Bone marrow adiposity and the hematopoietic niche: A historical perspective of reciprocity, heterogeneity, and...

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.

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.

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.