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

Baryawno, Ninib; Przybylski, Dariusz; Kowalczyk, Monika S.; Kfoury, Youmna; Sévère, Nicolas; Gustafsson, Karin; Kokkaliaris, Konstantinos D.; Mercier, François; 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.

doi:10.1016/j.cell.2019.04.040

Cited by 703 publications

(953 citation statements)

References 115 publications

(165 reference statements)

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“…Instead, they express constellation of groupdefining genes, including Ly6a, CD34, and Thy1, which have been shown to mark other adult stem cells, such as HSCs, keratinocyte stem cells, cancer stem cells, muscle stem cells etc [34][35][36][37] . 20 Along the differentiation routes of MSCs, the expression levels of lineage specific genes, such as A recent report examined the same question by performing scRNA-seq on Ter119 -CD71 -Linbone marrow cells from WT mice 8 and generated a similar clustering pattern and gene expression signature as ours, demonstrating the robustness of scRNA-seq methodology of identifying bone marrow mesenchymal populations. Based on a previous study showing that…”

Section: Discussionmentioning

confidence: 60%

“…As a positive control, chondrocyte cluster 9, corresponding to proliferative and prehypertrophic growth plate chondrocytes, had the highest proliferative status. It appeared that within bone marrow mesenchymal lineage cells, MSCs are less proliferative than late MSCs; 8 MBPs, LCPs, and osteoblasts are the most proliferative; adipocytes and osteocytes are nonproliferative. These results further supported our cluster annotation.…”

Section: Single Cell Transcriptomic Profiling Of Bone Marrow Mesenchymentioning

confidence: 99%

“…The other two studies depleted hematopoietic cells from bone marrow to analyze the remaining bone marrow cells 8,9 . Interestingly, all those studies identified a large MSC cluster expressing many adipocyte markers.…”

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confidence: 99%

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Single cell transcriptomics identifies a unique adipocyte population that regulates bone marrow environment

Zhong

Yao

Tower

et al. 2019

Preprint

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Bone marrow mesenchymal lineage cells are a heterogeneous cell population involved in bone homeostasis and diseases such as osteoporosis. While it is long postulated that they originate from mesenchymal stem cells (MSCs), the true identity of MSCs and their in vivo bifurcated differentiation routes into osteoblasts and adipocytes remain poorly understood. Here, by employing single cell transcriptome analysis, we identified MSCs and delineated their bilineage differentiation paths in young, adult and aging mice. Among several newly discovered mesenchymal subpopulations, one is a distinct population of adipose-lineage cells that we named marrow environment regulating adipose cells (MERAs). MERAs are non-proliferative, postprogenitor cells that express many mature adipocyte markers but are devoid of lipid droplets. They are abundant in the bone marrow of young mice, acting as pericytes and stromal cells that form numerous connections among themselves and with other cells inside bone, including endothelial cells. Genetic ablation of MERAs disrupts marrow vessel structure, promotes de novo bone formation. Taken together, MERAs represent a unique population of adipose lineage cells that exist only in the bone marrow with critical roles in regulating bone and vessel homeostasis.

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Section: Discussionmentioning

confidence: 60%

Section: Single Cell Transcriptomic Profiling Of Bone Marrow Mesenchymentioning

confidence: 99%

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Single cell transcriptomics identifies a unique adipocyte population that regulates bone marrow environment

Zhong

Yao

Tower

et al. 2019

Preprint

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“…More studies are needed to evaluate the heterogeneity of fibroblasts in fibrosis of the liver and kidney. Of note, scRNA sequencing of mouse bone marrow stroma identified five fibroblast subpopulations with gene expression profiles reminiscent of MSCs, with a possible role in niche regulation of tenocytes and tendon or ligament cells . These findings are intriguing, as they indicate heterogeneity in the bone marrow‐derived fibroblast subpopulation.…”

Section: Single‐cell Resolution Of Fibroblastsmentioning

confidence: 98%

Origin and functional heterogeneity of fibroblasts

2020

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The inherent plasticity and resiliency of fibroblasts make this cell type a conventional tool for basic research. But where do they come from, are all fibroblasts the same, and how do they function in disease? The first fibroblast lineages in mammalian development emerge from the ooze of primary mesenchyme during gastrulation. They are cells that efficiently create and negotiate the extracellular matrix of the mesoderm in order to migrate and meet their developmental fate. Mature fibroblasts in epithelial tissues live in the interstitial spaces between basement membranes that spatially delimit complex organ structures. While the function of resident fibroblasts in healthy tissues is largely conjecture, the accumulation of fibroblasts in pathologic lesions offers insight into biologic mechanisms that control their function; fibroblasts are poised to coordinate fibrogenesis in tissue injury, neoplasia, and aging. Here, we examine the developmental origin and plasticity of fibroblasts, their molecular and functional definitions, the epigenetic control underlying their identity and activation, and the evolution of their immune regulatory functions. These topics are reviewed through the lens of fate mapping using genetically engineered mouse models and from the perspective of single‐cell RNA sequencing. Recent observations suggest dynamic and heterogeneous functions for fibroblasts that underscore their complex molecular signatures and utility in injured tissues.

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“…Ex vivo manipulation and expansion of B‐lymphocytes that synthesize immunoglobulins and antibodies is another important target to leverage biomaterial‐directed clinical research . The recapitulation of 3D tissue architecture and tissue‐specific stromal cells found in the niche are essential to capturing key cellular processes which support hematopoietic‐lymphoid cells and are necessary to further the development of blood‐based therapeutics . The present study demonstrates the potential of biomaterial strategies in the engineering of scalable, well‐defined 3D coculture platforms to expand hematopoietic‐lymphoid cells.…”

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confidence: 99%

Thermoresponsive Inverted Colloidal Crystal Hydrogel Scaffolds for Lymphoid Tissue Engineering

Kwak

Lee

2020

Adv Healthcare Materials

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Inverted colloidal crystal (ICC) hydrogel scaffolds represent unique opportunities in modeling lymphoid tissues and expanding hematopoietic‐lymphoid cells. Fully interconnected spherical pore arrays direct the formation of stromal networks and facilitate interactions between stroma and hematopoietic‐lymphoid cells. However, due to the intricate architecture of these materials, release of expanded cells is restricted and requires mechanical disruption or chemical dissolution of the hydrogel scaffold. One potent biomaterials strategy to release pore‐entrapped hematopoietic‐lymphoid cells without breaking the scaffolds apart is to transiently increase the dimensions of these materials using stimuli‐responsive polymers. Having this mindset, thermoresponsive ICC scaffolds that undergo rapid (<1 min) and substantial (>300%) diameter change over a physiological temperature range (4–37 °C) by using poly(N‐isopropylacrylamide) (PNIPAM) with nanogel crosslinkers is developed. For a proof‐of‐concept study, the stromal niche by creating osteospheroids, aggregates of osteoblasts, and bone chips is first replicated, and subsequently Nalm‐6 model hematopoietic‐lymphoid cells are introduced. A sixfold increase in cell count is harvested when ICC hydrogel scaffolds are expanded without termination of the established 3D stromal cell culture. It is envisioned that thermoresponsive ICC hydrogel scaffolds will enable for scalable and sustainable ex vivo expansion of hematopoietic‐lymphoid cells.

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

Cited by 703 publications

References 115 publications

Single cell transcriptomics identifies a unique adipocyte population that regulates bone marrow environment

Single cell transcriptomics identifies a unique adipocyte population that regulates bone marrow environment

Origin and functional heterogeneity of fibroblasts

Thermoresponsive Inverted Colloidal Crystal Hydrogel Scaffolds for Lymphoid Tissue Engineering

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