Inhibition of Wnt/β-catenin pathway promotes regenerative repair of cutaneous and cartilage injury

FASEB Journal

Volumn 29, Issue 12, 2015, Pages 4881-4892

  Bastakoty, Dikshya ^a   Saraswati, Sarika ^a,c   Cates, Justin ^a   Lee, Ethan ^b   Nanney, Lillian B ^a   Young, Pampee P ^a,c  

^a VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

Hair follicle; Scar; Skin; Wound healing

Indexed keywords

7,8 DIHYDRO 2 [4 (TRIFLUOROMETHYL)PHENYL] 5H THIOPYRANO[4,3 D]PYRIMIDIN 4 OL; ALPHA SMOOTH MUSCLE ACTIN; BETA CATENIN; BETA GALACTOSIDASE; COLLAGEN TYPE 1; CYCLIN D1; DICKKOPF 1 PROTEIN; MYC PROTEIN; PYRVINIUM EMBONATE; WNT PROTEIN;

ANIMAL CELL; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CARTILAGE INJURY; CONTROLLED STUDY; EAR CARTILAGE; EXTRACELLULAR MATRIX; FIBROSIS; HAIR FOLLICLE; HISTOLOGY; MOUSE; MYOFIBROBLAST; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; SKIN INJURY; TISSUE REGENERATION; WNT SIGNALING PATHWAY; WOUND CLOSURE; WOUND CONTRACTION; WOUND HEALING; ANIMAL; ANTAGONISTS AND INHIBITORS; C57BL MOUSE; CARTILAGE; INJURIES; METABOLISM; REGENERATION; SKIN;

ANIMALS; BETA CATENIN; CARTILAGE; HAIR FOLLICLE; MICE; MICE, INBRED C57BL; REGENERATION; SKIN; WNT PROTEINS; WOUND HEALING;

EID: 84973547635     PISSN: 08926638     EISSN: 15306860     Source Type: Journal    
DOI: 10.1096/fj.15-275941     Document Type: Article

References (61)

1. Centers for Disease Control and Prevention (2011) National Hospital Ambulatory Medical Care Survey: 2011 Emergency Department Summary Tables. Accessed August 5, 2015 at: http://www.cdc.gov/nchs/data/ahcd/nhamcs-emergency/2011-ed-web-tables.pdf
2. Atala, A., Irvine, D. J., Moses, M., and Shaunak, S. (2010) Wound healing versus regeneration: role of the tissue environment in regenerative medicine. MRS Bull. 35, 35-57
3. Gourevitch, D., Clark, L., Chen, P., Seitz, A., Samulewicz, S. J., and Heber-Katz, E. (2003) Matrix metalloproteinase activity correlates with blastema formation in the regenerating MRL mouse ear hole model. Dev. Dyn. 226, 377-387
4. Clark, L. D., Clark, R. K., and Heber-Katz, E. (1998) A new murine model for mammalian wound repair and regeneration. Clin. Immunol. Immunopathol. 88, 35-45
5. Seifert, A. W., Kiama, S. G., Seifert, M. G., Goheen, J. R., Palmer, T. M., and Maden, M. (2012) Skin shedding and tissue regeneration in African spiny mice (Acomys). Nature 489, 561-565
6. Bedelbaeva, K., Snyder, A., Gourevitch, D., Clark, L., Zhang, X. M., Leferovich, J., Cheverud, J. M., Lieberman, P., and Heber-Katz, E. (2010) Lack of p21 expression links cell cycle control and appendage regeneration in mice. Proc. Natl. Acad. Sci. USA 107, 5845-5850
7. Gourevitch, D., Kossenkov, A. V., Zhang, Y., Clark, L., Chang, C., Showe, L. C., and Heber-Katz, E. (2014) Inflammation and its correlates in regenerative wound healing: an alternate perspective. Adv. Wound Care (New Rochelle) 3, 592-603
8. Alfaro, M. P., Pagni, M., Vincent, A., Atkinson, J., Hill, M. F., Cates, J., Davidson, J. M., Rottman, J., Lee, E., and Young, P. P. (2008) The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair. Proc. Natl. Acad. Sci. USA 105, 18366-18371
9. Saraswati, S., Alfaro, M. P., Thorne, C. A., Atkinson, J., Lee, E., and Young, P. P. (2010) Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling. PLoS One 5, e15521
10. He, W., Zhang, L., Ni, A., Zhang, Z., Mirotsou, M., Mao, L., Pratt, R. E., and Dzau, V. J. (2010) Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction. Proc. Natl. Acad. Sci. USA 107, 21110-21115
11. Brack, A. S., Murphy-Seiler, F., Hanifi, J., Deka, J., Eyckerman, S., Keller, C., Aguet, M., and Rando, T. A. (2009) BCL9 is an essential component of canonical Wnt signaling that mediates the differentiation of myogenic progenitors during muscle regeneration. Dev. Biol. 335, 93-105
12. Kim, T. H., Kim, S. H., Seo, J. Y., Chung, H., Kwak, H. J., Lee, S. K., Yoon, H. J., Shin, D. H., Park, S. S., and Sohn, J. W. (2011) Blockade of the Wnt/β-catenin pathway attenuates bleomycin-induced pulmonary fibrosis. Tohoku J. Exp. Med. 223, 45-54
13. He, W., Dai, C., Li, Y., Zeng, G., Monga, S. P., and Liu, Y. (2009) Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J. Am. Soc. Nephrol. 20, 765-776
14. Saraswati, S., Deskins, D. L., Holt, G. E., and Young, P. P. (2012) Pyrvinium, a potent small molecule Wnt inhibitor, increases engraftment and inhibits lineage commitment of mesenchymal stem cells (MSCs). Wound Repair Regen. 20, 185-193
15. Cheon, S. S., Cheah, A. Y., Turley, S., Nadesan, P., Poon, R., Clevers, H., and Alman, B. A. (2002) beta-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds. Proc. Natl. Acad. Sci. USA 99, 6973-6978
16. Akhmetshina, A., Palumbo, K., Dees, C., Bergmann, C., Venalis, P., Zerr, P., Horn, A., Kireva, T., Beyer, C., Zwerina, J., Schneider, H., Sadowski, A., Riener, M. O., MacDougald, O. A., Distler, O., Schett, G., and Distler, J. H. (2012) Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat. Commun. 3, 735-747
17. Russell, S. B., Russell, J. D., Trupin, K. M., Gayden, A. E., Opalenik, S. R., Nanney, L. B., Broquist, A. H., Raju, L., and Williams, S. M. (2010) Epigenetically altered wound healing in keloid fibroblasts. J. Invest. Dermatol. 130, 2489-2496
18. Alman, B. A., Li, C., Pajerski, M. E., Diaz-Cano, S., and Wolfe, H. J. (1997) Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors). Am. J. Pathol. 151, 329-334
19. Tejpar, S., Nollet, F., Li, C., Wunder, J. S., Michils, G., dal Cin, P., Van Cutsem, E., Bapat, B., van Roy, F., Cassiman, J. J., and Alman, B. A. (1999) Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor). Oncogene 18, 6615-6620
20. Whyte, J. L., Smith, A. A., Liu, B., Manzano, W. R., Evans, N. D., Dhamdhere, G. R., Fang, M. Y., Chang, H. Y., Oro, A. E., and Helms, J. A. (2013) Augmenting endogenous Wnt signaling improves skin wound healing. PLoS One 8, e76883
21. Ito, M., Yang, Z., Andl, T., Cui, C., Kim, N., Millar, S. E., and Cotsarelis, G. (2007) Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447, 316-320
22. Lowry, W. E., Blanpain, C., Nowak, J. A., Guasch, G., Lewis, L., and Fuchs, E. (2005) Defining the impact of beta-catenin/Tcf transactivation on epithelial stem cells. Genes Dev. 19, 1596-1611
23. Gay, D., Kwon, O., Zhang, Z., Spata, M., Plikus, M. V., Holler, P. D., Ito, M., Yang, Z., Treffeisen, E., Kim, C. D., Nace, A., Zhang, X., Baratono, S., Wang, F., Ornitz, D. M., Millar, S. E., and Cotsarelis, G. (2013) Fgf9 from dermal gd T cells induces hair follicle neogenesis after wounding. Nat. Med. 19, 916-923
24. Andl, T., Reddy, S. T., Gaddapara, T., and Millar, S. E. (2002) WNT signals are required for the initiation of hair follicle development. Dev. Cell 2, 643-653
25. Choi, Y. S., Zhang, Y., Xu, M., Yang, Y., Ito, M., Peng, T., Cui, Z., Nagy, A., Hadjantonakis, A. K., Lang, R. A., Cotsarelis, G., Andl, T., Morrisey, E. E., and Millar, S. E. (2013) Distinct functions for Wnt/β-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis. Cell Stem Cell 13, 720-733
26. Werner, S., Peters, K. G., Longaker, M. T., Fuller-Pace, F., Banda, M. J., and Williams, L. T. (1992) Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc. Natl. Acad. Sci. USA 89, 6896-6900
27. Cheon, S. S., Wei, Q., Gurung, A., Youn, A., Bright, T., Poon, R., Whetstone, H., Guha, A., and Alman, B. A. (2006) Beta-catenin regulates wound size and mediates the effect of TGF-beta in cutaneous healing. FASEB J. 20, 692-701
28. Thorne, C. A., Hanson, A. J., Schneider, J., Tahinci, E., Orton, D., Cselenyi, C. S., Jernigan, K. K., Meyers, K. C., Hang, B. I., Waterson, A. G., Kim, K., Melancon, B., Ghidu, V. P., Sulikowski, G. A., LaFleur, B., Salic, A., Lee, L. A., Miller III, D. M., and Lee, E. (2010) Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat. Chem. Biol. 6, 829-836
29. Huang, S.-M. A., Mishina, Y. M., Liu, S., Cheung, A., Stegmeier, F., Michaud, G. A., Charlat, O., Wiellette, E., Zhang, Y., Wiessner, S., Hild, M., Shi, X., Wilson, C. J., Mickanin, C., Myer, V., Fazal, A., Tomlinson, R., Serluca, F., Shao, W., Cheng, H., Shultz, M., Rau, C., Schirle, M., Schlegl, J., Ghidelli, S., Fawell, S., Lu, C., Curtis, D., Kirschner, M. W., Lengauer, C., Finan, P. M., Tallarico, J. A., Bouwmeester, T., Porter, J. A., Bauer, A., and Cong, F. (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614-620
30. Aisagbonhi, O., Rai, M., Ryzhov, S., Atria, N., Feoktistov, I., and Hatzopoulos, A. K. (2011) Experimental myocardial infarction triggers canonical Wnt signaling and endothelial-to-mesenchymal transition. Dis. Model. Mech. 4, 469-483
31. Rai, M. F., Hashimoto, S., Johnson, E. E., Janiszak, K. L., Fitzgerald, J., Heber-Katz, E., Cheverud, J. M., and Sandell, L. J. (2012) Heritability of articular cartilage regeneration and its association with ear wound healing in mice. Arthritis Rheum. 64, 2300-2310
32. Fonck, E., Feigl, G. G., Fasel, J., Sage, D., Unser, M., Rüfenacht, D. A., and Stergiopulos, N. (2009) Effect of aging on elastin functionality in human cerebral arteries. Stroke 40, 2552-2556
33. Rezakhaniha, R., Agianniotis, A., Schrauwen, J. T., Griffa, A., Sage, D., Bouten, C. V., van de Vosse, F. N., Unser, M., and Stergiopulos, N. (2012) Experimental investigation of collagen waviness and orientation in the arterial adventitia using confocal laser scanning microscopy. Biomech. Model. Mechanobiol. 11, 461-473
34. Heydemann, A. (2012) The super super-healing MRL mouse strain. Front. Biol. (Beijing) 7, 522-538
35. Hedgepeth, C. M., Conrad, L. J., Zhang, J., Huang, H. C., Lee, V. M., and Klein, P. S. (1997) Activation of the Wnt signaling pathway: a molecular mechanism for lithium action. Dev. Biol. 185, 82-91
36. Nguyen, D. T., Orgill, D. P., and Murphy, G. F. (2009) The pathophysiologic basis of wound healing and cutaneous regeneration. In Biomaterials for Treating Skin Loss (Orgill, D. P., and Blanco, C., eds.), pp. 25-53, Woodhead Publishing, Cambridge, UK
37. Stramer, B. M., Mori, R., and Martin, P. (2007) The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J. Invest. Dermatol. 127, 1009-1017
38. Heber-Katz, E., Leferovich, J., Bedelbaeva, K., Gourevitch, D., and Clark, L. (2004) The scarless heart and the MRL mouse. Philos. Trans. R. Soc. Lond. B Biol. Sci. 359, 785-793
39. Akiyama, H., Chaboissier, M. C., Martin, J. F., Schedl, A., and de Crombrugghe, B. (2002) The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 16, 2813-2828
40. Liu, Y., Lyle, S., Yang, Z., and Cotsarelis, G. (2003) Keratin 15 promoter targets putative epithelial stem cells in the hair follicle bulge. J. Invest. Dermatol. 121, 963-968
41. McGowan, K. M., and Coulombe, P. A. (2000) Keratin 17 expression in the hard epithelial context of the hair and nail, and its relevance for the pachyonychia congenita phenotype. J. Invest. Dermatol. 114, 1101-1107
42. Vidal, V. P., Chaboissier, M. C., Lützkendorf, S., Cotsarelis, G., Mill, P., Hui, C. C., Ortonne, N., Ortonne, J. P., and Schedl, A. (2005) Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr. Biol. 15, 1340-1351
43. De la Roche, M., Ibrahim, A. E., Mieszczanek, J., and Bienz, M. (2014) LEF1 and B9L shield β-catenin from inactivation by Axin, desensitizing colorectal cancer cells to tankyrase inhibitors. Cancer Res. 74, 1495-1505
44. Wynn, T. A., and Ramalingam, T. R. (2012) Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028-1040
45. Wei, J., Melichian, D., Komura, K., Hinchcliff, M., Lam, A. P., Lafyatis, R., Gottardi, C. J., MacDougald, O. A., and Varga, J. (2011) Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum. 63, 1707-1717
46. Tsai, S. Y., Sennett, R., Rezza, A., Clavel, C., Grisanti, L., Zemla, R., Najam, S., and Rendl, M. (2014) Wnt/β-catenin signaling in dermal condensates is required for hair follicle formation. Dev. Biol. 385, 179-188
47. Gat, U., DasGupta, R., Degenstein, L., and Fuchs, E. (1998) De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell 95, 605-614
48. Lim, X., and Nusse, R. (2013) Wnt signaling in skin development, homeostasis, and disease. Cold Spring Harb. Perspect. Biol. 5, 5-25
49. Bergmann, M. W. (2010) WNT signaling in adult cardiac hypertrophy and remodeling: lessons learned from cardiac development. Circ. Res. 107, 1198-1208
50. Beyer, C., Reichert, H., Akan, H., Mallano, T., Schramm, A., Dees, C., Palumbo-Zerr, K., Lin, N. Y., Distler, A., Gelse, K., Varga, J., Distler, O., Schett, G., and Distler, J. H. (2013) Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis. Ann. Rheum. Dis. 72, 1255-1258
51. Rudnicki, J. A., and Brown, A. M. (1997) Inhibition of chondrogenesis by Wnt gene expression in vivo and in vitro. Dev. Biol. 185, 104-118
52. Day, T. F., Guo, X., Garrett-Beal, L., and Yang, Y. (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 8, 739-750
53. Hwang, S. G., Ryu, J. H., Kim, I. C., Jho, E. H., Jung, H. C., Kim, K., Kim, S. J., and Chun, J. S. (2004) Wnt-7a causes loss of differentiated phenotype and inhibits apoptosis of articular chondrocytes via different mechanisms. J. Biol. Chem. 279, 26597-26604
54. Gaur, T., Lengner, C. J., Hovhannisyan, H., Bhat, R. A., Bodine, P. V., Komm, B. S., Javed, A., van Wijnen, A. J., Stein, J. L., Stein, G. S., and Lian, J. B. (2005) Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J. Biol. Chem. 280, 33132-33140
55. Otto, T. C., and Lane, M. D. (2005) Adipose development: from stem cell to adipocyte. Crit. Rev. Biochem. Mol. Biol. 40, 229-242
56. Oikonomopoulos, A., Sereti, K. I., Conyers, F., Bauer, M., Liao, A., Guan, J., Crapps, D., Han, J. K., Dong, H., Bayomy, A. F., Fine, G. C., Westerman, K., Biechele, T. L., Moon, R. T., Force, T., and Liao, R. (2011) Wnt signaling exerts an antiproliferative effect on adult cardiac progenitor cells through IGFBP3. Circ. Res. 109, 1363-1374
57. DasGupta, R., and Fuchs, E. (1999) Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126, 4557-4568
58. Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G., and Birchmeier, W. (2001) beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533-545
59. Zhu, X. J., Liu, Y., Dai, Z. M., Zhang, X., Yang, X., Li, Y., Qiu, M., Fu, J., Hsu, W., Chen, Y., and Zhang, Z. (2014) BMP-FGF signaling axis mediates Wnt-induced epidermal stratification in developing mammalian skin. PLoS Genet. 10, e1004687
60. Ito, M., Liu, Y., Yang, Z., Nguyen, J., Liang, F., Morris, R. J., and Cotsarelis, G. (2005) Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat. Med. 11, 1351-1354
61. Novartis Pharmaceuticals (2014) A Study of Oral LGK974 in Patients with Malignancies Dependent on Wnt Ligands. Available at: https://clinicaltrials.gov/ct2/show/NCT01351103