title: Epidermal β-catenin activation remodels the dermis via paracrine signalling to distinct fibroblast lineages.
abstract: Sustained epidermal Wnt/β-catenin signalling expands the stem cell compartment and induces ectopic hair follicles (EFs). This is accompanied by extensive fibroblast proliferation and extracellular matrix (ECM) remodelling in the underlying dermis. Here we show that epidermal Hedgehog (Hh) and Transforming growth factor-beta (TGF-β) signalling mediate the dermal changes. Pharmacological inhibition or genetic deletion of these pathways prevents β-catenin-induced dermal reprogramming and EF formation. Epidermal Shh stimulates proliferation of the papillary fibroblast lineage, whereas TGF-β2 controls proliferation, differentiation and ECM production by reticular fibroblasts. Hh inhibitors do not affect TGF-β target gene expression in reticular fibroblasts, and TGF-β inhibition does not prevent Hh target gene induction in papillary fibroblasts. However, when Hh signalling is inhibited the reticular dermis does not respond to epidermal β-catenin activation. We conclude that the dermal response to epidermal Wnt/β-catenin signalling depends on distinct fibroblast lineages responding to different paracrine signals.
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.|Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Beate M
authors.initials: BM
authors.lastname: Lichtenberger
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Mastrogiannaki
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D020405:Dermis / Q000378:metabolism* / Q000473:pathology; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D018859:Hair Follicle / Q000166:cytology / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D019899:Paracrine Communication; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; C509042:Tgfb2 protein, mouse; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D051176:beta Catenin
references.citation: Cell. 2000 Oct 13;103(2):295-309
references.pmid: 11057902
references.citation: J Invest Dermatol. 2015 Dec;135(12):2926-34
references.pmid: 26288357
references.citation: Cell. 2003 Jan 24;112(2):169-80
references.pmid: 12553906
references.citation: Mol Cell Biol. 2003 Jun;23(11):4013-25
references.pmid: 12748302
references.citation: Development. 2004 Apr;131(8):1787-99
references.pmid: 15084463
references.citation: Am J Pathol. 2004 Jul;165(1):203-17
references.pmid: 15215176
references.citation: Cell. 1995 May 5;81(3):313-6
references.pmid: 7736584
references.citation: Burns. 1996 May;22(3):200-2
references.pmid: 8726257
references.citation: Miner Electrolyte Metab. 1998;24(2-3):111-9
references.pmid: 9525693
references.citation: Matrix Biol. 1998 Feb;16(7):387-98
references.pmid: 9524359
references.citation: Nature. 1999 Feb 18;397(6720):617-21
references.pmid: 10050855
references.citation: Development. 1999 Jun;126(12):2611-21
references.pmid: 10331973
references.citation: J Clin Invest. 1999 Oct;104(7):855-64
references.pmid: 10510326
references.citation: Dev Cell. 2005 Jul;9(1):121-31
references.pmid: 15992546
references.citation: Nat Rev Cancer. 2006 May;6(5):392-401
references.pmid: 16572188
references.citation: Exp Dermatol. 2006 Sep;15(9):667-77
references.pmid: 16881963
references.citation: Nature. 2007 May 17;447(7142):316-20
references.pmid: 17507982
references.citation: Development. 2007 Dec;134(24):4335-45
references.pmid: 18039967
references.citation: Development. 2008 Jul;135(13):2321-9
references.pmid: 18539925
references.citation: Br J Cancer. 2008 Jun 17;98(12):1886-93
references.pmid: 18506144
references.citation: Cell. 2008 Jul 25;134(2):215-30
references.pmid: 18662538
references.citation: Rheumatology (Oxford). 2008 Oct;47 Suppl 5:v5-7
references.pmid: 18784145
references.citation: Nature. 2008 Sep 18;455(7211):406-10
references.pmid: 18754008
references.citation: Nat Neurosci. 2008 Dec;11(12):1392-401
references.pmid: 18849983
references.citation: J Med Chem. 2009 Jul 23;52(14):4400-18
references.pmid: 19522463
references.citation: Nat Neurosci. 2010 Jan;13(1):133-40
references.pmid: 20023653
references.citation: Development. 2010 May;137(10):1721-9
references.pmid: 20430747
references.citation: Br J Dermatol. 2010 Apr;162(4):717-23
references.pmid: 19995368
references.citation: Cell Stem Cell. 2011 May 6;8(5):552-65
references.pmid: 21549329
references.citation: Cell. 2011 Sep 2;146(5):761-71
references.pmid: 21884937
references.citation: Development. 2011 Dec;138(23):5189-99
references.pmid: 22031549
references.citation: Lab Invest. 2012 Feb;92(2):214-23
references.pmid: 21946856
references.citation: Oncogene. 2012 Feb 23;31(8):992-1000
references.pmid: 21765471
references.citation: Nat Commun. 2012;3:735
references.pmid: 22415826
references.citation: Am J Pathol. 2012 Apr;180(4):1441-53
references.pmid: 22342522
references.citation: Ann Rheum Dis. 2012 May;71(5):761-7
references.pmid: 22328737
references.citation: Arthritis Rheum. 2012 Aug;64(8):2724-33
references.pmid: 22354771
references.citation: Curr Opin Cell Biol. 2013 Apr;25(2):254-64
references.pmid: 23347562
references.citation: PLoS One. 2013;8(7):e70128
references.pmid: 23922933
references.citation: Stem Cell Reports. 2013;1(1):19-27
references.pmid: 24052938
references.citation: Cell Stem Cell. 2013 Oct 3;13(4):471-82
references.pmid: 23954751
references.citation: BMC Genomics. 2013;14:656
references.pmid: 24066673
references.citation: Nature. 2013 Dec 12;504(7479):277-81
references.pmid: 24336287
references.citation: Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):E1501-9
references.pmid: 24706781
references.citation: Cancer Cell. 2014 Jun 16;25(6):735-47
references.pmid: 24856585
references.citation: Cancer Cell. 2014 Jun 16;25(6):719-34
references.pmid: 24856586
references.citation: J Am Soc Nephrol. 2014 Oct;25(10):2187-200
references.pmid: 24744439
references.citation: Science. 2014 Oct 3;346(6205):1248012
references.pmid: 25278615
references.citation: Science. 2014 Nov 21;346(6212):937-40
references.pmid: 25414300
references.citation: J Pathol. 2015 Apr;235(5):686-97
references.pmid: 25385294
references.citation: Science. 2015 Apr 17;348(6232):aaa2151
references.pmid: 25883361
references.citation: Development. 2001 Dec;128(24):5099-108
references.pmid: 11748145