO | 2026/09/11

REPOSITORIES: GEO

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Commitment of haematopoietic stem cells to erythroid, megakaryocyte and mast cell lineages is accelerated by IL-33 in humans

Project description:The understanding of human haematopoiesis has much improved in the last decade. It is now accepted that lineage commitment decisions already occur at the level of single haematopoietic stem cells (HSCs). It is also thought that the balance of such decisions is highly influenced by stress, inflammation, age or disease. However, a lack of tractable models that recapitulate human HSC function and blood formation hampers insights into mechanistic understanding. To address this, we developed an in vitro model of the earliest differentiation trajectories of human HSCs to study perturbations at single-cell resolution. Within 5 days, long-term (LT) HSCs (defined by CD19−CD34+CD38−CD45RA−CD49f+CD90+) plated in this model produced progenitors committed to all major blood lineages: myeloid, erythroid (Ery), lymphoid, megakaryocytes (Meg) and mast cells (MC). We uncovered a common cultured Ery, Meg and MC progenitor (cMEMP), marked by high expression of IL1RL1, encoding the receptor for IL-33, ST2. When exposed to IL-33, LT-HSCs show accelerated production of cMEMP and further enhanced differentiation towards the Meg, MC and Ery lineages (in vitro and Ery in vivo). This effect is dependent on MAPK signalling downstream of ST2. In summary our study: i) presents a novel model to study the earliest divisions of human haematopoiesis, ii) reports a common progenitor for Ery, Meg and MC and iii) identifies IL-33 as a novel mediator of the Ery, Meg and MC lineages through cMEMP. This dataset contains LT-HSCs cultured for 3 or 5 days ± IL-33 then 10x scRNA-seq.

2026-09-11 | GSE317320 | GEO

Commitment of haematopoietic stem cells to erythroid, megakaryocyte and mast cell lineages is accelerated by IL-33 in humans [Multiome]

2026-09-11 | GSE317321 | GEO

Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis

Project description:Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, SCL/TAL1 and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary megakaryocytes (MEG) and erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, SCL/TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-specific cis-regulatory modules in multipotential hematopoietic progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming occurs is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential precursor via overlapping and divergent functions of shared hematopoietic transcription factors. Gene expression changes during the development of primary megakaryocytes (MEG) and erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells

2013-08-09 | E-GEOD-49664 | biostudies-arrayexpress

Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis

Project description:Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-associated cis-regulatory modules (CRMs) in multipotential progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential progenitor via overlapping and divergent functions of shared hematopoietic transcription factors. Genome-wide chromatin occupancy using ChIP-seq on 4 transcription factors (GATA1, GATA2, TAL1, and FLII) and three histone marks (H3K4me1, H3K4me3, and H3K27me3) in lineage-commited primary erythoblasts (ERY) and primary cultured megakaryocytes (MEG).

2014-11-14 | E-GEOD-51337 | biostudies-arrayexpress

Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis

Project description:Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-associated cis-regulatory modules (CRMs) in multipotential progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential progenitor via overlapping and divergent functions of shared hematopoietic transcription factors.

2014-11-14 | GSE51337 | GEO

Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis

2013-08-09 | GSE49664 | GEO

Mast Cells Control Lung Type 2 Inflammation via Prostaglandin E2-Driven Soluble ST2.

Project description:Severe asthma and sinus disease is a consequence of Type 2 inflammation (T2I), mediated by IL-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E2 (PGE2) drives production of sST2 to limit features of lung T2I. PGE2 deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE2 metabolites correlate with serum sST2. In mice, PGE2 enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs or EP2 receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE2 or ST2 expression by MCs back to control levels. PGE2 deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE2 thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE2 states.

2024-05-20 | GSE266501 | GEO

RNA-Sequencing of ST2+ Treg cells in response to IL-33 stimulation

Project description:The effects of IL-33 on ST2+ Treg cells were not studied thouroughly. We FACS-sorted in vitro expanded ST2+ Treg cells from C57BL/6 Foxp3-IRES-mRFP (B6 FIR) mice. We next used RNA-seq techonology to define how recombinant IL-33 (rIL-33) may impact mouse Treg by to assessing the transcriptome of IL-33-stimulated ST2+ Treg cells compared to that of untreated ST2+ Treg cells. Our data revealed that ST2+ Treg stimulated with rIL-33 for 6 hours exhibited increased expression of Il10 and Il13 compared to unstimulated ST2+ Treg cells.

2019-05-17 | GSE123922 | GEO

IL-33 promotes transcriptional and metabolic adaptations of tissue-resident Th2 cells

Project description:The polarization of naïve CD4+ T cells into Th2 cells is initiated in lymphoid organs and completed as the cells become tissue resident, where they express ST2, the receptor for the alarmin IL-33, which may be a key signal for tissue integration. Cellular metabolic requirements associated with this transition remain poorly understood. To address this, we compared the response of lymphoid tissue (LT) Th2 cells from helminth parasite-infected mice to stimulation by IL-33 versus through the T cell receptor via anti-CD3/CD28. We found that IL-33, but not anti-CD3/CD28, induced the development of tissue-resident like Th2 cells expressing ST2. This was associated with IL-33 induced changes in arginine metabolism linked to mTORC1 activation and polyamine synthesis, which were required for the development of tissue-resident like Th2 cells. Furthermore, IL-33 induced transcriptional changes in genes involved in chemotaxis and cell adhesion that may be critical for tissue integration. Our findings provide insights into adaptations of Th2 cells responding to tissue-integration cues

2026-04-22 | GSE312875 | GEO

The alarmin IL-33 amplifies an immune response in the degenerating retina

Project description:ST2 heterodimerizes with IL-1RAcp to form the receptor for IL-33, which is primarily associated with allergic inflammation by inducing Th2 responses. Recently, however, IL-33 was found to be expressed in the central nervous system and in retinal Muller cells which imply functions, as yet undescribed, beyond Th2 mediated inflammation. Muller cells support the health of the retina and photoreceptors and are also involved in inflammation in retinal degeneration. It is not known how IL-33/ST2 functions in this capacity. We recently found that ST2 ko mice are protected from CLE-induced photoreceptor loss, implying a detrimental effect of IL33/ST2 in CLE. We wish to perform microarray analysis using WT and ST2 KO mice in CLE model to better understand the mechanism by which IL-33/ST2 regulates retinal degeneration.

2015-12-17 | GSE74695 | GEO

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