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Bone marrow adiposity and the hematopoietic niche: A historical perspective of reciprocity, heterogeneity, and lineage commitment
Best Practice & Research Clinical Endocrinology & Metabolism ( IF 7.4 ) Pub Date : 2021-08-10 , DOI: 10.1016/j.beem.2021.101564
Josefine Tratwal 1 , Shanti Rojas-Sutterlin 1 , Charles Bataclan 1 , Sabine Blum 2 , Olaia Naveiras 3
Affiliation  

Purpose

Here we review the current knowledge on bone marrow adipocytes (BMAds) as active contributors to the regulation of the hematopoietic niche, and as potentially pivotal players in the progression of hematological malignancies. We highlight the hierarchical and functional heterogeneity of the adipocyte lineage within the bone marrow, and how potentially different contexts dictate their interactions with hematopoietic populations.

Recent findings

Growing evidence associates the adipocyte lineage with important functions in hematopoietic regulation within the BM niche. Initially proposed to serve as negative regulators of the hematopoietic microenvironment, studies have also demonstrated that BMAds positively influence the survival and maintenance of hematopoietic stem cells (HSCs). These seemingly incongruous findings may at least be partially explained by stage-specificity across the adipocytic differentiation axis and by BMAds subtypes, suggesting that the heterogeneity of these populations allows for differential context-based interactions. One such distinction relies on the location of adipocytes. Constitutive bone marrow adipose tissue (cBMAT) historically associates to the “yellow” marrow containing so-called “stable” BMAs larger in size, less responsive to stimuli, and linked to HSC quiescence. On the other hand, regulated bone marrow adipose tissue (rBMAT)-associated adipocytes, also referred to as “labile” are smaller, more responsive to hematopoietic demand and strategically situated in hematopoietically active regions of the skeleton. Here we propose a model where the effect of distinct BM stromal cell populations (BMSC) in hematopoiesis is structured along the BMSC-BMAd differentiation axis, and where the effects on HSC maintenance versus hematopoietic proliferation are segregated. In doing so, it is possible to explain how recently identified, adipocyte-primed leptin receptor-expressing, CXCL12-high adventitial reticular cells (AdipoCARs) and marrow adipose lineage precursor cells (MALPs) best support active hematopoietic cell proliferation, while adipose progenitor cells (APCs) and maturing BMAd gradually lose the capacity to support active hematopoiesis, favoring HSC quiescence. Implicated soluble mediators include MCP-1, PAI-1, NRP1, possibly DPP4 and limiting availability of CXCL12 and SCF. How remodeling occurs within the BMSC-BMAd differentiation axis is yet to be elucidated and will likely unravel a three-way regulation of the hematopoietic, bone, and adipocytic compartments orchestrated by vascular elements. The interaction of malignant hematopoietic cells with BMAds is precisely contributing to unravel specific mechanisms of remodeling.

Summary

BMAds are important operative components of the hematopoietic microenvironment. Their heterogeneity directs their ability to exert a range of regulatory capacities in a manner dependent on their hierarchical, spatial, and biological context. This complexity highlights the importance of (i) developing experimental tools and nomenclature adapted to address stage-specificity and heterogeneity across the BMSC-BMAd differentiation axis when reporting effects in hematopoiesis, (ii) interpreting gene reporter studies within this framework, and (iii) quantifying changes in all three compartments (hematopoiesis, adiposity and bone) when addressing interdependency.



中文翻译:

骨髓肥胖和造血生态位:互惠、异质性和谱系承诺的历史视角

目的

在这里,我们回顾了目前关于骨髓脂肪细胞 (BMads) 作为造血生态位调节的积极贡献者以及作为血液系统恶性肿瘤进展的潜在关键参与者的知识。我们强调骨髓内脂肪细胞谱系的层次和功能异质性,以及潜在的不同背景如何决定它们与造血种群的相互作用。

最近的发现

越来越多的证据将脂肪细胞谱系与 BM 生态位内造血调节的重要功能联系起来。最初提出作为造血微环境的负调节剂,研究还表明 BMAds 对造血干细胞 (HSC) 的存活和维持有积极影响。这些看似不协调的发现至少可以部分解释为脂肪细胞分化轴的阶段特异性和 BMAds 亚型,这表明这些群体的异质性允许基于不同背景的相互作用。一种这样的区别取决于脂肪细胞的位置。组成性骨髓脂肪组织 (cBMAT) 在历史上与含有所谓“稳定” BMA 的“黄色”骨髓相关联,该 BMA 尺寸较大,对刺激反应较弱,并与 HSC 静止相关。另一方面,受调节的骨髓脂肪组织 (rBMAT) 相关脂肪细胞,也称为“不稳定”,更小,对造血需求更敏感,并且战略性地位于骨骼的造血活跃区域。在这里,我们提出了一个模型,其中不同 BM 基质细胞群 (BMSC) 在造血中的影响是沿着 BMSC-BMad 分化轴构建的,并且对 HSC 维持与造血增殖的影响是分开的。通过这样做,可以解释最近发现的脂肪细胞引发的瘦素受体表达、CXCL12-高外膜网状细胞 (AdipoCARs) 和骨髓脂肪谱系前体细胞 (MALPs) 如何最好地支持活跃的造血细胞增殖,而脂肪祖细胞 (APC) 和成熟的 BMAd 逐渐失去支持活跃造血的能力,有利于 HSC 静止。涉及的可溶性介质包括 MCP-1、PAI-1、NRP1,可能还有 DPP4,并限制了 CXCL12 和 SCF 的可用性。BMSC-BMad 分化轴内的重塑如何发生尚待阐明,并且可能会解开由血管元素协调的造血、骨骼和脂肪细胞室的三向调节。恶性造血细胞与 BMAds 的相互作用正是有助于解开特定的重塑机制。BMSC-BMad 分化轴内的重塑如何发生尚待阐明,并且可能会解开由血管元素协调的造血、骨骼和脂肪细胞室的三向调节。恶性造血细胞与 BMAds 的相互作用正是有助于解开特定的重塑机制。BMSC-BMad 分化轴内的重塑如何发生尚待阐明,并且可能会解开由血管元素协调的造血、骨骼和脂肪细胞室的三向调节。恶性造血细胞与 BMAds 的相互作用正是有助于解开特定的重塑机制。

概括

BMAds 是造血微环境的重要组成部分。它们的异质性引导它们以依赖于其等级、空间和生物背景的方式发挥一系列监管能力的能力。这种复杂性突出了(i)开发实验工具和命名法的重要性,以在报告造血作用时解决跨 BMSC-BMad 分化轴的阶段特异性和异质性,(ii)在此框架内解释基因报告研究,以及(iii)在解决相互依赖关系时,量化所有三个部分(造血、肥胖和骨骼)的变化。

更新日期:2021-09-19
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