A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia

• Published in: Cell Vol. 177; no. 7; pp. 1915 - 1932.e16
• Main Authors: Baryawno, Ninib, Przybylski, Dariusz, Kowalczyk, Monika S., Kfoury, Youmna, Severe, Nicolas, Gustafsson, Karin, Kokkaliaris, Konstantinos D., Mercier, Francois, Tabaka, Marcin, Hofree, Matan, Dionne, Danielle, Papazian, Ani, Lee, Dongjun, Ashenberg, Orr, Subramanian, Ayshwarya, Vaishnav, Eeshit Dhaval, Rozenblatt-Rosen, Orit, Regev, Aviv, Scadden, David T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.06.2019
• Subjects: Animals; bone formation; bone marrow; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; bone marrow niche; Cell Differentiation; hematopoiesis; Homeostasis; Humans; leukemia; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; myeloid leukemia; neoplasm cells; osteoblasts; Osteoblasts - metabolism; Osteoblasts - pathology; Osteogenesis; regulator genes; sequence analysis; single-cell RNA-sequencing; stem cell; stem cells; stroma; Stromal Cells - metabolism; Stromal Cells - pathology; taxonomy; Tumor Microenvironment; single-cell RNA-sequencing; leukemia; hematopoiesis; stem cell; stroma; bone marrow niche; tumor microenvironment
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.04.040

Stroma is a poorly defined non-parenchymal component of virtually every organ with key roles in organ development, homeostasis, and repair. Studies of the bone marrow stroma have defined individual populations in the stem cell niche regulating hematopoietic regeneration and capable of initiating leukemia. Here, we use single-cell RNA sequencing (scRNA-seq) to define a cellular taxonomy of the mouse bone marrow stroma and its perturbation by malignancy. We identified seventeen stromal subsets expressing distinct hematopoietic regulatory genes spanning new fibroblastic and osteoblastic subpopulations including distinct osteoblast differentiation trajectories. Emerging acute myeloid leukemia impaired mesenchymal osteogenic differentiation and reduced regulatory molecules necessary for normal hematopoiesis. These data suggest that tissue stroma responds to malignant cells by disadvantaging normal parenchymal cells. Our taxonomy of the stromal compartment provides a comprehensive bone marrow cell census and experimental support for cancer cell crosstalk with specific stromal elements to impair normal tissue function and thereby enable emergent cancer. [Display omitted] •A single-cell bone marrow stromal cell atlas at steady-state and emergent leukemia•A portal for comparative cell and molecular analyses of bone marrow stromal cells•Distinction among putative niche cells and types of osteolineage differentiation•Leukemia remodeling of stroma to the disadvantage of normal hematopoietic cells Molecular definition of the cell populations comprising bone marrow stroma is provided with single-cell resolution. Seventeen distinct cell subsets with new mesenchymal, pericyte, fibroblast, and endothelial subpopulations, new inferred osteolineage differentiation trajectories, and distinctions among Lepr, Nestin, and NG2-expressing HSC niche populations are defined. The changes imposed by an emergent AML indicate impaired stromal differentiation among mesenchymal cells and decreased expression of hematopoietic regulatory genes consistent with cancer cells indirectly impairing the normal hematopoietic cells with whom they must compete.