In Vivo Labeling by CD73 Marks Multipotent Stromal Cells and Highlights Endothelial Heterogeneity in the Bone Marrow Niche

Breitbach, Martin; Kimura, Kenichi; Luís, Tiago C.; Fuegemann, Christopher J.; Woll, Petter S.; Hesse, Michael; Facchini, R; Rieck, Sarah; Jobin, Katarzyna; Reinhardt, Julia; Onodera, Osamu; Wenzel, Daniela; Geisen, Caroline; Kurts, Christian; Kastenmüller, Wolfgang; Hölzel, Michael; Jacobsen, Sten Eirik W.; Fleischmann, Bernd K.

doi:10.1016/j.stem.2018.01.008

Cited by 51 publications

(50 citation statements)

References 41 publications

(49 reference statements)

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“…Concomitantly, cells falling into the Sca-1 int CD105 hi gate were highly enriched in expression of the sinusoidal marker Flt-4 (vascular endothelial growth factor receptor-3) 12 . In agreement with previous work and with their reported role in recruitment of circulating cells to BM, sorted SECs displayed highest levels of expression of adhesion molecules such as P-, E-selectin and VCAM-1 60 – 62 at messenger RNA and/or protein levels (Supplementary Fig. 3c, d ).…”

Section: Resultssupporting

confidence: 92%

Quantitative spatial analysis of haematopoiesis-regulating stromal cells in the bone marrow microenvironment by 3D microscopy

et al. 2018

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Sinusoidal endothelial cells and mesenchymal CXCL12-abundant reticular cells are principal bone marrow stromal components, which critically modulate haematopoiesis at various levels, including haematopoietic stem cell maintenance. These stromal subsets are thought to be scarce and function via highly specific interactions in anatomically confined niches. Yet, knowledge on their abundance, global distribution and spatial associations remains limited. Using three-dimensional quantitative microscopy we show that sinusoidal endothelial and mesenchymal reticular subsets are remarkably more abundant than estimated by conventional flow cytometry. Moreover, both cell types assemble in topologically complex networks, associate to extracellular matrix and pervade marrow tissues. Through spatial statistical methods we challenge previous models and demonstrate that even in the absence of major specific interaction forces, virtually all tissue-resident cells are invariably in physical contact with, or close proximity to, mesenchymal reticular and sinusoidal endothelial cells. We further show that basic structural features of these stromal components are preserved during ageing.

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Section: Resultssupporting

confidence: 92%

Quantitative spatial analysis of haematopoiesis-regulating stromal cells in the bone marrow microenvironment by 3D microscopy

et al. 2018

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“…CD73 is a well-known surface marker for identifying mesenchymal stem cells [23]. Recent investigations revealed the potential for CD73+ photoreceptor precursors in future cell replacement therapy [39], and showed that CD73 could mark a multipotent stromal population [40]. CD73 was also reported to mark a fraction of mammary cells endowed with lineage plasticity [41].…”

Section: Discussionmentioning

confidence: 99%

CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma

Lü

Tang

et al. 2020

J Hematol Oncol

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Background: Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. Methods: CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation. Results: We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73-counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis. Conclusions: Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.

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“…Contrariwise, the loss of function for ECC and ECC-differentiated neuron-like cells is the diminished capacity of authentic stemness (eg, their inability to become mature neurons, defect in functional integration, etc.). Following this novel route of logical reasoning, cautions are deemed necessary when trying to use the NT2/N cells in vitro for investigating NSC and adult neuronal properties, modeling neuronal diseases, or discovering neuronal therapeutics [ 109 , 110 ]. We believe that data extrapolation without factoring the essential cell biology discrepancy could yield misleading information because changes in survival metabolic events may induce alterations of stemness marker presentations.…”

Section: Cscs Are Tumor Survival Cellsmentioning

confidence: 99%

“…To add special insight to the word “stem” when it is used to describe cancer cells for research and therapeutic development [ 110 ].…”

Section: Potential Benefits Of Adopting Tsc As a New Nomenclature To mentioning

confidence: 99%

Cancer Stem Cells or Tumor Survival Cells?

Teng

Wang

Kabataş

et al. 2018

Stem Cells and Development

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Research endeavors originally generated stem cell definitions for the purpose of describing normally sustainable developmental and tissue turnover processes in various species, including humans. The notion of investigating cells that possess a vague capacity of “stamm (phylum)” can be traced back to the late 19th century, mainly concentrating on cells that could produce the germline or the entire blood system. Lately, such undertakings have been recapitulated for oncogenesis, tumor growth, and cancer cell resistance to oncolytic therapies. However, due to the complexity and basic life-origin mechanisms comprising the genetic and epigenetic repertoire of the stemness in every developing or growing cell, presently there are ongoing debates regarding the biological essentials of the stem cell-like tumor initiation cells (ie, cancer stem cells; CSCs). This conceptual analysis focuses on the potential pitfalls of extrapolating that CSCs bear major traits of stemness. We propose a novel nomenclature of Tumor Survival Cells (TSCs) to further define tumor cells behaving like CSCs, based on the ruthless and detrimental features of Cancer Cell Survivology that appears fundamentally different from stem cell biology. Hence, precise academic separation of TSCs from all the stem cell-related labels applied to these unique tumor cells may help to improve scientific reasoning and strategies to decode the desperado-like survival behaviors of TSCs to eventually overcome cancer.

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In Vivo Labeling by CD73 Marks Multipotent Stromal Cells and Highlights Endothelial Heterogeneity in the Bone Marrow Niche

Cited by 51 publications

References 41 publications

Quantitative spatial analysis of haematopoiesis-regulating stromal cells in the bone marrow microenvironment by 3D microscopy

Quantitative spatial analysis of haematopoiesis-regulating stromal cells in the bone marrow microenvironment by 3D microscopy

CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma

Cancer Stem Cells or Tumor Survival Cells?

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