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Stromal niche inflammation mediated by IL-1 signaling is a targetable driver of hematopoietic aging

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE169162 | GEO | 2022/11/02

REPOSITORIES: GEO

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Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing.

Project description:Haematopoietic ageing is marked by a loss of regenerative capacity and skewed differentiation from haematopoietic stem cells (HSCs), leading to impaired blood production. Signals from the bone marrow niche tailor blood production, but the contribution of the old niche to haematopoietic ageing remains unclear. Here we characterize the inflammatory milieu that drives both niche and haematopoietic remodelling. We find decreased numbers and functionality of osteoprogenitors at the endosteum and expansion of central marrow LepR+ mesenchymal stromal cells associated with deterioration of the sinusoidal vasculature. Together, they create a degraded and inflamed old bone marrow niche. Niche inflammation in turn drives the chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors, which promotes myeloid differentiation and hinders haematopoietic regeneration. Moreover, we show how production of interleukin-1β (IL-1β) by the damaged endosteum acts in trans to drive the proinflammatory nature of the central marrow, with damaging consequences for the old blood system. Notably, niche deterioration, HSC dysfunction and defective regeneration can all be ameliorated by blocking IL-1 signalling. Our results demonstrate that targeting IL-1 as a key mediator of niche inflammation is a tractable strategy to improve blood production during ageing.

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Stromal niche inflammation mediated by IL-1 signaling is a targetable driver of hematopoietic aging

Project description:Stromal niche inflammation mediated by IL-1 signaling is a targetable driver of hematopoietic aging

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Stromal inflammation is a targetable driver of hematopoietic aging [Microarray analysis]

Project description:We performed integrated analyses of hematopoietic stem and progenitor cells as well as bone marrow stromal cells to better understand the underlying mechanisms of blood aging. To determine how the molecular state of multipotent progenitor (MPP) cells change with age we performed transcriptomic analyses of myeloid-biased MPP3 and lymphoid-biased MPP4 populations from young and old mice.

2022-11-02 | GSE168661 | GEO

Stromal inflammation is a targetable driver of hematopoietic aging [droplet-based scRNAseq]

Project description:To investigate global changes in the structure of the bone marrow niche with age, we performed droplet-based scRNAseq (10X Genomics) of unfractionated endosteal and central marrow stromal cells (Ter119-/CD45-). 8,735 cells passed QC, and hematopoietic clusters of cells were excluded based on marker gene expression, leaving 2359 cells distributed across 9 distinct clusters for final presentation.

2022-11-02 | GSE168586 | GEO

Stromal inflammation is a targetable driver of hematopoietic aging [Microarray analysis]

Project description:Stromal inflammation is a targetable driver of hematopoietic aging [Microarray analysis]

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Stromal inflammation is a targetable driver of hematopoietic aging [droplet-based scRNAseq]

Project description:Stromal inflammation is a targetable driver of hematopoietic aging [droplet-based scRNAseq]

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Stromal inflammation is a targetable driver of blood aging [droplet-based scRNAseq - Batch 2]

Project description:To investigate the role of IL1 signaling in hematopoietic aging, we performed droplet-based scRNAseq (10X Genomics) of hematopoietic stem and progenitor cells (LK/LSK) and unfractionated endosteal and central marrow stromal cells (Ter119-/CD45-) from young wild type and young and old wild type and IL1R1-/- C57BL/6 mice.

2022-11-02 | GSE189217 | GEO

Cohesin-mediated NF-?B signaling limits hematopoietic stem cell self-renewal in aging and inflammation.

Project description:Organism aging is characterized by increased inflammation and decreased stem cell function, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells (HSPCs) exhibit increased ground-stage NF-?B activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-?B signaling, which increases chromatin accessibility in the vicinity of NF-?B target genes in response to inflammation. Rad21 is required for normal differentiation, but limits self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-?B-dependent manner. HSCs from aged mice fail to down-regulate Rad21/cohesin and inflammation/differentiation signals in the resolution phase of inflammation. Inhibition of cohesin/NF-?B reverts hypersensitivity of aged HSPCs to inflammation-induced differentiation and myeloid-biased HSCs with disrupted/reduced expression of Rad21/cohesin are increasingly selected during aging. Together, Rad21/cohesin-mediated NF-?B signaling limits HSPC function during aging and selects for cohesin-deficient HSCs with myeloid-skewed differentiation.

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Rad21-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation

Project description:MTD project_description Inflammation and decreased stem cell function characterize organism aging, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signals, by increasing chromatin accessibility of inter-/intra-genic and enhancer regions. Rad21/NF-κB are required for normal differentiation, but limit self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB dependent manner. HSCs from aged mice fail to downregulate Rad21/cohesin and inflammation/differentiation inducing signals in the resolution phase after acute inflammation. and The inhibition of cohesin/NF-κB is sufficient to revert the hypersensitivity of aged HSPCs to inflammation-induced differentiation. During aging, myeloid-biased HSCs with disrupted and naturally occurring reduced expression of Rad21/cohesin are increasingly selected over lymphoid-biased HSCs. Together, Rad21/cohesin mediated NF-κB signaling limits HSPC function during aging and selects for cohesin deficient HSCs with myeloid skewed differentiation.

2018-11-28 | PXD011537 | Pride

TAOK1 negatively regulates IL-17-mediated signaling and inflammation.

Project description:Interleukin 17 (IL-17) is an important cytokine that can induce tissue inflammation and is involved in the pathogenesis of numerous autoimmune diseases. However, the regulation of its signaling transduction has not been well described. In this study, we report that thousand and one kinase 1 (TAOK1) functions as a negative regulator of IL-17-mediated signal transduction and inflammation. TAOK1 knockdown promotes IL-17-induced cytokine and chemokine expression and the activation of mitogen-activated protein kinases and nuclear factor-κB. We further demonstrate that TAOK1 interacts with IL-17 receptor A (IL-17RA) independent of its kinase activity, and TAOK1 dose-dependently prevents the formation of the IL-17R-Act1 (nuclear factor activator 1, also known as tumor necrosis factor receptor-associated factor 3 interacting protein 2) complex. Consistent with this, TAOK1 deficiency exacerbates colitis in the 2,4,6-trinitrobenzenesulfonic acid)-induced experimental model of inflammatory bowel disease, likely by its promotion of the IL-17-mediated signaling pathway. TAOK1 expression is decreased in the colons of ulcerative colitis patients. In conclusion, these findings suggest that TAOK1 is involved in the development of IL-17-related autoimmune disorders.

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