Dermal fibroblast expression of stromal cellderived factor-1 (SDF-1) promotes epidermal keratinocyte proliferation in normal and diseased skin
Received date: 13 May 2015
Accepted date: 16 Jul 2015
Published date: 04 Jan 2016
Copyright
Stromal cells provide a crucial microenvironment for overlying epithelium. Hereweinvestigated the expression and function of a stromal cell-specific protein, stromal cell-derived factor-1 (SDF-1), in normal human skin and in the tissues of diseased skin. Immunohistology and laser capture microdissection (LCM)-coupled quantitative realtime RT-PCR revealed that SDF-1 is constitutively and predominantly expressed in dermal stromal cells in normalhuman skin in vivo. To our surprise, an extremely high level of SDF-1 transcription was observed in the dermis of normal human skin in vivo, evidenced by much higher mRNA expression level than type I collagen, the most abundant and highly expressed protein in human skin. SDF-1 was also upregulated in the tissues of manyhuman skin disorders including psoriasis, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Double immunostaining for SDF-1 and HSP47 (heat shock protein 47), a marker of fibroblasts, revealed that fibroblasts were the major source of stroma-cell-derived SDF-1 in both normal and diseased skin. Functionally, SDF-1 activates the ERK (extracellular-signal-regulated kinases) pathway and functions as a mitogen to stimulate epidermal keratinocyte proliferation. Both overexpression of SDF-1 in dermal fibroblasts and treatment with rhSDF-1 to the skin equivalent cultures significantly increased the number of keratinocyte layers and epidermal thickness. Conversely, the stimulative function of SDF-1 on keratinocyte proliferation was nearly completely eliminated by interfering with CXCR4, a specific receptor of SDF-1, or by knock-down of SDF-1 in fibroblasts. Our data reveal that extremely high levels of SDF-1 provide a crucial microenvironment for epidermal keratinocyte proliferation in both physiologic and pathologic skin conditions.
Key words: SDF-1; dermal fibroblast; keratinocyte; proliferation; skin cancer; psoriasis
Chunji Quan , Moon Kyun Cho , Yuan Shao , Laurel E. Mianecki , Eric Liao , Daniel Perry , Taihao Quan . Dermal fibroblast expression of stromal cellderived factor-1 (SDF-1) promotes epidermal keratinocyte proliferation in normal and diseased skin[J]. Protein & Cell, 2015 , 06(12) : 890 -903 . DOI: 10.1007/s13238-015-0198-5
1 |
Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337
|
2 |
Blanpain C, Fuchs E (2009) Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev 10:207–217
|
3 |
Boelsma E, Verhoeven MC, Ponec M (1999) Reconstruction of a human skin equivalent using a spontaneously transformed keratinocyte cell line (HaCaT). J Investig Dermatol 112:489–498
|
4 |
Bollag WB, Hill WD (2013) CXCR4 in epidermal keratinocytes: crosstalk within the skin. J Investig Dermatol 133:2505–2508
|
5 |
Byrne SN, Sarchio SN (2014) AMD3100 protects from UV-induced skin cancer. Oncoimmunology3:e27562
|
6 |
Chambard JC, Lefloch R, Pouyssegur J, Lenormand P (2007) ERK implication in cell cycle regulation. Biochimica et biophysica acta 1773:1299–1310
|
7 |
Chen GS, Yu HS, Lan CC, Chow KC, Lin TY, Kok LF, Lu MP, Liu CH, Wu MT (2006) CXC chemokine receptor CXCR4 expression enhances tumorigenesis and angiogenesis of basal cell carcinoma. Br J Dermatol 154:910–918
|
8 |
Chen SJ, Nakahara T, Kido M, Takahara M, Uchi H, Takeuchi S, Dugu L, Tu YT, Moroi Y, Furue M (2009) Stromal cell-derived factor 1 expression in various skin tumours. Br J Dermatol 160:710–713
|
9 |
Chu CY, Cha ST, Lin WC, Lu PH, Tan CT, Chang CC, Lin BR, Jee SH, Kuo ML (2009) Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12)-enhanced angiogenesis of human basal cell carcinoma cells involves ERK1/2-NF-kappaB/interleukin-6 pathway. Carcinogenesis 30:205–213
|
10 |
Donjacour AA, Cunha GR (1991) Stromal regulation of epithelial function. Cancer Treat Res 53:335–364
|
11 |
Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK (2011) CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin Cancer Res 17:2074–2080
|
12 |
Eckert RL, Efimova T, Dashti SR, Balasubramanian S, Deucher A, Crish JF, Sturniolo M, Bone F (2002) Keratinocyte survival, differentiation, and death: many roads lead to mitogen-activated protein kinase. J Investig Dermatol 7:36–40
|
13 |
El Ghalbzouri A, Lamme E,Ponec M (2002) Crucial role of fibroblasts in regulating epidermal morphogenesis. Cell Tissue Res 310:189–199
|
14 |
Farage MA, Miller KW, Maibach HI, SpringerLink (Online Service) (2010) Textbook of aging skin. Springer, Berlin
|
15 |
Fisher GJ, Esmann J, Griffiths CE, Talwar HS, Duell EA, Hammerberg C, Elder JT, Finkel LJ, Karabin GD, Nickoloff BJ
|
16 |
Fisher GJ, Varani J, Voorhees JJ (2008) Looking older: fibroblast collapse and therapeutic implications. Arch Dermatol 144:666–672
|
17 |
Fisher GJ, Quan T, Purohit T, Shao Y, Cho MK, He T, Varani J, Kang S, Voorhees JJ (2009) Collagen fragmentation promotes oxidative stress and elevates matrix metalloproteinase-1 in fibroblasts in aged human skin. The American journal of pathology. 174:101–114
|
18 |
Gallagher KA, Liu ZJ, Xiao M, Chen H, Goldstein LJ, Buerk DG, Nedeau A, Thom SR, Velazquez OC (2007) Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. J Clin Investig 117:1249–1259
|
19 |
Henderson PW, Singh SP, Krijgh DD, Yamamoto M, Rafii DC, Sung JJ, Rafii S, Rabbany SY, Spector JA (2011) Stromal-derived factor-1 delivered via hydrogel drug-delivery vehicle accelerates wound healing in vivo. Wound Repair Regener 19:420–425
|
20 |
Hu TH, Yao Y, Yu S, Han LL, Wang WJ, Guo H, Tian T, Ruan ZP, Kang XM, Wang J, Wang SH, Nan KJ (2014) SDF-1/CXCR4 promotes epithelial-mesenchymal transition and progression of colorectal cancer by activation of the Wnt/beta-catenin signaling pathway. Cancer Lett 354:417–426
|
21 |
Jost M, Huggett TM, Kari C, Boise LH, Rodeck U (2001) Epidermal growth factor receptor-dependent control of keratinocyte survival and Bcl-xL expression through a MEK-dependent pathway. J Biol Chem 276:6320–6326
|
22 |
Kalatskaya I, Berchiche YA, Gravel S, Limberg BJ, Rosenbaum JS, Heveker N (2009) AMD3100 is a CXCR7 ligand with allosteric agonist properties. Mol Pharm 75:1240–1247
|
23 |
Kijima T, Maulik G, Ma PC, Tibaldi EV, Turner RE, Rollins B, Sattler M, Johnson BE, Salgia R (2002) Regulation of cellular proliferation, cytoskeletal function, and signal transduction through CXCR4 and c-Kit in small cell lung cancer cells. Cancer Res 62:6304–6311
|
24 |
Koster MI (2009) Making an epidermis. Ann N Y Acad Sci 1170:7–10
|
25 |
Kryczek I, Wei S, Keller E, Liu R, Zou W (2007) Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am J Physiol 292:C987–995
|
26 |
Lapidot T, Dar A, Kollet O (2005) How do stem cells find their way home? Blood 106:1901–1910
|
27 |
Li X, Ma Q, Xu Q, Liu H, Lei J, Duan W, Bhat K, Wang F, Wu E, Wang Z (2012) SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through noncanonical activation of Hedgehog pathway. Cancer Lett 322:169–176
|
28 |
Li X, Li P, Chang Y, Xu Q, Wu Z, Ma Q, Wang Z (2014) The SDF-1/CXCR4 axis induces epithelial-mesenchymal transition in hepatocellular carcinoma. Mol Cell Biochem 392:77–84
|
29 |
Lin Q, Wesson RN, Maeda H, Wang Y, Cui Z, Liu JO, Cameron AM, Gao B, Montgomery RA, Williams GM, Sun Z (2014) Pharmacological mobilization of endogenous stem cells significantly promotes skin regeneration after full-thickness excision: the synergistic activity of AMD3100 and tacrolimus. J Investig Dermatol 134:2458–2468
|
30 |
Luker KE, Luker GD (2006) Functions of CXCL12 and CXCR4 in breast cancer. Cancer letters. 238:30–41
|
31 |
Maas-Szabowski N, Shimotoyodome A, Fusenig NE (1999) Keratinocyte growth regulation in fibroblast cocultures via a double paracrine mechanism. J Cell Sci 112(Pt 12):1843–1853
|
32 |
Maksym RB, Tarnowski M, Grymula K, Tarnowska J, Wysoczynski M, Liu R, Czerny B, Ratajczak J, Kucia M, Ratajczak, MZ (2009) The role of stromal-derived factor-1- CXCR7 axis in development and cancer. Eur J Pharmacol 625:31–40
|
33 |
Mine S, Fortunel NO, Pageon H, Asselineau D (2008) Aging alters functionally human dermal papillary fibroblasts but not reticular fibroblasts: a new view of skin morphogenesis and aging. PloS One 3:e4066
|
34 |
Mueller MM, Fusenig NE (2004) Friends or foes- bipolar effects of the tumour stroma in cancer. Nature reviews. Cancer. 4:839–849
|
35 |
Nie Y,Han YC, Zou YR(2008)CXCR4is required for the quiescence of primitive hematopoietic cells. J Exp Med 205:777–783
|
36 |
Nishimura Y, Ii M, Qin G, Hamada H, Asai J, Takenaka H, Sekiguchi H, Renault MA, Jujo K, Katoh N, Kishimoto S, Ito A, Kamide C, Kenny J, Millay M, Misener S, Thorne T, Losordo DW (2012) CXCR4 antagonist AMD3100 accelerates impaired wound healing in diabetic mice. J Investig Dermatol 132:711–720
|
37 |
Onoue T, Uchida D, Begum NM, Tomizuka Y, Yoshida H, Sato M (2006) Epithelial-mesenchymal transition induced by the stromal cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma cells. Int J Oncol 29:1133–1138
|
38 |
Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348
|
39 |
Pablos JL, Amara A, Bouloc A, Santiago B, Caruz A, Galindo M, Delaunay T, Virelizier JL, Arenzana-Seisdedos F (1999) Stromalcell derived factor is expressed by dendritic cells and endothelium in human skin. Am J Pathol 155:1577–1586
|
40 |
Pickard A, Cichon AC, Menges C, Patel D, McCance DJ (2012) Regulation of epithelial differentiation and proliferation by the stroma: a role for the retinoblastoma protein. J Investig Dermatol 132:2691–2699
|
41 |
Potten CS (1981) Cell replacement in epidermis (keratopoiesis) via discrete units of proliferation. Int Rev Cytol 69:271–318
|
42 |
Qin Z, Fisher GJ, Quan T (2013) CCN1 domain-specific stimulation of matrix metalloproteinase-1 expression through alphaVbeta3 integrin in human skin fibroblasts. J Biol Chem 288:12386–12394
|
43 |
Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437
|
44 |
Quan T, He T, Voorhees JJ, Fisher GJ (2001) Ultraviolet irradiation blocks cellular responses to transforming growth factor-β by down-regulating its type-II receptor and inducing Smad7. J Biol Chem 276:26349–26356
|
45 |
Quan T, Qin Z, Xia W, Shao Y, Voorhees JJ, Fisher GJ (2009) Matrixdegrading metalloproteinases in photoaging. J Investig Dermatol Symp Proc 14:20–24
|
46 |
Quan T, Shao Y, He T, Voorhees JJ, Fisher GJ (2010) Reduced expression of connective tissue growth factor (CTGF/CCN2) mediates collagen loss in chronologically aged human skin. J Investig Dermatol 130:415–424
|
47 |
Quan T, Wang F, Shao Y, Rittié L, Xia W, Orringer JS, Voorhees JJ, Fisher GJ (2013) Enhancing structural support of the dermal microenvironment activates fibroblasts, endothelial cells, and keratinocytes in aged human skin in vivo. J Investig Dermatol 133:658–667
|
48 |
Rabbany SY, Pastore J, Yamamoto M, Miller T, Rafii S, Aras R, Penn M (2010) Continuous delivery of stromal cell-derived factor-1 from alginate scaffolds accelerateswoundhealing. CellTranspl 19:399–408
|
49 |
Ridky TW, Chow JM, Wong DJ, Khavari PA (2010) Invasive threedimensional organotypic neoplasia from multiple normal human epithelia. Nat Med 16:1450–1455
|
50 |
Sarchio SN, Scolyer RA, Beaugie C, McDonald D, Marsh-Wakefield F, Halliday GM, Byrne SN (2014) Pharmacologically antagonizing the CXCR4-CXCL12 chemokine pathway with AMD3100 inhibits sunlight-induced skin cancer. J Investig Dermatol 134:1091–1100
|
51 |
Sarkar A, Tatlidede S, Scherer SS, Orgill DP, Berthiaume F (2011) Combination of stromal cell-derived factor-1 and collagen-glycosaminoglycan scaffold delays contraction and accelerates reepithelialization of dermal wounds in wild-type mice. Wound Repair Regener 19:71–79
|
52 |
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A,Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB,Ribas A, Lo RS, Flaherty KT, Ogino S,Wargo JA,Golub TR(2012)Tumourmicro-environment elicits innate resistance toRAF inhibitors through HGF secretion. Nature 487:500–504
|
53 |
Sugiyama T, Kohara H, Noda M, Nagasawa T (2006) Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25:977–988
|
54 |
Tuan TL, Keller LC, Sun D, Nimni ME, Cheung D (1994) Dermal fibroblasts activate keratinocyte outgrowth on collagen gels. J Cell Sci 107(Pt 8):2285–2289
|
55 |
Uitto J (1986) Connective tissue biochemistry of the aging dermis. Agerelated alterations in collagen and elastin. Dermatol Clin 4:433–446
|
56 |
Wang J, Wang J, Sun Y, Song W, Nor JE, Wang CY, Taichman RS (2005) Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis. Cell Signal 17:1578–1592
|
57 |
Wright DE, Bowman EP, Wagers AJ, Butcher EC, Weissman IL (2002) Hematopoietic stem cells are uniquely selective in their migratory response to chemokines. J Exp Med 195:1145–1154
|
58 |
Zgraggen S, Huggenberger R, Kerl K, Detmar M (2014) An important role of the SDF-1/CXCR4 axis in chronic skin inflammation. PloS One9:e93665
|
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