CoChat
Sign Up
Cited by 78Hematopoietic Stem Cell TransplantationBlood disorders and treatmentsMesenchymal stem cell research

Chronic activation of endothelial MAPK disrupts hematopoiesis via NFKB dependent inflammatory stress reversible by SCGF

Open access
Ramalingam, Pradeep, Poulos, Michael G., Lazzari, Elisa, Gutkin, Michael C., Lopez, David, Kloss, Christopher C., Crowley, Michael J., Katsnelson, Lizabeth +4 more·2020·Nature Communications
DOI 10.1038/s41467-020-14478-8PMC PMC6997369
Open this paper in CoChat — free accountOpen PDF

Abstract

Inflammatory signals arising from the microenvironment have emerged as critical regulators of hematopoietic stem cell (HSC) function during diverse processes including embryonic development, infectious diseases, and myelosuppressive injuries caused by irradiation and chemotherapy. However, the contributions of cellular subsets within the microenvironment that elicit niche-driven inflammation remain poorly understood. Here, we identify endothelial cells as a crucial component in driving bone marrow (BM) inflammation and HSC dysfunction observed following myelosuppression. We demonstrate that sustained activation of endothelial MAPK causes NF-κB-dependent inflammatory stress response within the BM, leading to significant HSC dysfunction including loss of engraftment ability and a myeloid-biased output. These phenotypes are resolved upon inhibition of endothelial NF-κB signaling. We identify SCGF as a niche-derived factor that suppresses BM inflammation and enhances hematopoietic recovery following myelosuppression. Our findings demonstrate that chronic endothelial inflammation adversely impacts niche activity and HSC function which is reversible upon suppression of inflammation.

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 · 10.1038/s41467-020-14478-8

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

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

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • MAOA inhibition and TAAR1 activation by LDX might influence MAPK3 activation, which is crucial for downstream modulation of a large number of proteins involved in many biological processes, such as neuroinflammation.

    “On the other hand, MAOA inhibition and TAAR1 activation by LDX (both direct targets of LDX) might influence MAPK3 activation, which is crucial for the downstream modulation of a large number of proteins involved in many biological processes, such as neuroinflammation [200].”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [200]

    The Results section on endothelial MAPK and NF-κB reports that MAPK activation increased ERK1/2 and p65 phosphorylation and drove an inflammatory response in bone-marrow endothelial cells. That supports a general link between MAPK signaling and downstream inflammation, but the paper does not address LDX, MAOA, TAAR1, or neuroinflammation, and it does not identify a MAPK3-specific effect. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

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

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

Cites

Flagged first, then by citations

Research works printed but not linked: 76

  1. [1]Wagers AJ The stem cell niche in regenerative medicine Cell Stem Cell 2012 10 362 369 10.1016/j.stem.2012.02.018 22482502 · DOI
  2. [2]Lane SW Williams DA Watt FM Modulating the stem cell niche for tissue regeneration Nat. Biotechnol. 2014 32 795 803 10.1038/nbt.2978 25093887 PMC4422171 · DOI
  3. [3]Schepers K Campbell TB Passegue E Normal and leukemic stem cell niches: insights and therapeutic opportunities Cell Stem Cell 2015 16 254 267 10.1016/j.stem.2015.02.014 25748932 PMC4391962 · DOI
  4. [4]Baldridge MT King KY Goodell MA Inflammatory signals regulate hematopoietic stem cells Trends Immunol. 2011 32 57 65 10.1016/j.it.2010.12.003 21233016 PMC3042730 · DOI
  5. [5]Zhao JL Baltimore D Regulation of stress-induced hematopoiesis Curr. Opin. Hematol. 2015 22 286 292 10.1097/MOH.0000000000000149 26049748 PMC4573392 · DOI
  6. [6]Boettcher S Manz MG Regulation of inflammation- and infection-driven hematopoiesis Trends Immunol. 2017 38 345 357 10.1016/j.it.2017.01.004 28216309 · DOI
  7. [7]Espin-Palazon R Weijts B Mulero V Traver D Proinflammatory signals as fuel for the fire of hematopoietic stem cell emergence Trends Cell Biol. 2018 28 58 66 10.1016/j.tcb.2017.08.003 28882414 · DOI
  8. [8]Bowers E Granulocyte-derived TNFalpha promotes vascular and hematopoietic regeneration in the bone marrow Nat. Med. 2018 24 95 102 10.1038/nm.4448 29155425 PMC5760474 · DOI
  9. [9]Kovtonyuk LV Fritsch K Feng X Manz MG Takizawa H Inflamm-aging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment Front. Immunol. 2016 7 502 10.3389/fimmu.2016.00502 27895645 PMC5107568 · DOI · Paper page
  10. [10]Pietras EM Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal Nat. Cell Biol. 2016 18 607 618 10.1038/ncb3346 27111842 PMC4884136 · DOI · Paper page
  11. [11]Lussana F Rambaldi A Inflammation and myeloproliferative neoplasms J. Autoimmun. 2017 85 58 63 10.1016/j.jaut.2017.06.010 28669446 · DOI · Paper page
  12. [12]Pietras EM Inflammation: a key regulator of hematopoietic stem cell fate in health and disease Blood 2017 130 1693 1698 10.1182/blood-2017-06-780882 28874349 PMC5639485 · DOI · Paper page
  13. [13]Hooper AT Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells Cell Stem Cell 2009 4 263 274 10.1016/j.stem.2009.01.006 19265665 PMC3228275 · DOI
  14. [14]Butler JM Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells Cell Stem Cell 2010 6 251 264 10.1016/j.stem.2010.02.001 20207228 PMC2866527 · DOI
  15. [15]Kobayashi H Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells Nat. Cell Biol. 2010 12 1046 1056 10.1038/ncb2108 20972423 PMC2972406 · DOI
  16. [16]Winkler IG Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance Nat. Med. 2012 18 1651 1657 10.1038/nm.2969 23086476 · DOI
  17. [17]Ding L Saunders TL Enikolopov G Morrison SJ Endothelial and perivascular cells maintain haematopoietic stem cells Nature 2012 481 457 462 10.1038/nature10783 22281595 PMC3270376 · DOI
  18. [18]Poulos MG Endothelial jagged-1 is necessary for homeostatic and regenerative hematopoiesis Cell Rep. 2013 4 1022 1034 10.1016/j.celrep.2013.07.048 24012753 PMC3805263 · DOI
  19. [19]Greenbaum A CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance Nature 2013 495 227 230 10.1038/nature11926 23434756 PMC3600148 · DOI
  20. [20]Doan PL Epidermal growth factor regulates hematopoietic regeneration after radiation injury Nat. Med. 2013 19 295 304 10.1038/nm.3070 23377280 PMC3594347 · DOI
  21. [21]Poulos MG Endothelial-specific inhibition of NF-kappaB enhances functional haematopoiesis Nat. Commun. 2016 7 13829 10.1038/ncomms13829 28000664 PMC5187502 · DOI
  22. [22]Kusumbe AP Age-dependent modulation of vascular niches for haematopoietic stem cells Nature 2016 532 380 384 10.1038/nature17638 27074508 PMC5035541 · DOI
  23. [24]Rafii S Butler JM Ding BS Angiocrine functions of organ-specific endothelial cells Nature 2016 529 316 325 10.1038/nature17040 26791722 PMC4878406 · DOI
  24. [26]Boettcher S Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis Blood 2014 124 1393 1403 10.1182/blood-2014-04-570762 24990886 PMC4148762 · DOI
  25. [28]Sanchez A Map3k8 controls granulocyte colony-stimulating factor production and neutrophil precursor proliferation in lipopolysaccharide-induced emergency granulopoiesis Sci. Rep. 2017 7 5010 10.1038/s41598-017-04538-3 28694430 PMC5503936 · DOI
  26. [29]Roth Flach RJ Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis Nat. Commun. 2015 6 8995 10.1038/ncomms9995 26688060 PMC4703891 · DOI
  27. [30]Vandoorne K Imaging the vascular bone marrow niche during inflammatory stress Circ. Res. 2018 123 415 427 10.1161/CIRCRESAHA.118.313302 29980569 PMC6202141 · DOI
  28. [31]Baker RG Hayden MS Ghosh S NF-kappaB, inflammation, and metabolic disease Cell Metab. 2011 13 11 22 10.1016/j.cmet.2010.12.008 21195345 PMC3040418 · DOI · Paper page
  29. [32]Bottero V Withoff S Verma IM NF-kappaB and the regulation of hematopoiesis Cell Death Differ. 2006 13 785 797 10.1038/sj.cdd.4401888 16528384 · DOI
  30. [33]Brown K Park S Kanno T Franzoso G Siebenlist U Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha Proc. Natl Acad. Sci. USA 1993 90 2532 2536 10.1073/pnas.90.6.2532 8460169 PMC46122 · DOI
  31. [34]Wu C Ghosh S Differential phosphorylation of the signal-responsive domain of I kappa B alpha and I kappa B beta by I kappa B kinases J. Biol. Chem. 2003 278 31980 31987 10.1074/jbc.M304278200 12791687 · DOI
  32. [35]Yang F Tang E Guan K Wang CY IKK beta plays an essential role in the phosphorylation of RelA/p65 on serine 536 induced by lipopolysaccharide J. Immunol. 2003 170 5630 5635 10.4049/jimmunol.170.11.5630 12759443 · DOI
  33. [36]Wessel AW Hanson EP A method for the quantitative analysis of stimulation-induced nuclear translocation of the p65 subunit of NF-kappaB from patient-derived dermal fibroblasts Methods Mol. Biol. 2015 1280 413 426 10.1007/978-1-4939-2422-6_25 25736764 PMC5597957 · DOI
  34. [37]Boehm JS Integrative genomic approaches identify IKBKE as a breast cancer oncogene Cell 2007 129 1065 1079 10.1016/j.cell.2007.03.052 17574021 · DOI
  35. [38]Brown K Gerstberger S Carlson L Franzoso G Siebenlist U Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation Science 1995 267 1485 1488 10.1126/science.7878466 7878466 · DOI · Paper page
  36. [39]Kisseleva T NF-kappaB regulation of endothelial cell function during LPS-induced toxemia and cancer J. Clin. Invest. 2006 116 2955 2963 10.1172/JCI27392 17053836 PMC1616192 · DOI
  37. [40]Wei Q Frenette PS Niches for hematopoietic stem cells and their progeny. Immunity 2018 48 632 648 10.1016/j.immuni.2018.03.024 29669248 PMC6103525 · DOI
  38. [42]Comazzetto S Restricted hematopoietic progenitors and erythropoiesis require SCF from leptin receptor+ niche cells in the bone marrow Cell Stem Cell 2019 24 477 486.e476 10.1016/j.stem.2018.11.022 30661958 PMC6813769 · DOI
  39. [43]Inra CN A perisinusoidal niche for extramedullary haematopoiesis in the spleen Nature 2015 527 466 471 10.1038/nature15530 26570997 PMC4838203 · DOI
  40. [44]Sorensen I Adams RH Gossler A DLL1-mediated Notch activation regulates endothelial identity in mouse fetal arteries Blood 2009 113 5680 5688 10.1182/blood-2008-08-174508 19144989 · DOI
  41. [45]Langen UH Cell-matrix signals specify bone endothelial cells during developmental osteogenesis Nat. Cell Biol. 2017 19 189 201 10.1038/ncb3476 28218908 PMC5580829 · DOI
  42. [47]Kilani B Comparison of endothelial promoter efficiency and specificity in mice reveals a subset of Pdgfb-positive hematopoietic cells J. Thromb. Haemost. 2019 17 827 840 10.1111/jth.14417 30801958 · DOI
  43. [48]Forde A Constien R Grone HJ Hammerling G Arnold B Temporal Cre-mediated recombination exclusively in endothelial cells using Tie2 regulatory elements Genesis 2002 33 191 197 10.1002/gene.10117 12203917 · DOI
  44. [49]Tang Y Harrington A Yang X Friesel RE Liaw L The contribution of the Tie2+ lineage to primitive and definitive hematopoietic cells Genesis 2010 48 563 567 10.1002/dvg.20654 20645309 PMC2944906 · DOI
  45. [50]Gareus R Endothelial cell-specific NF-kappaB inhibition protects mice from atherosclerosis Cell Metab. 2008 8 372 383 10.1016/j.cmet.2008.08.016 19046569 · DOI
  46. [51]Korhonen H Anaphylactic shock depends on endothelial Gq/G11 J. Exp. Med. 2009 206 411 420 10.1084/jem.20082150 19171764 PMC2646572 · DOI
  47. [53]Karhausen J Haase VH Colgan SP Inflammatory hypoxia: role of hypoxia-inducible factor Cell Cycle 2005 4 256 258 10.4161/cc.4.2.1407 15655360 · DOI
  48. [54]Eltzschig HK Carmeliet P Hypoxia and inflammation N. Engl. J. Med. 2011 364 656 665 10.1056/NEJMra0910283 21323543 PMC3930928 · DOI · Paper page
  49. [55]Mittal M Siddiqui MR Tran K Reddy SP Malik AB Reactive oxygen species in inflammation and tissue injury Antioxid. Redox Signal. 2014 20 1126 1167 10.1089/ars.2012.5149 23991888 PMC3929010 · DOI · Paper page
  50. [56]Bigarella CL Liang R Ghaffari S Stem cells and the impact of ROS signaling Development 2014 141 4206 4218 10.1242/dev.107086 25371358 PMC4302918 · DOI
  51. [57]Takubo K Regulation of the HIF-1alpha level is essential for hematopoietic stem cells Cell Stem Cell 2010 7 391 402 10.1016/j.stem.2010.06.020 20804974 · DOI · Paper page
  52. [58]Ludin A Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment Antioxid. Redox Signal. 2014 21 1605 1619 10.1089/ars.2014.5941 24762207 PMC4175025 · DOI
  53. [60]Ding L Morrison SJ Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches Nature 2013 495 231 235 10.1038/nature11885 23434755 PMC3600153 · DOI
  54. [61]Mossadegh-Keller N M-CSF instructs myeloid lineage fate in single haematopoietic stem cells Nature 2013 497 239 243 10.1038/nature12026 23575636 PMC3679883 · DOI
  55. [62]Yue, R., Shen, B. & Morrison, S. J. Clec11a/osteolectin is an osteogenic growth factor that promotes the maintenance of the adult skeleton. Elife5, 10.7554/eLife.18782 (2016). PMC5158134 27976999 · DOI
  56. [63]Keller CC Suppression of a novel hematopoietic mediator in children with severe malarial anemia Infect. Immun. 2009 77 3864 3871 10.1128/IAI.00342-09 19528216 PMC2737985 · DOI
  57. [64]Ito C Serum stem cell growth factor for monitoring hematopoietic recovery following stem cell transplantation Bone Marrow Transplant. 2003 32 391 398 10.1038/sj.bmt.1704152 12900775 · DOI
  58. [65]Mazumder B Li X Barik S Translation control: a multifaceted regulator of inflammatory response J. Immunol. 2010 184 3311 3319 10.4049/jimmunol.0903778 20304832 PMC2860598 · DOI
  59. [66]McDermott BT Peffers MJ McDonagh B Tew SR Translational regulation contributes to the secretory response of chondrocytic cells following exposure to Interleukin-1beta J. Biol. Chem. 2019 10.1074/jbc.RA118.006865 31300557 PMC6721953 · DOI
  60. [67]Lu X Bone marrow sinusoidal endothelial cells undergo nonapoptotic cell death and are replaced by proliferating sinusoidal cells in situ to maintain the vascular niche following lethal irradiation. Exp. Hematol. 2008 36 1143 1156 10.1016/j.exphem.2008.04.013 18718416 · DOI
  61. [68]Baselet B Sonveaux P Baatout S Aerts A Pathological effects of ionizing radiation: endothelial activation and dysfunction Cell Mol. Life Sci. 2019 76 699 728 10.1007/s00018-018-2956-z 30377700 PMC6514067 · DOI
  62. [69]Zhang H Sepsis induces hematopoietic stem cell exhaustion and myelosuppression through distinct contributions of TRIF and MYD88 Stem Cell Rep. 2016 6 940 956 10.1016/j.stemcr.2016.05.002 PMC4911503 27264973 · DOI
  63. [70]Mirantes C Passegue E Pietras EM Pro-inflammatory cytokines: emerging players regulating HSC function in normal and diseased hematopoiesis Exp. Cell Res. 2014 329 248 254 10.1016/j.yexcr.2014.08.017 25149680 PMC4250307 · DOI · Paper page
  64. [71]Geest CR Coffer PJ MAPK signaling pathways in the regulation of hematopoiesis J. Leukoc. Biol. 2009 86 237 250 10.1189/jlb.0209097 19498045 · DOI
  65. [72]Xiao L Liu Y Wang N New paradigms in inflammatory signaling in vascular endothelial cells Am. J. Physiol. Heart Circ. Physiol. 2014 306 H317 H325 10.1152/ajpheart.00182.2013 24285111 · DOI
  66. [73]Korpela E Liu SK Endothelial perturbations and therapeutic strategies in normal tissue radiation damage Radiat. Oncol. 2014 9 266 10.1186/s13014-014-0266-7 25518850 PMC4279961 · DOI
  67. [74]Halle M Sustained inflammation due to nuclear factor-kappa B activation in irradiated human arteries J. Am. Coll. Cardiol. 2010 55 1227 1236 10.1016/j.jacc.2009.10.047 20298930 · DOI
  68. [75]Munshi A Ramesh R Mitogen-activated protein kinases and their role in radiation response Genes Cancer 2013 4 401 408 10.1177/1947601913485414 24349638 PMC3863336 · DOI
  69. [76]Wang Y Liu L Zhou D Inhibition of p38 MAPK attenuates ionizing radiation-induced hematopoietic cell senescence and residual bone marrow injury Radiat. Res. 2011 176 743 752 10.1667/RR2727.1 22014293 PMC3390189 · DOI · Paper page
  70. [77]Dong F Cadmium induces vascular permeability via activation of the p38 MAPK pathway Biochem. Biophys. Res. Commun. 2014 450 447 452 10.1016/j.bbrc.2014.05.140 24909688 · DOI
  71. [78]Li L P38/MAPK contributes to endothelial barrier dysfunction via MAP4 phosphorylation-dependent microtubule disassembly in inflammation-induced acute lung injury Sci. Rep. 2015 5 8895 10.1038/srep08895 25746230 PMC4352893 · DOI
  72. [79]Brown GD Willment JA Whitehead L C-type lectins in immunity and homeostasis Nat. Rev. Immunol. 2018 18 374 389 10.1038/s41577-018-0004-8 29581532 · DOI
  73. [80]Srinivasan L PI3 kinase signals BCR-dependent mature B cell survival Cell 2009 139 573 586 10.1016/j.cell.2009.08.041 19879843 PMC2787092 · DOI
  74. [81]Benedito R The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis Cell 2009 137 1124 1135 10.1016/j.cell.2009.03.025 19524514 · DOI
  75. [82]DeFalco J Virus-assisted mapping of neural inputs to a feeding center in the hypothalamus Science 2001 291 2608 2613 10.1126/science.1056602 11283374 · DOI
  76. [83]Hu Y Smyth GK ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays J. Immunol. Methods 2009 347 70 78 10.1016/j.jim.2009.06.008 19567251 · DOI

Cited by

Sorted by citations

Authors
Ramalingam, P., Poulos, M. G., Lazzari, E., Gutkin, M. C., Lopez, D., Kloss, C. C., Crowley, M. J., Katsnelson, L., Freire, A. G., Greenblatt, M. B., Park, C. Y., & Butler, J. M.
Affiliations
  • Weill Cornell Medicine (US)
  • Hackensack University Medical Center (US)
  • NYU Langone Health (US)
Corresponding author
Butler, Jason M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-02-03
Volume
11
Issue
1
Pages
666-666
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-14478-8
PMC
PMC6997369
OpenAlex
W3003515112
Cited by
78
References
8
Citations by year
2026: 7 · 2025: 12 · 2024: 15 · 2023: 14 · 2022: 14 · 2021: 12 · 2020: 4
FWCI
6.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Leukemia and Lymphoma Society
  • Starr Foundation
  • National Institutes of Health
  • National Institute on Aging (R01AG065436)
  • National Heart, Lung, and Blood Institute (R01HL133021)
  • National Cancer Institute (R01CA204308)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR075585)
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
endothelial cells, MAPK signaling, NF-κB signaling, hematopoietic stem cells, bone marrow inflammation, myelosuppression, hematopoietic recovery, hematopoietic niche, engraftment, chronic inflammation
MeSH terms
Cadherin 5, Animals, Bone Marrow, Female, Hematopoiesis, Hematopoietic Stem Cells, Inflammation, Male, Transplantation, Autologous, Signal Transduction, Antigens, CD, Cadherins, Hematopoietic Cell Growth Factors, NF-kappa B, Hematopoietic Stem Cell Transplantation, Mitogen-Activated Protein Kinase Kinases, Lectins, C-Type, Endothelial Cells, Mice

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