Identification of CXCL12‐abundant reticular cells in human adult bone marrow

Abstract

A population of mesenchymal stem cells, termed CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells or leptin receptor-expressing cells, are the major cellular component of niches for haematopoietic stem cells (HSCs) in murine bone marrow. CAR cells are characterized by several salient features, including much higher expression of CXCL12, stem cell factor (SCF), forkhead box C1 (FOXC1) and early B-cell factor 3 (EBF3), which are essential for HSC maintenance, than other cells. However, the human counterpart of CAR cells has not been fully described. Here, we show the presence of cells expressing much higher CXCL12 than other cells in human adult bone marrow using a flow cytometry-based in situ technique that enables high-throughput detection of mRNA at single-cell resolution. Most CXCL12 hi cells expressed high levels of SCF, FOXC1 and EBF3 and had the potential to differentiate into adipocytes and osteoblasts. Histologically, the nuclei of CXCL12 hi cells were identified and quantified by EBF3 expression in fixed marrow sections. CXCL12 hi cells sorted from residual bone marrow aspirates of chronic myeloid leukaemia patients expressed reduced levels of CXCL12, SCF, FOXC1 and EBF3 in correlation with increased leukaemic burden. Together, we identified the human counterpart of CAR cells, enabling the evaluation of their alterations in various haematological disorders by flow cytometric and histological analyses.

Deciphering Tumor Niches: Lessons From Solid and Hematological Malignancies

“…These CAR cells constitute a major component of HSPC niches by their capacities to produce such niche factors as CXCL12, SCF and IL-7. Similar stromal cells with salient features of CAR cells have been identified in human adult BM (10,71). In line with these findings, the CXCL12/CXCR4 axis is key in immunosuppression and metastatic spread in solid tumors, through reciprocal crosstalk between FAP High CAFs and regulatory T cells (Tregs), as well as FAP High CAFs and cancer cells, respectively (24,25,27).…”

Deconvolution of the hematopoietic stem cell microenvironment reveals a high degree of specialization and conservation

“…In that sense, our results, despite the low number of cells, may represent the first dataset that includes scRNAseq from the human endothelial and mesenchymal BM microenvironment. While we were able to identify mesenchymal and endothelial cells based on canonical markers shared with mice ( Aoki et al., 2021 ; Baryawno et al., 2019 ; Kalucka et al., 2020 ; Leimkühler et al., 2021 ; Matthews et al., 2020 ; Severe et al., 2019 ; Stumpf et al., 2020 ; Tikhonova et al., 2019 ; Wang et al., 2020 ; Xie et al., 2021 ), our human scRNAseq did not possess enough resolution to elucidate the heterogeneity of the human BM stroma to the same level as with the mouse data. Based on the extensive knowledge generated in the mouse, we therefore focused on characterizing how much of the information and targets from the mouse can be of interest in human characterization.…”

Therapeutically Targeting Cancers That Overexpress FOXC1: A Transcriptional Driver of Cell Plasticity, Partial EMT, and Cancer Metastasis

“…In murine reticular cells, FOXC1 expression is essential for maintenance of the niche where adult hematopoietic stem cells reside (170). These finding were later corroborated in the human system as well (171). These studies collectively highlight the role FOXC1 as a key transcriptional regulator of normal stem cell activity.…”