美国哥伦比亚大学欧文医学中心Emmanuelle Passegué团队近期取得重要工作进展，他们研究发现IL-1信号介导的间质生态位炎症是造血功能老化的可靶向驱动因素。相关研究成果2023年1月17日在线发表于《自然-细胞生物学》杂志上。

据介绍，造血老化的特点是再生能力丧失和造血干细胞（HSC）偏向性的分化，导致造血功能受损。来自骨髓生态位的信号调节血液生成，但旧生态位对造血老化的贡献仍不清楚。

研究人员描述了驱动生态位和造血重塑的炎症环境。研究人员发现，内骨的骨祖细胞的数量和功能减少，中央骨髓LepR⁺间充质基质细胞的扩张与窦状血管系统的恶化有关。它们一起创造了一个退化和发炎的旧骨髓生态位。生态位炎症反过来又促使老龄HSC和多能干祖细胞中紧急骨髓造血途径的慢性激活，从而促进骨髓的分化并阻碍造血功能的再生。

此外，研究人员还展示了受损的内膜如何产生白细胞介素-1β（IL-1β）来驱动中央骨髓的促炎性，并对旧血液系统造成损害性后果。值得注意的是，生态位恶化，HSC功能障碍和再生缺陷都可以通过阻断IL-1信号来改善。

总之，研究结果表明，靶向IL-1作为生态位炎症的关键介质是改善衰老过程中血液生成的一种容易控制的策略。

附：英文原文

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

Author: Mitchell, Carl A., Verovskaya, Evgenia V., Calero-Nieto, Fernando J., Olson, Oakley C., Swann, James W., Wang, Xiaonan, Hrault, Aurlie, Dellorusso, Paul V., Zhang, Si Yi, Svendsen, Arthur Flohr, Pietras, Eric M., Bakker, Sietske T., Ho, Theodore T., Gttgens, Berthold, Passegu, Emmanuelle

Issue&Volume: 2023-01-17

Abstract: 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.

DOI: 10.1038/s41556-022-01053-0

Source: https://www.nature.com/articles/s41556-022-01053-0