CoChat
Sign Up
Cited by 53Mesenchymal stem cell researchWound Healing and TreatmentsTGF-β signaling in diseases

EGFR Ligands Drive Multipotential Stromal Cells to Produce Multiple Growth Factors and Cytokines via Early Growth Response-1

Open access
Kerpedjieva, Svetoslava S., Kim, Duk Soo, Barbeau, Dominique J., Tamama, Kenichi·2012·Stem Cells and Development
DOI 10.1089/scd.2011.0711PMC PMC3424970
Open this paper in CoChat — free account

Abstract

Cell therapy with adult bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) presents a promising approach to promote wound healing and tissue regeneration. The strong paracrine capability of various growth factors and cytokines is a key mechanism of MSC-mediated wound healing and tissue regeneration, and the goal of this study is to understand the underlying mechanism that supports the strong paracrine machineries in MSCs. Microarray database analyses revealed that early growth response-1 (EGR1) is highly expressed in MSCs. Our previous studies showed that epidermal growth factor (EGF) treatment induces growth factor production in MSCs in vitro. Since EGF strongly upregulates EGR1, we hypothesized that EGF receptor (EGFR)–EGR1 signaling plays a pivotal role in MSC paracrine activity. EGF treatment upregulated the gene expression of growth factors and cytokines, including EGFR ligands in a protein kinase C (PKC)- and/or mitogen-activated protein kinase–extracellular-signal-regulated kinase-dependent manner, and it was reversed by shRNA against EGR1. PKC activator phorbol 12-myristate 13-acetate enhanced EGFR tyrosyl phosphorylation and upregulated the gene expression of growth factors and cytokines in a heparin-binding EGF-like growth factor (HBEGF) inhibitor CRM197 sensitive manner, indicating an involvement of autocrined HBEGF in the downstream of PKC signaling. Moreover, stimulation with growth factors and cytokines induced the expression of EGFR ligands, presumably via EGR1 upregulation. These data indicate EGR1 as a convergence point of multiple signaling pathways, which in turn augments the production of multiple growth factors and cytokines by enhancing the autocrine signaling with EGFR ligands.

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 · 10.1089/scd.2011.0711

Cites

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?

Self-check

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

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

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 45 · Cited by 53

Research works printed but not linked: 46

  1. [1]Tamama K. Kim D. Kerpedjieva SS. Molecular mechanisms of hypoxia-mediated enhanced in vitro expansion, augmented self-renewal, and increased therapeutic potential of mesenchymal stem cells. In: Vordermark D, editor. Hypoxia: Causes, Types and Management. Nova Science Publishers, Inc.; Hauppauge, NY: (In press). [Google Scholar]
  2. [2]Tamama K. Kawasaki H. Kerpedjieva SS. Guan J. Ganju RK. Sen CK. Differential roles of hypoxia inducible factor subunits in multipotential stromal cells under hypoxic condition. J Cell Biochem. 2011;112:804–817. doi: 10.1002/jcb.22961. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  3. [3]Huss R. Stem cell therapeutics: hope for patients and biopharma! Stem Cells Dev. 2010;19:593–594. doi: 10.1089/scd.2010.1500. [DOI] [PubMed] [Google Scholar] · DOI
  4. [4]Spencer ND. Gimble JM. Lopez MJ. Mesenchymal stromal cells: past, present, and future. Vet Surg. 2011;40:129–139. doi: 10.1111/j.1532-950X.2010.00776.x. [DOI] [PubMed] [Google Scholar] · DOI
  5. [5]Barry FP. Murphy JM. Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol. 2004;36:568–584. doi: 10.1016/j.biocel.2003.11.001. [DOI] [PubMed] [Google Scholar] · DOI
  6. [6]Phinney DG. Prockop DJ. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views. Stem Cells. 2007;25:2896–2902. doi: 10.1634/stemcells.2007-0637. [DOI] [PubMed] [Google Scholar] · DOI
  7. [7]Tamama K. Fan VH. Griffith LG. Blair HC. Wells A. Epidermal growth factor as a candidate for ex vivo expansion of bone marrow-derived mesenchymal stem cells. Stem Cells. 2006;24:686–695. doi: 10.1634/stemcells.2005-0176. [DOI] [PubMed] [Google Scholar] · DOI
  8. [8]Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276:71–74. doi: 10.1126/science.276.5309.71. [DOI] [PubMed] [Google Scholar] · DOI
  9. [9]Pittenger MF. Mackay AM. Beck SC. Jaiswal RK. Douglas R. Mosca JD. Moorman MA. Simonetti DW. Craig S. Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–147. doi: 10.1126/science.284.5411.143. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  10. [10]Owen M. Friedenstein AJ. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp. 1988;136:42–60. doi: 10.1002/9780470513637.ch4. [DOI] [PubMed] [Google Scholar] · DOI
  11. [11]Kinnaird T. Stabile E. Burnett MS. Epstein SE. Bone marrow-derived cells for enhancing collateral development: mechanisms, animal data, and initial clinical experiences. Circ Res. 2004;95:354–363. doi: 10.1161/01.RES.0000137878.26174.66. [DOI] [PubMed] [Google Scholar] · DOI
  12. [12]Friedenstein AJ. Gorskaja JF. Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol. 1976;4:267–274. [PubMed] [Google Scholar]
  13. [13]Oswald J. Boxberger S. Jorgensen B. Feldmann S. Ehninger G. Bornhauser M. Werner C. Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells. 2004;22:377–384. doi: 10.1634/stemcells.22-3-377. [DOI] [PubMed] [Google Scholar] · DOI
  14. [14]Tamama K. Sen CK. Wells A. Differentiation of bone marrow mesenchymal stem cells into the smooth muscle lineage by blocking ERK/MAPK signaling pathway. Stem Cells Dev. 2008;17:897–908. doi: 10.1089/scd.2007.0155. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  15. [15]Caplan AI. Why are MSCs therapeutic? New data: new insight. J Pathol. 2009;217:318–324. doi: 10.1002/path.2469. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  16. [16]Salgado AJ. Reis RL. Sousa NJ. Gimble JM. Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Curr Stem Cell Res Ther. 2010;5:103–110. doi: 10.2174/157488810791268564. [DOI] [PubMed] [Google Scholar] · DOI
  17. [17]Chen L. Tredget EE. Wu PY. Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008;3:e1886. doi: 10.1371/journal.pone.0001886. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  18. [18]Kinnaird T. Stabile E. Burnett MS. Lee CW. Barr S. Fuchs S. Epstein SE. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 2004;94:678–685. doi: 10.1161/01.RES.0000118601.37875.AC. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  19. [19]Kinnaird T. Stabile E. Burnett MS. Shou M. Lee CW. Barr S. Fuchs S. Epstein SE. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004;109:1543–1549. doi: 10.1161/01.CIR.0000124062.31102.57. [DOI] [PubMed] [Google Scholar] · DOI
  20. [20]Silverman ES. Collins T. Pathways of Egr-1-mediated gene transcription in vascular biology. Am J Pathol. 1999;154:665–670. doi: 10.1016/S0002-9440(10)65312-6. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  21. [21]Thiel G. Cibelli G. Regulation of life and death by the zinc finger transcription factor Egr-1. J Cell Physiol. 2002;193:287–292. doi: 10.1002/jcp.10178. [DOI] [PubMed] [Google Scholar] · DOI
  22. [22]De Luca A. Gallo M. Aldinucci D. Ribatti D. Lamura L. D'Alessio A. De Filippi R. Pinto A. Normanno N. Role of the EGFR ligand/receptor system in the secretion of angiogenic factors in mesenchymal stem cells. J Cell Physiol. 2011;226:2131–2138. doi: 10.1002/jcp.22548. [DOI] [PubMed] [Google Scholar] · DOI
  23. [23]Tamama K. Kawasaki H. Wells A. Epidermal growth factor (EGF) treatment on multipotential stromal cells (MSCs). Possible enhancement of therapeutic potential of MSC. J Biomed Biotechnol. 2010;2010:795385. doi: 10.1155/2010/795385. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  24. [24]Wang Y. Crisostomo PR. Wang M. Markel TA. Novotny NM. Meldrum DR. TGF-alpha increases human mesenchymal stem cell-secreted VEGF by MEK- and PI3-K- but not JNK- or ERK-dependent mechanisms. Am J Physiol Regul Integr Comp Physiol. 2008;295:R1115–R1123. doi: 10.1152/ajpregu.90383.2008. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  25. [25]Herrmann JL. Abarbanell AM. Weil BR. Wang Y. Poynter JA. Manukyan MC. Meldrum DR. Postinfarct intramyocardial injection of mesenchymal stem cells pretreated with TGF-alpha improves acute myocardial function. Am J Physiol Regul Integr Comp Physiol. 2010;299:R371–R378. doi: 10.1152/ajpregu.00084.2010. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  26. [26]Herrmann JL. Wang Y. Abarbanell AM. Weil BR. Tan J. Meldrum DR. Preconditioning mesenchymal stem cells with transforming growth factor-alpha improves mesenchymal stem cell-mediated cardioprotection. Shock. 2010;33:24–30. doi: 10.1097/SHK.0b013e3181b7d137. [DOI] [PubMed] [Google Scholar] · DOI
  27. [27]Okamoto T. Aoyama T. Nakayama T. Nakamata T. Hosaka T. Nishijo K. Nakamura T. Kiyono T. Toguchida J. Clonal heterogeneity in differentiation potential of immortalized human mesenchymal stem cells. Biochem Biophys Res Commun. 2002;295:354–361. doi: 10.1016/s0006-291x(02)00661-7. [DOI] [PubMed] [Google Scholar] · DOI
  28. [28]Kubo H. Shimizu M. Taya Y. Kawamoto T. Michida M. Kaneko E. Igarashi A. Nishimura M. Segoshi K, et al. Identification of mesenchymal stem cell (MSC)-transcription factors by microarray and knockdown analyses, and signature molecule-marked MSC in bone marrow by immunohistochemistry. Genes Cells. 2009;14:407–424. doi: 10.1111/j.1365-2443.2009.01281.x. [DOI] [PubMed] [Google Scholar] · DOI
  29. [29]Kawahara K. Shimazu A. Expression and intracellular localization of progesterone receptors in cultured human gingival fibroblasts. J Periodontal Res. 2003;38:242–246. doi: 10.1034/j.1600-0765.2003.00654.x. [DOI] [PubMed] [Google Scholar] · DOI
  30. [30]ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science. 2004;306:636–640. doi: 10.1126/science.1105136. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  31. [31]ENCODE Project Consortium. A user's guide to the encyclopedia of DNA elements (ENCODE) PLoS Biol. 2011;9:e1001046. doi: 10.1371/journal.pbio.1001046. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  32. [32]Yan SF. Harja E. Andrassy M. Fujita T. Schmidt AM. Protein kinase C beta/early growth response-1 pathway: a key player in ischemia, atherosclerosis, and restenosis. J Am Coll Cardiol. 2006;48:A47–A55. doi: 10.1016/j.jacc.2006.05.063. [DOI] [PubMed] [Google Scholar] · DOI
  33. [33]Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J. 1995;9:484–496. [PubMed] [Google Scholar]
  34. [34]Wells A. EGF receptor. Int J Biochem Cell Biol. 1999;31:637–643. doi: 10.1016/s1357-2725(99)00015-1. [DOI] [PubMed] [Google Scholar] · DOI
  35. [35]Pricola KL. Kuhn NZ. Haleem-Smith H. Song Y. Tuan RS. Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism. J Cell Biochem. 2009;108:577–588. doi: 10.1002/jcb.22289. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  36. [36]Uccelli A. Moretta L. Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8:726–736. doi: 10.1038/nri2395. [DOI] [PubMed] [Google Scholar] · DOI
  37. [37]Elenius K. Paul S. Allison G. Sun J. Klagsbrun M. Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation. EMBO J. 1997;16:1268–1278. doi: 10.1093/emboj/16.6.1268. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  38. [38]Krampera M. Pasini A. Rigo A. Scupoli MT. Tecchio C. Malpeli G. Scarpa A. Dazzi F. Pizzolo G. Vinante F. HB-EGF/HER-1 signaling in bone marrow mesenchymal stem cells: inducing cell expansion and reversibly preventing multilineage differentiation. Blood. 2005;106:59–66. doi: 10.1182/blood-2004-09-3645. [DOI] [PubMed] [Google Scholar] · DOI
  39. [39]Cochet C. Gill GN. Meisenhelder J. Cooper JA. Hunter T. C-kinase phosphorylates the epidermal growth factor receptor and reduces its epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem. 1984;259:2553–2558. [PubMed] [Google Scholar]
  40. [40]Friedman B. Frackelton AR., Jr. Ross AH. Connors JM. Fujiki H. Sugimura T. Rosner MR. Tumor promoters block tyrosine-specific phosphorylation of the epidermal growth factor receptor. Proc Natl Acad Sci U S A. 1984;81:3034–3038. doi: 10.1073/pnas.81.10.3034. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  41. [41]Mitamura T. Higashiyama S. Taniguchi N. Klagsbrun M. Mekada E. Diphtheria toxin binds to the epidermal growth factor (EGF)-like domain of human heparin-binding EGF-like growth factor/diphtheria toxin receptor and inhibits specifically its mitogenic activity. J Biol Chem. 1995;270:1015–1019. doi: 10.1074/jbc.270.3.1015. [DOI] [PubMed] [Google Scholar] · DOI
  42. [42]Tamama K. Kerpedjieva SS. Acceleration of wound healing by multiple growth factors and cytokines secreted from multipotential stromal cells/mesenchymal stem cells (MSCs) In: Sen CK, editor. Wound Healing Society Year Book (WHSYB)—Advances in Wound Care. Mary Ann Liebert, Inc.; New Rochelle, NY: (In press). [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. [43]Chase LG. Lakshmipathy U. Solchaga LA. Rao MS. Vemuri MC. A novel serum-free medium for the expansion of human mesenchymal stem cells. Stem Cell Res Ther. 2010;1:8. doi: 10.1186/scrt8. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  44. [44]Wells A. Marti U. Signalling shortcuts: cell-surface receptors in the nucleus? Nat Rev Mol Cell Biol. 2002;3:697–702. doi: 10.1038/nrm905. [DOI] [PubMed] [Google Scholar] · DOI
  45. [45]Sakamoto KM. Frank DA. CREB in the pathophysiology of cancer: implications for targeting transcription factors for cancer therapy. Clin Cancer Res. 2009;15:2583–2587. doi: 10.1158/1078-0432.CCR-08-1137. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  46. [46]Caplan AI. Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–1084. doi: 10.1002/jcb.20886. [DOI] [PubMed] [Google Scholar] · DOI · Paper page

Authors
Kerpedjieva, S. S., Kim, D. S., Barbeau, D. J., & Tamama, K.
Affiliations
University of Pittsburgh (US)
Corresponding author
Tamama, Kenichi
ORCID
Venue
Stem Cells and Development
Publisher
SAGE Publications
Published
2012-02-08
Volume
21
Issue
13
Pages
2541-2551
ISSN
  • 1525-8165 (ISSN-L)
  • 1547-3287
  • 1557-8534
DOI
10.1089/scd.2011.0711
PMC
PMC3424970
OpenAlex
W2072005732
Cited by
53
References
45
Citations by year
2025: 1 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 7 · 2015: 3 · 2014: 8 · 2013: 7 · 2012: 1
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Stem Cells and Development (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • University of Pittsburgh
Topics
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
mesenchymal stem cells, epidermal growth factor receptor, EGF ligands, early growth response 1, paracrine signaling, growth factors, cytokines, autocrine signaling, HB-EGF, CRM197, protein kinase C, ERK signaling, wound healing, tissue regeneration, cell therapy
MeSH terms
Fibroblasts, Glycoproteins, Humans, Ligands, Protein Kinase C, Tetradecanoylphorbol Acetate, Interleukin-6, Autocrine Communication, Paracrine Communication, Oligonucleotide Array Sequence Analysis, MAP Kinase Signaling System, RNA, Small Interfering, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Early Growth Response Protein 1, Gene Knockdown Techniques, Mesenchymal Stem Cells, ErbB Receptors, EGF Family of Proteins, Heparin-binding EGF-like Growth Factor, Amphiregulin

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