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IL-10 Signaling Restricts Murine Progenitor Cell Expansion and Preserves Stem Cell Function

ABSTRACT: Inflammation causes increased signaling and proliferation in hematopoietic stem and progenitor cells (HSPCs), but the specific role of anti-inflammatory cytokines such as IL-10 on HSPCs is less clear. Using IL-10 receptor (IL-10R)-deficient mice we observed an increased frequency and number of HSPCs in the bone marrow (BM) relative to wild-type (WT) mice with an increased frequency of mature myeloid cells. Consistent with this, we observed reduced expansion of WT lineage-negative HSPCs after in vitro exposure to IL-10 with a specifically pronounced suppression of MPP2 cells. This reduced expansion was not observed with IL-22 or IFN-λ2, cytokines which signal through receptors that also contain the IL-10 receptor common β chain or with HSPCs from Il10ra-/- mice. To understand the mechanism of reduced expansion of MPP2 cells and preserved HSC numbers in mice with intact IL-10 signaling, we stimulated FACS-purified WT cells with IL-10 and performed expression analysis. IL-10 stimulation of HSCs increased the non-canonical Wnt pathway gene Wnt4 which is implicated in HSC quiescence and long-term function. In contrast, IL-10 stimulation in MPP2 cells modulated the TGFβ pathway and increased the expression of E2f5, a transcription factor that negatively regulates proliferation. Taken together, this study reveals a previously unrecognized role for IL-10 in suppressing HSPC cell expansion and promoting HSC function.

ORGANISM(S): Mus musculus

PROVIDER: GSE188677 | GEO | 2021/11/19

REPOSITORIES: GEO

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MYCT1 CONTROLS ENVIRONMENTAL SENSING IN HUMAN HEMATOPOIETIC STEM CELLS

Project description:Hematopoietic stem cells (HSC) rely on a unique regulatory machinery that facilitates life-long blood production and enables reconstitution of the entire hematopoietic system upon transplantation. However, the biological processes governing human HSC self-renewal and engraftment ability are poorly understood and challenging to recapitulate ex vivo to facilitate robust human HSC expansion. We discovered a novel HSC regulatory protein, MYCT1 (MYCT target 1), that is selectively expressed in endothelial cells (EC) and undifferentiated human HSPCs but becomes drastically downregulated during HSC culture. Lentiviral knockdown of MYCT1 in human foetal liver and cord blood HSPCs revealed a critical role for MYCT1 in governing human HSPC expansion and engraftment ability. Single cell RNAseq of human CB HSPCs after MYCT1 knockdown and overexpression revealed that MYCT1 governs HSC functional competence and modulates cellular properties essential for HSC stemness, such as low mitochondrial metabolic activity. Indeed, restoring the compromised MYCT1 expression in cultured human CB HSPCs improved ex vivo expansion of the most undifferentiated human HSPCs and enhanced their engraftment ability. We found that MYCT1 is localized in the endosomal membrane and interacts with vesicle trafficking regulators and signalling machinery essential for HSC and EC function. Loss of MYCT1 led to excessive endocytosis and hyperactive signalling responses to cytokines, whereas restoring MYCT1 expression in cultured CB HSPCs balanced the abnormal endocytosis associated with prolonged culture and fine-tuned signalling responses. Our work identifies MYCT1-moderated endocytosis and environmental sensing as an essential regulatory mechanism required to preserve human HSC stemness, and pinpoints silencing of MYCT1 as a critical contributor to the dysfunction of cultured human HSCs that needs to be addressed to improve human HSC culture strategies.

2024-04-15 | PXD042257 | Pride

IL-1 Mediates Microbiome-Induced Inflamm-Aging of Hematopoietic Stem Cells

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2021-09-16 | GSE163503 | GEO

Gene expression analysis of human fetal liver hematopoietic stem and progenitor cells (HSPC) in culture

Project description:One of the long-standing goals in the field has been to establish a culture system that would allow maintenance of HSC properties ex vivo. In the absence of such system, the ability to model human hematopoiesis in vitro has been limited, and there has been little progress in the expansion of human HSCs for clinical application. To that end, we defined a mesenchyml stem cell co-culture system for expansion of clonally multipotent human HSPCs that are protected from apoptosis and immediate differentiation, and retain the HSPC phenotype. By performing a genome-wide gene expression analysis of purified HSPCs isolated at different stages of co-culture, we asked at the molecular level, to what degree hematopetic stem cell properties can be preserved during culture. This temporal gene expression data from in vivo derived- and ex vivo expanded human HSPCs will serve as a resource to identify novel regulatory pathways that control HSC properties, and to develop clinically applicable protocols for HSC expansion. Human CD34+ fetal liver cells were co-cultured on a subclone of OP9 stomal cells (OP9M2 sublemented with supportive cytokines (see below)). To distinguish between molecular changes acquired over prolonged culture versus immediately after exposure to culture, gene expression in isolated CD45+CD34+CD38-CD90+ HSPCs was assessed after 12 hours, 2 weeks and 5 weeks in culture. Cultured CD45+CD34+CD38-CD90+HSPCs were compared to freshly isolated CD45+CD34+CD38-CD90+HSPCs and their more differentiated CD45+CD34+CD38+CD90- downstream progenitor cells.

2013-01-31 | E-GEOD-34972 | biostudies-arrayexpress

Aging-induced pseudouridine synthase 10 impairs hematopoietic stem cells

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2021-06-26 | GSE178951 | GEO

MYCT1 Controls Environmental Sensing in human Hematopoietic Stem Cells [scRNA-seq]

Project description:We identified a novel HSC regulatory gene, MYCT1 (MYC target 1), that is selectively expressed in undifferentiated human HSPC and is critical for human HSC expansion and engraftment. MYCT1 knockdown (KD) in human fetal liver and cord blood (CB) HSPCs impaired expansion ex vivo and engraftment after transplantation, whereas restoring the compromised MYCT1 expression via lentiviral overexpression (OE) in cultured human CB HSPCs improved ex vivo expansion of the most undifferentiated human HSPCs (CD34+CD38-CD90+CD45RA-EPCR+ITGA3+) and enhanced their engraftment ability. We performed single cell RNAseq of uncultured human CB HSPCs, as well as 72 hours after MYCT1 KD and OE to identify MYCT1-regulated programs in HSC and understand the role of MYCT1 in governing human HSPC expansion and engraftment ability. Functional enrichment analysis linked the loss of MYCT1 in HLF+ HSCs to a profound dysregulation of multiple cellular programs essential for HSC stemness, such as oxidative phosphorylation or proteostasis, while MYCT1 OE had the opposite effect and showed closer similarity to uncultured HLF+ HSCs. These data indicate that the loss or gain of MYCT1 expression elicits major effects on programs regulating human HSC functional competence.

2024-04-08 | GSE232361 | GEO

Hematopoietic stem cells from mice treated with G-CSF or saline alone for 7 days

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2014-02-19 | E-GEOD-55094 | biostudies-arrayexpress

Hematopoietic stem cells from mice treated with G-CSF or saline alone for 36 hours

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2014-02-19 | E-GEOD-55093 | biostudies-arrayexpress

Label-free quantitative proteomics analysis of bone marrow cells of MK-LCM WT versus KO mice

Project description:High ploidy large cytoplasmic megakaryocytes (LCM) are critical negative regulators of hematopoietic stem cells (HSC) and are responsible for platelet formation. Using a mouse knockout model with normal megakaryocyte numbers but essentially devoid of LCM (MK-LCM KO), we demonstrated a pronounced increase in bone marrow HSC concurrent with endogenous mobilization and extramedullary hematopoiesis. When HSC isolated from a MK-LCM KO microenvironment were transplanted in lethally irradiated mice, the absence of LCM increased HSC in BM, blood and spleen. Severe thrombocytopenia was observed in animals with diminished LCM, although there was no change in megakaryocyte ploidy distribution. In contrast, WT HSC-generated LCM regulated a normal HSC pool and prevented thrombocytopenia. The present label-free quantitative LC-MSMS data was used to determine proteins that are differentially expressed in bone marrow cells of MK-LCM WT versus MK-LCM KO mice.

2023-05-10 | PXD040423 | Pride

MYCT1 Controls Environmental Sensing in human Hematopoietic Stem Cells [scRNA-seq Dextran]

2024-04-08 | GSE254857 | GEO

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