Student or educator? Sign up with your school email and get 6 months of Pro free.
CoChat
Sign Up
Cited by 884

The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.

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

Open access
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.·2019·Cell
DOI 10.1016/j.cell.2019.04.040
Open this paper in CoChat — free account

Abstract

SUMMARY 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-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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.cell.2019.04.040

Cites

21 of 21 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Research works printed but not linked: 94

  1. Abdallah, 2015, CD34 defines an osteoprogenitor cell population in mouse bone marrow stromal cells, Stem Cell Res. (Amst.), 15, 449, 10.1016/j.scr.2015.09.005 · DOI
  2. Acar, 2015, Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal, Nature, 526, 126, 10.1038/nature15250 · DOI · Paper page
  3. Angerer, 2016, destiny: diffusion maps for large-scale single-cell data in R, Bioinformatics, 32, 1241, 10.1093/bioinformatics/btv715 · DOI · Paper page
  4. Arai, 2004, Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche, Cell, 118, 149, 10.1016/j.cell.2004.07.004 · DOI
  5. Armulik, 2011, Pericytes: developmental, physiological, and pathological perspectives, problems, and promises, Dev. Cell, 21, 193, 10.1016/j.devcel.2011.07.001 · DOI · Paper page
  6. Arnold, 2007, MEF2C transcription factor controls chondrocyte hypertrophy and bone development, Dev. Cell, 12, 377, 10.1016/j.devcel.2007.02.004 · DOI
  7. Bauche, 2007, Overexpression of adiponectin targeted to adipose tissue in transgenic mice: impaired adipocyte differentiation, Endocrinology, 148, 1539, 10.1210/en.2006-0838 · DOI
  8. Bernad, 1994, Interleukin-6 is required in vivo for the regulation of stem cells and committed progenitors of the hematopoietic system, Immunity, 1, 725, 10.1016/S1074-7613(94)80014-6 · DOI
  9. Blondel, 2008, Fast unfolding of communities in large networks, arXiv
  10. Boyd, 2017, Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche, Nat. Cell Biol., 19, 1336, 10.1038/ncb3625 · DOI
  11. Butler, 2010, Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells, Cell Stem Cell, 6, 251, 10.1016/j.stem.2010.02.001 · DOI · Paper page
  12. Calvi, 2003, Osteoblastic cells regulate the haematopoietic stem cell niche, Nature, 425, 841, 10.1038/nature02040 · DOI
  13. Chan, 1995, A COL2A1 mutation in achondrogenesis type II results in the replacement of type II collagen by type I and III collagens in cartilage, J. Biol. Chem., 270, 1747, 10.1074/jbc.270.4.1747 · DOI
  14. Chan, 2015, Identification and specification of the mouse skeletal stem cell, Cell, 160, 285, 10.1016/j.cell.2014.12.002 · DOI · Paper page
  15. Chen, 2017, Prognostic significance of osteopontin in acute myeloid leukemia: A meta-analysis, Mol. Clin. Oncol., 7, 275
  16. Corada, 2001, Monoclonal antibodies directed to different regions of vascular endothelial cadherin extracellular domain affect adhesion and clustering of the protein and modulate endothelial permeability, Blood, 97, 1679, 10.1182/blood.V97.6.1679 · DOI · Paper page
  17. Corral, 1996, An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes, Cell, 85, 853, 10.1016/S0092-8674(00)81269-6 · DOI · Paper page
  18. Coutu, 2017, Three-dimensional map of nonhematopoietic bone and bone-marrow cells and molecules, Nat. Biotechnol., 35, 1202, 10.1038/nbt.4006 · DOI
  19. Coutu, 2018, Multicolor quantitative confocal imaging cytometry, Nat. Methods, 15, 39, 10.1038/nmeth.4503 · DOI
  20. Delmas, 1986, [Osteocalcin (or bone gla-protein), a new biological marker for studying bone pathology], Presse Med., 15, 643
  21. Ding, 2013, Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches, Nature, 495, 231, 10.1038/nature11885 · DOI · Paper page
  22. Ding, 2012, Endothelial and perivascular cells maintain haematopoietic stem cells, Nature, 481, 457, 10.1038/nature10783 · DOI
  23. Doan, 2013, Tie2(+) bone marrow endothelial cells regulate hematopoietic stem cell regeneration following radiation injury, Stem Cells, 31, 327, 10.1002/stem.1275 · DOI
  24. Doege, 1991, Complete coding sequence and deduced primary structure of the human cartilage large aggregating proteoglycan, aggrecan. Human-specific repeats, and additional alternatively spliced forms, J. Biol. Chem., 266, 894, 10.1016/S0021-9258(17)35257-2 · DOI · Paper page
  25. Dong, 2016, Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment, Nature, 539, 304, 10.1038/nature20131 · DOI · Paper page
  26. Duarte, 2018, Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML, Cell Stem Cell, 22, 64, 10.1016/j.stem.2017.11.006 · DOI
  27. Foster, 1994, Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene, Nature, 372, 525, 10.1038/372525a0 · DOI · Paper page
  28. Frisch, 2012, Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia, Blood, 119, 540, 10.1182/blood-2011-04-348151 · DOI
  29. Fuady, 2014, Hypoxia-inducible factor-mediated induction of WISP-2 contributes to attenuated progression of breast cancer, Hypoxia, 2, 23
  30. Geyh, 2016, Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia, Leukemia, 30, 683, 10.1038/leu.2015.325 · DOI
  31. Gomei, 2010, Functional differences between two Tie2 ligands, angiopoietin-1 and -2, in regulation of adult bone marrow hematopoietic stem cells, Exp. Hematol., 38, 82, 10.1016/j.exphem.2009.11.007 · DOI
  32. Greenbaum, 2013, CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance, Nature, 495, 227, 10.1038/nature11926 · DOI · Paper page
  33. Grünberg, 2014, The Novel Secreted Adipokine WNT1-inducible Signaling Pathway Protein 2 (WISP2) Is a Mesenchymal Cell Activator of Canonical WNT, J. Biol. Chem., 289, 6899, 10.1074/jbc.M113.511964 · DOI
  34. Hammarstedt, 2013, WISP2 regulates preadipocyte commitment and PPARγ activation by BMP4, Proc. Natl. Acad. Sci. USA, 110, 2563, 10.1073/pnas.1211255110 · DOI
  35. Hanoun, 2014, Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche, Cell Stem Cell, 15, 365, 10.1016/j.stem.2014.06.020 · DOI · Paper page
  36. Hawkins, 2016, T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments, Nature, 538, 518, 10.1038/nature19801 · DOI
  37. Hooper, 2009, Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells, Cell Stem Cell, 4, 263, 10.1016/j.stem.2009.01.006 · DOI
  38. Huang, 2007, Signaling and transcriptional regulation in osteoblast commitment and differentiation, Front. Biosci., 12, 3068, 10.2741/2296 · DOI · Paper page
  39. Inada, 1999, Maturational disturbance of chondrocytes in Cbfa1-deficient mice, Dev. Dyn., 214, 279, 10.1002/(SICI)1097-0177(199904)214:4<279::AID-AJA1>3.0.CO;2-W · DOI
  40. Itkin, 2016, Distinct bone marrow blood vessels differentially regulate haematopoiesis, Nature, 532, 323, 10.1038/nature17624 · DOI · Paper page
  41. Jacomy, 2014, ForceAtlas2, a continuous graph layout algorithm for handy network visualization designed for the Gephi software, PLoS ONE, 9, e98679, 10.1371/journal.pone.0098679 · DOI · Paper page
  42. Kalluri, 2016, The biology and function of fibroblasts in cancer, Nat. Rev. Cancer, 16, 582, 10.1038/nrc.2016.73 · DOI · Paper page
  43. Kanatani, 2000, Stimulatory effect of insulin-like growth factor binding protein-5 on mouse osteoclast formation and osteoclastic bone-resorbing activity, J. Bone Miner. Res., 15, 902, 10.1359/jbmr.2000.15.5.902 · DOI
  44. Kfoury, 2015, Mesenchymal cell contributions to the stem cell niche, Cell Stem Cell, 16, 239, 10.1016/j.stem.2015.02.019 · DOI
  45. Kim, 2009, Hypoxic tumor microenvironment and cancer cell differentiation, Curr. Mol. Med., 9, 425, 10.2174/156652409788167113 · DOI
  46. Kobayashi, 2010, Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells, Nat. Cell Biol., 12, 1046, 10.1038/ncb2108 · DOI · Paper page
  47. Kode, 2014, Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts, Nature, 506, 240, 10.1038/nature12883 · DOI · Paper page
  48. Kowalczyk, 2015, Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells, Genome Res., 25, 1860, 10.1101/gr.192237.115 · DOI · Paper page
  49. Krevvata, 2014, Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts, Blood, 124, 2834, 10.1182/blood-2013-07-517219 · DOI
  50. Kumar, 2018, Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion, Leukemia, 32, 575, 10.1038/leu.2017.259 · DOI · Paper page
  51. Kunisaki, 2013, Arteriolar niches maintain haematopoietic stem cell quiescence, Nature, 502, 637, 10.1038/nature12612 · DOI · Paper page
  52. Kusumbe, 2016, Age-dependent modulation of vascular niches for haematopoietic stem cells, Nature, 532, 380, 10.1038/nature17638 · DOI
  53. Lara-Castro, 2007, Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease, Curr. Opin. Lipidol., 18, 263, 10.1097/MOL.0b013e32814a645f · DOI · Paper page
  54. Liaw, 2002, Classification and regression by randomforest, R News, 2, 18
  55. Lo Celso, 2009, Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche, Nature, 457, 92, 10.1038/nature07434 · DOI
  56. Luo, 1997, Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein, Nature, 386, 78, 10.1038/386078a0 · DOI · Paper page
  57. Mabuchi, 2013, LNGFR(+)THY-1(+)VCAM-1(hi+) cells reveal functionally distinct subpopulations in mesenchymal stem cells, Stem Cell Reports, 1, 152, 10.1016/j.stemcr.2013.06.001 · DOI
  58. Méndez-Ferrer, 2010, Mesenchymal and haematopoietic stem cells form a unique bone marrow niche, Nature, 466, 829, 10.1038/nature09262 · DOI · Paper page
  59. Mercier, 2016, Single Targeted Exon Mutation Creates a True Congenic Mouse for Competitive Hematopoietic Stem Cell Transplantation: The C57BL/6-CD45.1(STEM) Mouse, Stem Cell Reports, 6, 985, 10.1016/j.stemcr.2016.04.010 · DOI · Paper page
  60. Mossadegh-Keller, 2013, M-CSF instructs myeloid lineage fate in single haematopoietic stem cells, Nature, 497, 239, 10.1038/nature12026 · DOI · Paper page
  61. Muegge, 1993, Interleukin-7: a cofactor for V(D)J rearrangement of the T cell receptor beta gene, Science, 261, 93, 10.1126/science.7686307 · DOI
  62. Nakashima, 2002, The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation, Cell, 108, 17, 10.1016/S0092-8674(01)00622-5 · DOI · Paper page
  63. Namen, 1988, Stimulation of B-cell progenitors by cloned murine interleukin-7, Nature, 333, 571, 10.1038/333571a0 · DOI · Paper page
  64. Nilsson, 2005, Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells, Blood, 106, 1232, 10.1182/blood-2004-11-4422 · DOI
  65. Nishimura, 2012, Osterix regulates calcification and degradation of chondrogenic matrices through matrix metalloproteinase 13 (MMP13) expression in association with transcription factor Runx2 during endochondral ossification, J. Biol. Chem., 287, 33179, 10.1074/jbc.M111.337063 · DOI
  66. Papayannopoulou, 1995, The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen, Proc. Natl. Acad. Sci. USA, 92, 9647, 10.1073/pnas.92.21.9647 · DOI · Paper page
  67. Park, 2012, Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration, Cell Stem Cell, 10, 259, 10.1016/j.stem.2012.02.003 · DOI · Paper page
  68. Passaro, 2017, Increased vascular permeability in the bone marrow microenvironment contributes to disease progression and drug response in acute myeloid leukemia, Cancer Cell, 32, 324, 10.1016/j.ccell.2017.08.001 · DOI · Paper page
  69. Rafii, 2016, Angiocrine functions of organ-specific endothelial cells, Nature, 529, 316, 10.1038/nature17040 · DOI
  70. Rauner, 2016, Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in EPO-Producing Cells, J. Bone Miner. Res., 31, 1877, 10.1002/jbmr.2857 · DOI
  71. Scadden, 2014, Nice neighborhood: emerging concepts of the stem cell niche, Cell, 157, 41, 10.1016/j.cell.2014.02.013 · DOI · Paper page
  72. Schepers, 2013, Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche, Cell Stem Cell, 13, 285, 10.1016/j.stem.2013.06.009 · DOI · Paper page
  73. Schiebinger, 2017, Reconstruction of developmental landscapes by optimal-transport analysis of single-cell gene expression sheds light on cellular reprogramming, bioRxiv
  74. Schmidt, 2011, Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinib-resistant Bcr-Abl1(+) leukemia, Cancer Cell, 19, 740, 10.1016/j.ccr.2011.05.007 · DOI
  75. Schofield, 1978, The relationship between the spleen colony-forming cell and the haemopoietic stem cells, Blood Cells, 4, 7
  76. Silha, 2003, Perturbations in bone formation and resorption in insulin-like growth factor binding protein-3 transgenic mice, J. Bone Miner. Res., 18, 1834, 10.1359/jbmr.2003.18.10.1834 · DOI
  77. Soundararajan, 2018, Fibroblasts and mesenchymal stem cells: Two sides of the same coin?, J. Cell. Physiol., 233, 9099, 10.1002/jcp.26860 · DOI
  78. Stier, 2005, Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size, J. Exp. Med., 201, 1781, 10.1084/jem.20041992 · DOI · Paper page
  79. Strutz, 1995, Identification and characterization of a fibroblast marker: FSP1, J. Cell Biol., 130, 393, 10.1083/jcb.130.2.393 · DOI · Paper page
  80. Sugimoto, 2013, Scx+/Sox9+ progenitors contribute to the establishment of the junction between cartilage and tendon/ligament, Development, 140, 2280, 10.1242/dev.096354 · DOI · Paper page
  81. Sugiyama, 2006, Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches, Immunity, 25, 977, 10.1016/j.immuni.2006.10.016 · DOI
  82. Tontonoz, 1994, Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor, Cell, 79, 1147, 10.1016/0092-8674(94)90006-X · DOI
  83. van den Brink, 2017, Single-cell sequencing reveals dissociation-induced gene expression in tissue subpopulations, Nat. Methods, 14, 935, 10.1038/nmeth.4437 · DOI · Paper page
  84. van der Maaten, 2008, Visualizing data using t-SNE, J. Mach. Learn. Res., 9, 2579
  85. Vortkamp, 1996, Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein, Science, 273, 613, 10.1126/science.273.5275.613 · DOI
  86. Wagner, 1994, Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9, Cell, 79, 1111, 10.1016/0092-8674(94)90041-8 · DOI · Paper page
  87. Worthley, 2015, Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential, Cell, 160, 269, 10.1016/j.cell.2014.11.042 · DOI · Paper page
  88. Wozney, 1988, Novel regulators of bone formation: molecular clones and activities, Science, 242, 1528, 10.1126/science.3201241 · DOI
  89. Xu, 2018, Stem cell factor is selectively secreted by arterial endothelial cells in bone marrow, Nat. Commun., 9, 2449, 10.1038/s41467-018-04726-3 · DOI
  90. Yang, 2014, Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation, Proc. Natl. Acad. Sci. USA, 111, 12097, 10.1073/pnas.1302703111 · DOI · Paper page
  91. Yu, 2015, Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow, J. Exp. Med., 212, 759, 10.1084/jem.20141843 · DOI
  92. Zhang, 2003, Identification of the haematopoietic stem cell niche and control of the niche size, Nature, 425, 836, 10.1038/nature02041 · DOI
  93. Zhang, 2012, Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia, Cancer Cell, 21, 577, 10.1016/j.ccr.2012.02.018 · DOI
  94. Zhou, 2014, Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice, PLoS Genet., 10, e1004820, 10.1371/journal.pgen.1004820 · DOI · Paper page

Cited by

See all 884

Metadata

Authors
Baryawno, N., Przybylski, D., Kowalczyk, M. S., Kfoury, Y., Severe, N., Gustafsson, K., Kokkaliaris, K. D., Mercier, F., Tabaka, M., Hofree, M., Dionne, D., Papazian, A., Lee, D., Ashenberg, O., Subramanian, A., Vaishnav, E. D., Rozenblatt-Rosen, O., Regev, A., & Scadden, D. T.
Venue
Cell
Publisher
Elsevier BV
Published
2019-06
Volume
177
Issue
7
Pages
1915-1932.e16
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2019.04.040
OpenAlex
W2946721812
Cited by
884
References
21
FWCI
68.29
Type
journal article
Language
en
Open access
bronze
Licence
Funders
  • Swedish Research Council
  • The Childhood Cancer Foundation
  • Charles A. King Trust Postdoctoral Research Fellowship Program
  • Simeon J. Fortin Charitable Foundation
  • Klarman Cell Observatory
  • HHMI
  • NIH (DK107784)
  • Gerald and Darlene Jordan Professorship

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.