TRANSFORMING GROWTH FACTOR β1/Smad3 SIGNAL TRANSDUCTION PATHWAY AND POST-TRAUMATIC SCAR FORMATION_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

YU Rong , CEN Ying

Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China;

Corresponding author：

Keywords：

Transforming growth factor β1; Smad3 Signal transduction; Pathological scar; Keloid

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【Abstract】 Objective To summarize the recent progress in related research on transforming growth factor β1 （TGF-β1）/Smad3 signal transduction pathway and post-traumatic scar formation. Methods Recent related literature at home and abroad on TGF-β1/Smad3 signal transduction pathway and post-traumatic scar formation was reviewed and summarized. Results TGF-β1 is an important influence factor of fibrotic diseases, and it plays biological effects by TGF-β1/Smad3 signal transduction pathway. The pathway is regulated by many factors and has crosstalk with other signal pathways at cellular and molecular levels. The pathway is involved in the early post-traumatic inflammatory response, wound healing, and late pathological scar formation. Intervening the transduction pathway at the molecular level can influence the process of fibrosis and extracellular matrix deposition. Conclusion TGF-β1/Smad3 signal transduction pathway is an important way to affect post-traumatic scar formation and extracellular matrix deposition. The further study on the pathway will provide a theoretical basis for promotion of wound healing, as well as prevention and treatment of pathological scar formation.

Citation： YU Rong,CEN Ying. TRANSFORMING GROWTH FACTOR β1/Smad3 SIGNAL TRANSDUCTION PATHWAY AND POST-TRAUMATIC SCAR FORMATION. Chinese Journal of Reparative and Reconstructive Surgery, 2012, 26(3): 330-335. doi: Copy

1.	46 Takagawa S, Lakos G, Mori Y, et al. Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma. J Invest Dermatol, 2003, 121(1): 41-50. 47 Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation: consequences for extracelluar matrix remodeling and wound healing. J Dermatol Sci, 2004, 35(2): 83-92.
2.
3.	Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell, 2000, 103(2): 295-309.
4.	Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nature Genet, 2001, 29(2): 117-129.
5.	Rhett JM, Ghatnekar GS, Palatinus JA, et al. Novel therapies for scar reduction and regenerative healing of skin wounds. Trends Biotechnol, 2008, 26(4): 173-180.
6.	Burt DW, Law AS. Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res, 1994, 5(1): 99-118.
7.	Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta, 2008, 1782(4): 197-228.
8.	曾惠芬, 王庆文. 转化生长因子-β及其Smad信号转导的研究进展. 中国药物与临床, 2010, 10(10): 1145-1147.
9.	Khalil N. TGF-beta: from latent to active. J Microbes Infect, 1999, 1(15): 1255-1263.
10.	Horimoto M, Kato J, Takimoto R, et al. Identification of a transforming growth factor beta-1 activator derived from a human gastric cancer cell line. Br J Cancer, 1995, 72(3): 676-682.
11.	Huse M, Chen YG, Massagué J, et al. Crystal structure of the cytoplasmic domain of the type I TGFbeta receptor in complex with FKBP12. Cell, 1999, 96(3): 425-436.
12.	Massagué J. TGF-beta signal transduction. Annu Rev Biochem, 1998, 67: 753-791.
13.	Letamendía A, Lastres P, Botella LM, et al. Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan. J Biol Chem, 1998, 273(49): 33011-33019.
14.	赵会平, 肖嵘, 刘伏友, 等. Smad家族与硬皮病. 国外医学: 生理、病理科学与临床分册, 2005, 25(2): 169-171.
15.	Shi Y, Wang YF, Jayaraman L, et al. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell, 1998, 94(5): 585-594.
16.	Wu G, Chen YG, Ozdamar B, et al. Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science, 2000, 287(5450): 92-97.
17.	Itoh S, Itoh F, Goumans MJ, et al. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem, 2000, 267(24): 6954-6967.
18.	Feng XH, Derynck R. A kinase subdomain of transforming growth factor-beta (TGF-beta) type I receptor determines the TGF-beta intracellular signaling specificity. EMBO J, 1997, 16(13): 3912-3923.
19.	Ishisaki A, Yamato K, Nakao A. et al. Smad7 is an Activin-inducible inhibitor of activin-induced growth arrest and apoptosis in mouse B cells. J Biol Chem, 1998, 273(38): 24293-24296.
20.	Tan R, He W, Lin X, et al. Smad ubiquitination regulatory factor-2 in the fibrotic kindney: regulation, target specificity, and functional implication. Am J Physiol Renal Physiol, 2008, 294(5): F1076-1083.
21.	Dong C, Li Z, Alvarez R Jr, et al. Microtubule binding to Smads may regulate TGF beta activity. Mol Cell, 2000, 5(1): 27-34.
22.	Lo RS, Massagué J. Ubiquitin-dependent degradation of TGF-beta-activated smad2. Nat Cell Biol, 1999, 1(8): 472-478.
23.	Kretzschmar M, Doody J, Timokhina I, et al. A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev, 1999, 13(7): 804-816.
24.	Yin JJ, Selander K, Chirgwin JM, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest, 1999, 103(2): 197-206.
25.	Boone B, Haspeslagh M, Brochez L. Clinical significance of the expression of c-Ski and SnoN, possible mediators in TGF-beta resistance, in primary cutaneous melanoma. J Dermatol Sci, 2009, 53(1): 26-33.
26.	张斌, 马显杰, 刘宾, 等. JNK和TGF-β信号途径协同介导CTGF在瘢痕疙瘩成纤维细胞中过度表达. 中国美容医学, 2009, 18(4): 506-509.
27.	Cuschieri J, Maier RV. Mitogen-activated protein kinase (MAPK). Crit Care Med, 2005, 33(12 Suppl): S417-419.
28.	Palmer EM, Beilfuss BA, Naqai T, et al. Human helper T cell activation and differentiation is suppressed by porcine small intestinal submucosa. Tissue Eng, 2002, 8(5): 893-900.
29.	邱振中, 李锐, 魏振雪. 皮肤伤口愈合中转化生长因子β 信号转导分子表达. 中国烧伤创疡杂志, 2003, 15(3): 173-175.
30.	陈伟, 付小兵, 王海滨, 等. 增生性瘢痕形成和成熟过程中转化生长因子-β1及下游信号分子的基因表达变化. 中华实验外科杂志, 2005, 22(6): 740-742.
31.	Xia W, Phan TT, Lim IJ, et al. Complex epithelial-mesenchymal interactions modulate transforming growth factor-beta expression in keloid-derived cells. Wound Repair Regen, 2004, 12(5): 546-556.
32.	罗梅, 姬永忠. 反义TGF-β1 抑制兔耳增生性瘢痕的实验研究. 中国美容医学, 2004, 13(1): 18-21.
33.	Schultze-Mosqau S, Blaese MA, Grabenbauer G, et al. Smad-3 and Smad-7 expression following anti-transforming growth factor beta 1 (TGFbeta1) -treatment in irradiated rat tissue. Radiother Oncol, 2004, 70(3): 249-259.
34.	庞久玲, 马征, 刘军, 等. Smad3和转化生长因子β1在瘢痕疙瘩、增生性瘢痕及正常皮肤中的表达: 48∶40∶40例标本病理检测. 中国组织工程研究与临床康复, 2010, 14(11): 1927-1930.
35.	孙燚, 宋建星, 汪滋民, 等. TGF-βRⅠ、Smad2、Smad3及Smad7在瘢痕疙瘩中的表达. 中华整形外科杂志, 2006, 22(5): 368-370.
36.	安纲, 蔡景龙, 董红, 等. 转化生长因子-β1Ⅱ型受体基因在瘢痕疙瘩中改变的实验研究. 中国美容整形外科杂志, 2006, 17(5): 328-331.
37.	Chin GS, Liu W, Peled Z, et al. Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg, 2001, 108(2): 423-429.
38.	Bock O, Yu H, Zitron S, et al. Studies of transforming growth factors beta 1-3 and their receptors I and II in fibroblasts of keloids and hypertrophic scars. Acta Derm Venereol, 2005, 85(3): 216-220.
39.	Goldberg HJ, Huszár T, Mózes MM, et al. Overexpression of the type II transforming growth factor-beta receptor inhibits fibroblast proliferation and activates extracellular signal regulated kinase and c-Jun N-terminal kinase. Cell Biol Int, 2002, 26(2): 165-174.
40.	Bran GM, Goessler UR, Schardt CS, et al. Effect of the abrogation of TGF-beta1 by antisense oligonucleotides on the expression of TGF-beta-isoforms and their receptors I and II in isolated fibroblasts from keloid scars. Int J Mol Med, 2010, 25(6): 915-921.
41.	Wang Y, Moges H, Bharucha Y, et al. Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex. Exp Neurol, 2007, 203(1): 168-184.
42.	毛春明, 杨晓, 张莉, 等. Smad3基因缺失加快小鼠皮肤创面收缩速度机制研究. 中国临床康复, 2004, 8(26): 5538-5540.
43.	Flanders KC, Sullivan CD, Fujii M, et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol, 2002, 160(3): 1057-1068.
44.	但洋, 沈为民, 果磊. shRNA抑制Smad3基因的表达对瘢痕疙瘩成纤维细胞Smad7表达的影响. 第三军医大学学报, 2009, 31(12): 1172-1176.
45.	但洋, 沈为民. shRNA对瘢痕疙瘩成纤维细胞Smad3及Ⅰ型胶原表达的影响. 激光杂志, 2009, 30(2): 78-80.
46.	刘波, 张恒术, 果磊. siRNA沉默Smad3对人KFB细胞增殖、凋亡及合成MMP3的影响. 免疫学杂志, 2009, 25(3): 301-307.
47.	Yu H, Bock O, Bayat A, et al. Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring. J Plast Reconstr Aesthet Surg, 2006, 59(3): 221-229.
48.	Saika S, Yamanaka O, Nishikawa-Ishida I, et al. Effect of Smad7 gene overexpression on transforming growth factor beta-induced retinal pigment fibrosis in a proliferative vitreoretinopathy mouse mode. Arch Ophtalmol, 2007, 125(5): 647-654.
49.	Kato M, Zhang J, Wang M, et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A, 2007, 104(9): 3432-3437.
50.	Postigo AA. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J, 2003, 22(10): 2443-2452.
51.	Zhang ZF, Zhang YG, Hu DH, et al. Smad interacting protein 1 as a regulator of skin fibrosis in pathological scars. Burns, 2011, 37(4): 665-672.
52.	Phan TT, Lim IJ, Chan SY, et al. Suppression of transforming growth factor beta/smad signaling in keloid-derived fibroblasts by quercetin: implications for the treatment of excessive scars. J Trauma, 2004, 57(5): 1032-1037.
53.	Wendling J, Marchand A, Mauviel A, et al. 5-fluorouracil blocks transforming growth feator-beta-induced alpha 2 type Ⅰcollagen gene (COL1A2) expression in human fibroblasts via c-Jun NH2-terminal kinase/activator protein-1 actvation. Mol Pharmacol, 2003, 64(3): 707-713.
54.	Suzawa H, Kikuchi S, Arai N, et al. The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblasts. Jpn J Pharmacol, 1992, 60(2): 91-96.
55.	Tang B, Zhu B, Liang Y, et al. Asiaticoside suppresses collagen expression and TGF-β/Smad signaling through inducing Smad7 and inhibiting TGF-βRI and TGF-βRII in keloid fibroblasts. Arch Dermatol Res, 2011, 303(8): 563-572.

1. 46 Takagawa S, Lakos G, Mori Y, et al. Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma. J Invest Dermatol, 2003, 121(1): 41-50. 47 Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation: consequences for extracelluar matrix remodeling and wound healing. J Dermatol Sci, 2004, 35(2): 83-92.
2.
3. Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell, 2000, 103(2): 295-309.
4. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nature Genet, 2001, 29(2): 117-129.
5. Rhett JM, Ghatnekar GS, Palatinus JA, et al. Novel therapies for scar reduction and regenerative healing of skin wounds. Trends Biotechnol, 2008, 26(4): 173-180.
6. Burt DW, Law AS. Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res, 1994, 5(1): 99-118.
7. Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta, 2008, 1782(4): 197-228.
8. 曾惠芬, 王庆文. 转化生长因子-β及其Smad信号转导的研究进展. 中国药物与临床, 2010, 10(10): 1145-1147.
9. Khalil N. TGF-beta: from latent to active. J Microbes Infect, 1999, 1(15): 1255-1263.
10. Horimoto M, Kato J, Takimoto R, et al. Identification of a transforming growth factor beta-1 activator derived from a human gastric cancer cell line. Br J Cancer, 1995, 72(3): 676-682.
11. Huse M, Chen YG, Massagué J, et al. Crystal structure of the cytoplasmic domain of the type I TGFbeta receptor in complex with FKBP12. Cell, 1999, 96(3): 425-436.
12. Massagué J. TGF-beta signal transduction. Annu Rev Biochem, 1998, 67: 753-791.
13. Letamendía A, Lastres P, Botella LM, et al. Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan. J Biol Chem, 1998, 273(49): 33011-33019.
14. 赵会平, 肖嵘, 刘伏友, 等. Smad家族与硬皮病. 国外医学: 生理、病理科学与临床分册, 2005, 25(2): 169-171.
15. Shi Y, Wang YF, Jayaraman L, et al. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell, 1998, 94(5): 585-594.
16. Wu G, Chen YG, Ozdamar B, et al. Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science, 2000, 287(5450): 92-97.
17. Itoh S, Itoh F, Goumans MJ, et al. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem, 2000, 267(24): 6954-6967.
18. Feng XH, Derynck R. A kinase subdomain of transforming growth factor-beta (TGF-beta) type I receptor determines the TGF-beta intracellular signaling specificity. EMBO J, 1997, 16(13): 3912-3923.
19. Ishisaki A, Yamato K, Nakao A. et al. Smad7 is an Activin-inducible inhibitor of activin-induced growth arrest and apoptosis in mouse B cells. J Biol Chem, 1998, 273(38): 24293-24296.
20. Tan R, He W, Lin X, et al. Smad ubiquitination regulatory factor-2 in the fibrotic kindney: regulation, target specificity, and functional implication. Am J Physiol Renal Physiol, 2008, 294(5): F1076-1083.
21. Dong C, Li Z, Alvarez R Jr, et al. Microtubule binding to Smads may regulate TGF beta activity. Mol Cell, 2000, 5(1): 27-34.
22. Lo RS, Massagué J. Ubiquitin-dependent degradation of TGF-beta-activated smad2. Nat Cell Biol, 1999, 1(8): 472-478.
23. Kretzschmar M, Doody J, Timokhina I, et al. A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev, 1999, 13(7): 804-816.
24. Yin JJ, Selander K, Chirgwin JM, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest, 1999, 103(2): 197-206.
25. Boone B, Haspeslagh M, Brochez L. Clinical significance of the expression of c-Ski and SnoN, possible mediators in TGF-beta resistance, in primary cutaneous melanoma. J Dermatol Sci, 2009, 53(1): 26-33.
26. 张斌, 马显杰, 刘宾, 等. JNK和TGF-β信号途径协同介导CTGF在瘢痕疙瘩成纤维细胞中过度表达. 中国美容医学, 2009, 18(4): 506-509.
27. Cuschieri J, Maier RV. Mitogen-activated protein kinase (MAPK). Crit Care Med, 2005, 33(12 Suppl): S417-419.
28. Palmer EM, Beilfuss BA, Naqai T, et al. Human helper T cell activation and differentiation is suppressed by porcine small intestinal submucosa. Tissue Eng, 2002, 8(5): 893-900.
29. 邱振中, 李锐, 魏振雪. 皮肤伤口愈合中转化生长因子β 信号转导分子表达. 中国烧伤创疡杂志, 2003, 15(3): 173-175.
30. 陈伟, 付小兵, 王海滨, 等. 增生性瘢痕形成和成熟过程中转化生长因子-β1及下游信号分子的基因表达变化. 中华实验外科杂志, 2005, 22(6): 740-742.
31. Xia W, Phan TT, Lim IJ, et al. Complex epithelial-mesenchymal interactions modulate transforming growth factor-beta expression in keloid-derived cells. Wound Repair Regen, 2004, 12(5): 546-556.
32. 罗梅, 姬永忠. 反义TGF-β1 抑制兔耳增生性瘢痕的实验研究. 中国美容医学, 2004, 13(1): 18-21.
33. Schultze-Mosqau S, Blaese MA, Grabenbauer G, et al. Smad-3 and Smad-7 expression following anti-transforming growth factor beta 1 (TGFbeta1) -treatment in irradiated rat tissue. Radiother Oncol, 2004, 70(3): 249-259.
34. 庞久玲, 马征, 刘军, 等. Smad3和转化生长因子β1在瘢痕疙瘩、增生性瘢痕及正常皮肤中的表达: 48∶40∶40例标本病理检测. 中国组织工程研究与临床康复, 2010, 14(11): 1927-1930.
35. 孙燚, 宋建星, 汪滋民, 等. TGF-βRⅠ、Smad2、Smad3及Smad7在瘢痕疙瘩中的表达. 中华整形外科杂志, 2006, 22(5): 368-370.
36. 安纲, 蔡景龙, 董红, 等. 转化生长因子-β1Ⅱ型受体基因在瘢痕疙瘩中改变的实验研究. 中国美容整形外科杂志, 2006, 17(5): 328-331.
37. Chin GS, Liu W, Peled Z, et al. Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg, 2001, 108(2): 423-429.
38. Bock O, Yu H, Zitron S, et al. Studies of transforming growth factors beta 1-3 and their receptors I and II in fibroblasts of keloids and hypertrophic scars. Acta Derm Venereol, 2005, 85(3): 216-220.
39. Goldberg HJ, Huszár T, Mózes MM, et al. Overexpression of the type II transforming growth factor-beta receptor inhibits fibroblast proliferation and activates extracellular signal regulated kinase and c-Jun N-terminal kinase. Cell Biol Int, 2002, 26(2): 165-174.
40. Bran GM, Goessler UR, Schardt CS, et al. Effect of the abrogation of TGF-beta1 by antisense oligonucleotides on the expression of TGF-beta-isoforms and their receptors I and II in isolated fibroblasts from keloid scars. Int J Mol Med, 2010, 25(6): 915-921.
41. Wang Y, Moges H, Bharucha Y, et al. Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex. Exp Neurol, 2007, 203(1): 168-184.
42. 毛春明, 杨晓, 张莉, 等. Smad3基因缺失加快小鼠皮肤创面收缩速度机制研究. 中国临床康复, 2004, 8(26): 5538-5540.
43. Flanders KC, Sullivan CD, Fujii M, et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol, 2002, 160(3): 1057-1068.
44. 但洋, 沈为民, 果磊. shRNA抑制Smad3基因的表达对瘢痕疙瘩成纤维细胞Smad7表达的影响. 第三军医大学学报, 2009, 31(12): 1172-1176.
45. 但洋, 沈为民. shRNA对瘢痕疙瘩成纤维细胞Smad3及Ⅰ型胶原表达的影响. 激光杂志, 2009, 30(2): 78-80.
46. 刘波, 张恒术, 果磊. siRNA沉默Smad3对人KFB细胞增殖、凋亡及合成MMP3的影响. 免疫学杂志, 2009, 25(3): 301-307.
47. Yu H, Bock O, Bayat A, et al. Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring. J Plast Reconstr Aesthet Surg, 2006, 59(3): 221-229.
48. Saika S, Yamanaka O, Nishikawa-Ishida I, et al. Effect of Smad7 gene overexpression on transforming growth factor beta-induced retinal pigment fibrosis in a proliferative vitreoretinopathy mouse mode. Arch Ophtalmol, 2007, 125(5): 647-654.
49. Kato M, Zhang J, Wang M, et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A, 2007, 104(9): 3432-3437.
50. Postigo AA. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J, 2003, 22(10): 2443-2452.
51. Zhang ZF, Zhang YG, Hu DH, et al. Smad interacting protein 1 as a regulator of skin fibrosis in pathological scars. Burns, 2011, 37(4): 665-672.
52. Phan TT, Lim IJ, Chan SY, et al. Suppression of transforming growth factor beta/smad signaling in keloid-derived fibroblasts by quercetin: implications for the treatment of excessive scars. J Trauma, 2004, 57(5): 1032-1037.
53. Wendling J, Marchand A, Mauviel A, et al. 5-fluorouracil blocks transforming growth feator-beta-induced alpha 2 type Ⅰcollagen gene (COL1A2) expression in human fibroblasts via c-Jun NH2-terminal kinase/activator protein-1 actvation. Mol Pharmacol, 2003, 64(3): 707-713.
54. Suzawa H, Kikuchi S, Arai N, et al. The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblasts. Jpn J Pharmacol, 1992, 60(2): 91-96.
55. Tang B, Zhu B, Liang Y, et al. Asiaticoside suppresses collagen expression and TGF-β/Smad signaling through inducing Smad7 and inhibiting TGF-βRI and TGF-βRII in keloid fibroblasts. Arch Dermatol Res, 2011, 303(8): 563-572.

Chinese Journal of Reparative and Reconstructive Surgery

TRANSFORMING GROWTH FACTOR β1/Smad3 SIGNAL TRANSDUCTION PATHWAY AND POST-TRAUMATIC SCAR FORMATION

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