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

Abstract

Hematopoietic aging is marked by a loss of regenerative capacity and skewed differentiation from hematopoietic stem cells (HSC) leading to impaired blood production. Signals from the bone marrow (BM) niche tailor blood production, but the contribution of the old niche to hematopoietic aging remains unclear. Here, we characterize the in ammatory milieu that drives both niche and hematopoietic remodeling. We nd decreased numbers and functionality of osteoprogenitors (OPr) and expansion of pro-in ammatory perisinusoidal mesenchymal stromal cells (MSC) with deterioration of the sinusoidal vasculature, which together create a degraded and in amed old BM niche. Niche in ammation, in turn, drives chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors (MPP), which promotes myeloid differentiation at the expense of lymphoid and erythroid commitment and hinders hematopoietic regeneration. Remarkably, niche deterioration, HSC dysfunction and defective hematopoietic regeneration can all be ameliorated by blocking IL-1 signaling. Our results demonstrate that targeting IL-1 as a key mediator of niche in ammation is a tractable strategy to improve blood production during aging. HighlightsBoth endosteal and central marrow niche populations are remodeled with age Old niche populations show disruption of cell identity and enrichment of in ammatory response genes Emergency myelopoiesis pathways are chronically activated in response to niche in ammation Targeting niche-mediated IL-1 signaling attenuates stromal and blood aging Etoc BlurbPassegué and colleagues examine the aged bone marrow niche microenvironment to understand its contribution to blood aging and identify targetable factor(s) for functional anti-aging interventions. They show that crosstalk between the in amed niche and the in amed hematopoietic system leads to degraded blood production both at steady state and during regeneration, and identify IL-1 as a major targetable driver of age-related niche and blood system deterioration.

Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging

“…92–94 Furthermore, an inflammatory bone marrow niche in aged mice, including IL-1β produced by a damaged endosteum, leads to increased myelopoiesis and impaired hematopoietic recovery. 95 In agreement with the second hypothesis are data from zebrafish where subclonal CH mutations lead to expression of pro-inflammatory genes in mature mutant myeloid cells but anti-inflammatory genes in mutant HSPCs, providing them with a relative fitness advantage. 96 In mice when TET2 MUT subclones are exposed to IL-1, they functionally outcompete WT HSCs.…”

Unraveling Heterogeneity in the Aging Hematopoietic Stem Cell Compartment: An Insight From Single-cell Approaches

“…72 Interestingly, the effects of IL-1-driven proinflammatory aging effects in the niche were reversible upon targeting of IL-1 signaling. 71,72…”

“…72 Interestingly, the effects of IL-1-driven proinflammatory aging effects in the niche were reversible upon targeting of IL-1 signaling. 71,72 A recent study demonstrated impaired mitochondrial function in aged HSPCs when stressed with LPSs. 73 HSPC malfunction during stress was supported by the accumulation of senescent, p16 INK4Apositive MSCs that naturally occur with aging in the bone marrow.…”

“…IL‐1 signaling has been identified as a key proinflammatory cytokine in the bone marrow niche in mice where IL‐1 exposure led to accelerate proliferation and myeloid differentiation of HSCs through PU.1‐mediated gene expression 71 . Moreover, IL1ß signaling stemming from the aging, damaged endosteum drives the proinflammatory phenotype of the central bone marrow, resulting in HSC dysfunction in old mice 72 . Interestingly, the effects of IL‐1‐driven proinflammatory aging effects in the niche were reversible upon targeting of IL‐1 signaling 71,72 …”

“…71 Moreover, IL1ß signaling stemming from the aging, damaged endosteum drives the proinflammatory phenotype of the central bone marrow, resulting in HSC dysfunction in old mice. 72 Interestingly, the effects of IL-1-driven proinflammatory aging effects in the niche were reversible upon targeting of IL-1 signaling. 71,72 A recent study demonstrated impaired mitochondrial function in aged HSPCs when stressed with LPSs.…”