title: The matrikine tenascin-C protects multipotential stromal cells/mesenchymal stem cells from death cytokines such as FasL.
abstract: Multipotential stromal cells/mesenchymal stem cells (MSCs) are attractive candidates for regenerative therapy due to the ability of these cells to differentiate and positively influence neighboring cells. However, on implantation for wound reconstruction, these cells are lost as they are challenged by nonspecific inflammation signals generated in the wound environment and in response to any implanted foreign body. We have previously shown that sustained and surface-restricted epidermal growth factor receptor (EGFR) signaling by a tethered form of its prototypal ligand EGF enhances survival of MSC in the presence of death cytokines such as FasL, serum deprivation, and low oxygen in vitro. This was proposed to be due to the plasma membrane restriction of EGFR signaling. Interestingly, during wound repair, an extracellular matrix (ECM) component Tenascin-C (TNC) containing EGF-like repeats (EGFL) and fibronectin-like repeats (FNL) is upregulated. A few of the 14 EGFL on each of the 6 arms, especially the 14th, bind as low-affinity/high-avidity ligands to EGFR causing sustained surface-restricted EGFR signaling. We queried whether signaling by this physiologically relevant EGFR matrikine also protects MSCs from FasL-induced death. MSCs grown on TNC and Collagen I (as TNC by itself is antiadhesive) displayed a survival advantage in the presence of FasL. TNC neither sequestered nor neutralized FasL; rather, the effects of survival were via cell signaling. This survival was dependent on TNC activating EGFR and downstream pathways of Erk and Akt through EGFL; to a much lesser extent, the FNL of TNC also contributed to survival. Taken together, these results suggest that providing MSCs with a nonimmunogenic naturally occurring ECM moiety such as TNC enhances their survival in the presence of death factors, and this advantage occurs via signaling through EGFR primarily and integrins only to a minor extent. This matrix component is proposed to supplement MSC delivery on the scaffolds to provide a survival advantage against death upon in vivo implantation.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Rodrigues
authors.forename: Cecelia C
authors.initials: CC
authors.lastname: Yates
authors.forename: Austin
authors.initials: A
authors.lastname: Nuschke
authors.forename: Linda
authors.initials: L
authors.lastname: Griffith
authors.forename: Alan
authors.initials: A
authors.lastname: Wells
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D053222:Fas Ligand Protein / Q000494:pharmacology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects*; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000187:drug effects*; D019063:Tenascin / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D053222:Fas Ligand Protein; D019063:Tenascin; D066246:ErbB Receptors
references.citation: J Cell Sci. 1999 Nov;112 ( Pt 22):3847-53
references.pmid: 10547346
references.citation: Nat Med. 2011 Nov 20;17(12):1594-601
references.pmid: 22101767
references.citation: Mol Biol Cell. 2002 Oct;13(10):3601-13
references.pmid: 12388760
references.citation: J Biomed Biotechnol. 2010;2010:795385
references.pmid: 20182548
references.citation: J Cell Biol. 1991 Nov;115(4):1127-36
references.pmid: 1720121
references.citation: Stem Cells. 2010 Mar 31;28(3):555-63
references.pmid: 20073042
references.citation: J Cell Physiol. 2007 Jun;211(3):748-58
references.pmid: 17311283
references.citation: Stem Cells. 2006 Mar;24(3):686-95
references.pmid: 16150920
references.citation: Transplantation. 2009 Mar 15;87(5):642-52
references.pmid: 19295307
references.citation: J Cell Biol. 1997 Oct 6;139(1):279-93
references.pmid: 9314546
references.citation: Panminerva Med. 2010 Mar;52(1):27-40
references.pmid: 20228724
references.citation: J Cell Mol Med. 2011 Jul;15(7):1505-14
references.pmid: 20716129
references.citation: J Cell Physiol. 2008 Feb;214(2):504-12
references.pmid: 17708541
references.citation: Biochim Biophys Acta. 2011 Sep;1810(9):875-8
references.pmid: 21640162
references.citation: J Biol Chem. 1999 Nov 26;274(48):34350-60
references.pmid: 10567412
references.citation: FEBS Lett. 1989 Jul 17;251(1-2):1-7
references.pmid: 2666164
references.citation: Wound Repair Regen. 2009 Mar-Apr;17(2):153-62
references.pmid: 19320882
references.citation: Am J Pathol. 2007 Aug;171(2):484-95
references.pmid: 17600132
references.citation: PLoS One. 2008 Jul 09;3(7):e2615
references.pmid: 18612428
references.citation: Cell Transplant. 2012;21(5):919-31
references.pmid: 22236446
references.citation: Annu Rev Pathol. 2011;6:457-78
references.pmid: 21073342
references.citation: Cell Stem Cell. 2011 Jul 8;9(1):11-5
references.pmid: 21726829
references.citation: PLoS One. 2011 Jan 10;6(1):e15945
references.pmid: 21264347
references.citation: Biomaterials. 2009 Sep;30(27):4629-38
references.pmid: 19540579
references.citation: Cancer Lett. 2005 Nov 8;229(1):101-5
references.pmid: 16157221
references.citation: Science. 1990 Feb 23;247(4945):962-4
references.pmid: 2305263
references.citation: FEBS Lett. 2000 Sep 1;480(2-3):189-92
references.pmid: 11034326
references.citation: J Cell Biol. 2001 Jul 23;154(2):459-68
references.pmid: 11470832
references.citation: Wound Repair Regen. 2004 May-Jun;12(3):262-8
references.pmid: 15225204
references.citation: Stem Cells. 2006 Feb;24(2):416-25
references.pmid: 16253984
references.citation: Stem Cells. 2008 Jul;26(7):1749-57
references.pmid: 18467662
references.citation: Crit Rev Immunol. 2011;31(2):115-45
references.pmid: 21542790
references.citation: Cell Transplant. 2012;21(10):2171-87
references.pmid: 22526333
references.citation: Cell. 1988 May 6;53(3):383-90
references.pmid: 2452695
references.citation: Stem Cell Res Ther. 2010 Oct 26;1(4):32
references.pmid: 20977782
references.citation: Stem Cells. 2013 Jan;31(1):104-16
references.pmid: 22948863
references.citation: Mol Biol Cell. 2010 Jul 1;21(13):2172-81
references.pmid: 20462956
references.citation: Tissue Eng Part A. 2011 Apr;17(7-8):1147-56
references.pmid: 21142699
references.citation: Cytotherapy. 2011 Mar;13(3):269-78
references.pmid: 20942778
references.citation: Eur J Neurosci. 2004 Nov;20(10):2524-40
references.pmid: 15548197
references.citation: J Cell Biol. 1987 Dec;105(6 Pt 1):2569-79
references.pmid: 2447094
references.citation: Mol Cell Biol. 2005 May;25(10):4176-88
references.pmid: 15870287
references.citation: J Cell Commun Signal. 2009 Dec;3(3-4):287-310
references.pmid: 19838819
references.citation: Mol Biol Cell. 1996 Jun;7(6):871-81
references.pmid: 8816994
references.citation: J Biol Chem. 2004 Dec 17;279(51):53867-74
references.pmid: 15471881
references.citation: J Biol Chem. 1999 Mar 26;274(13):8958-65
references.pmid: 10085141
references.citation: Cell Death Differ. 2010 Jun;17(6):952-61
references.pmid: 20019749
references.citation: Int J Biochem Cell Biol. 1999 Jun;31(6):637-43
references.pmid: 10404636
references.citation: Traffic. 2009 Aug;10(8):1115-27
references.pmid: 19531065
references.citation: Cell Transplant. 2011;20(10):1547-59
references.pmid: 21396164
references.citation: Nat Med. 2009 Jul;15(7):774-80
references.pmid: 19561617
references.citation: J Clin Invest. 2001 Apr;107(7):785-90
references.pmid: 11285293
references.citation: Matrix Biol. 2000 Dec;19(7):581-96
references.pmid: 11102748
references.citation: Stem Cells. 2007 May;25(5):1241-51
references.pmid: 17234993