Connecting the Dots: Resolving the Bone Marrow Niche Heterogeneity

Abstract

Single-cell sequencing approaches have transformed our understanding of stem cell systems, including hematopoiesis and its niche within the bone marrow. Recent reports examined the bone marrow microenvironment at single-cell resolution at steady state, following chemotherapy treatment, leukemic onset, and aging. These rapid advancements significantly informed our understanding of bone marrow niche heterogeneity. However, inconsistent representation and nomenclature among the studies hinder a comprehensive interpretation of this body of work. Here, we review recent reports interrogating bone marrow niche architecture and present an integrated overview of the published datasets.

The Hematopoietic Bone Marrow Niche Ecosystem

“…Analyses aimed at deciphering the composition of the murine BM niche in mice have identified over twenty different subpopulations of cells (Baryawno et al, 2019;Tikhonova et al, 2019;Baccin et al, 2020;Zhong et al, 2020) with distinct lineage relationships [designated populations P1 to P7 by Wolock et al (2019)]. An integrated analysis combining all of the datasets in these studies defined fourteen meta-clusters of cell subpopulations characterized by the expression of prohematopoietic factors (Dolgalev and Tikhonova, 2021). These fourteen clusters comprise endothelial cells [ECs: arterial (AEC), arteriolar, and sinusoidal (SEC), 32% of all cells], mesenchymal stem and progenitor cells [adipogenic and osteogenic MSPCs, also designated as CXCL12-abundant reticular (CAR) cells, 27%], osteoblasts (mature and immature, 5%), chondrocytes (16%), fibroblasts (18%), pericytes (1%), smooth muscle cells (0.1%), and Schwann cells (0.3%) 1 (Dolgalev and Tikhonova, 2021).…”

“…On the other hand, osteoblasts appear to be indispensable for HSC function (Calvi et al, 2003;Zhang et al, 2003). Both, adipo-and osteogenic lineages, are thought to arise from a common precursor, and, indeed, recent single cell studies show a consistent pattern of differentiation (Wolock et al, 2019), in which a multipotent subpopulation of osteoblastic markers corresponding to OsteoCAR cells (Dolgalev and Tikhonova, 2021), differentiates into apparently committed adipo-, osteo-, and chondrogenic precursors. Lineage fate decisions toward the osteogenic lineage may well depend on epigenetic KDM4B-dependent regulation as deletion of this methyltransferase leads to bone loss and osteoporosis (Deng et al, 2021).…”

“…The effects of estrogens on the niche have not been described in detail. It is clear, however, that the estrogen receptor Esr1 is expressed by both Adipo-and OsteoCAR cells, as well as fibroblasts (Dolgalev and Tikhonova, 2021). Thus, estrogen-directed signals affecting these cells of the niche may be expected in steady-state hematopoiesis and in transplantations.…”

“…One of the most important and earliest identified receptor/ligand interactions crucial for hematopoietic stem and progenitor cell function is the KITL (SCF) -KIT signaling axis (McCarthy et al, 1977;Broxmeyer et al, 1991;Ikuta et al, 1991;Waskow et al, 2002). In single cell studies from steady-state BM cells, expression of Kitl is mostly found in Lepr + AdipoCAR cells, AECs, some pericytes and OsteoCAR cells, whereas Kit is expressed in scattered AdipoCAR cells and SECs (Dolgalev and Tikhonova, 2021). Elegant, cell-type-specific depletion experiments have shown that mSCF provided by distinct niche cells can affect the function of different HSC and progenitor populations.…”

Bioengineering the Bone Marrow Vascular Niche

“…Recent advances in whole tissue imaging and deep learning ( Saçma et al, 2019 ) in mouse models have allowed to study the BM vascular network with unprecedent resolution, and specific endothelial cells lining specialized vessels have been defined as central actors of bone remodeling and cellular exchanges in homeostasis (reviewed in Hendriks and Ramasamy, 2020 ). Moreover, analytical integration of recently published data sets for BM stroma ‘omics analysis, on the single cell levels, allows the identification of additional stromal sub-types, revealing an undefined transitional population of ECs to be considered ( Dolgalev and Tikhonova, 2021 ). The BM vascular niche has also an important function in hematologic as well as solid cancer development and progression ( Batsivari et al, 2020 ; Haider et al, 2020 ).…”