Notch信号途径在增生性瘢痕形成中的作用机制研究
摘要
目的探讨Notch信号相关分子对兔耳增生性瘢痕的影响。
方法用16只新西兰大耳白兔建立耳增生性瘢痕模型,分别在伤后1、3、5、7和14 d向左耳瘢痕灶内注射含有100μmol/L Notch信号途径抑制剂N-[N-(3,5-二氟苯乙酰基-L-丙氨酰基)]-(S)-苯基甘氨酸叔丁酯(DAPT)的稀释液(二甲基亚砜和生理盐水稀释)0.1 ml(DAPT组),右耳在相同时点瘢痕灶内注射生理盐水稀释的二甲基亚砜(对照组)。术后第14、21、28、35天各处死4只兔,切取瘢痕标本,HE染色观察并计算瘢痕增生指数和成纤维细胞密度,免疫组织化学染色观察表皮分化标志物角蛋白19(K19)、K14、外皮蛋白(Involucrin)和Notch下游分子P21、P63的表达。
结果DAPT组术后21、28、35 d瘢痕增生指数(分别为1.93±0.32、1.82±0.36、1.79±0.25)和成纤维细胞密度[分别为(4.08±0.88)、(3.30±0.53)、(3.19±0.73)×103个/mm2]均明显低于对照组[2.56±0.29、2.61±0.30、2.58±0.39和(5.45±0.99)(、4.80±1.13)(、4.43±1.17)×103个/mm2,均P<0.01)]。DAPT组术后14 d瘢痕表皮K19、K14和P63表达阳性率(28.6%±5.7%、53.1%±4.5%、57.0%±5.8%)均明显高于对照组(10.1%±2.8%、30.8%±4.9%、16.5%±2.2%,均P<0.01),而Involucrin和P21表达阳性率(12.3%±1.9%、11.0%±1.7%)均明显低于对照组(29.3%±4.6%、44.3%±3.5%,均P <0.01)。
结论阻断Notch信号可以抑制表皮细胞的过度分化,从而抑制兔耳增生性瘢痕的形成。
Objective To investigate the effects of Notch signaling on scars in a rabbit ear model of hypertrophic scarring.
Methods The hypertrophic scar of rabbits' ears was reproduced. The left rabbit's ear wounds as the N-[N-(3,5-difluorophenacetyl-L-alanyl)]-(S)- phenylglycine t-butyl ester (DAPT) treated group were treated intradermally with theγ-secretase inhibitor DAPT to inhibit the activation of Notch at 1, 3, 7 and 14 day time points. The right ears as the control group were treated with normal saline at the same time points. Experimental and control wounds were harvested on days 14, 21, 28 and 35 post wounding, and then examined histologically to quantify hypertrophic index and fibroblasts. The expression of epidermal differentiation markers-keratin 14 (K14), keratin 19 (K19), Involucrin and Notch downstream molecules-P21, P63 were examined and analyzed with immunohistochemistry staining.
Results Both hypertrophic index(1.93±0.32、1.82±0.36、1.79±0.25)and number of fibroblasts [(4.08±0.88)、(3.30±0.53)、(3.19±0.73)×103/mm2]in the DAPT treated group were significantly reduced on days 21, 28 and 35, compared with the control group [2.56±0.29、2.61±0.30、2.58±0.39 and(5.45±0.99)、(4.80±1.13)、(4.43±1.17)×103/mm2, P<0.01)]. The K19、K14 and P63 increased their expression in the DAPT treated group (28.6%±5.7%、53.1%±4.5%、57.0%±5.8%) relative to the control group (10.1%±2.8%、30.8%±4.9%、16.5%±2.2%, P<0.01) on day 14 post wounding, while the Involucrin and P21 decreased their expression in the DAPT treated group (12.3%±1.9%、11.0%±1.7%) relative to the control group (29.3%±4.6%、44.3%±3.5%, P<0.01).
Conclusion Inactivation of Notch signaling will inhibit scar epidermis to over-differentiation, and thereby inhibit proliferation of hypertrophic scars in the rabbit ears.
方法用16只新西兰大耳白兔建立耳增生性瘢痕模型,分别在伤后1、3、5、7和14 d向左耳瘢痕灶内注射含有100μmol/L Notch信号途径抑制剂N-[N-(3,5-二氟苯乙酰基-L-丙氨酰基)]-(S)-苯基甘氨酸叔丁酯(DAPT)的稀释液(二甲基亚砜和生理盐水稀释)0.1 ml(DAPT组),右耳在相同时点瘢痕灶内注射生理盐水稀释的二甲基亚砜(对照组)。术后第14、21、28、35天各处死4只兔,切取瘢痕标本,HE染色观察并计算瘢痕增生指数和成纤维细胞密度,免疫组织化学染色观察表皮分化标志物角蛋白19(K19)、K14、外皮蛋白(Involucrin)和Notch下游分子P21、P63的表达。
结果DAPT组术后21、28、35 d瘢痕增生指数(分别为1.93±0.32、1.82±0.36、1.79±0.25)和成纤维细胞密度[分别为(4.08±0.88)、(3.30±0.53)、(3.19±0.73)×103个/mm2]均明显低于对照组[2.56±0.29、2.61±0.30、2.58±0.39和(5.45±0.99)(、4.80±1.13)(、4.43±1.17)×103个/mm2,均P<0.01)]。DAPT组术后14 d瘢痕表皮K19、K14和P63表达阳性率(28.6%±5.7%、53.1%±4.5%、57.0%±5.8%)均明显高于对照组(10.1%±2.8%、30.8%±4.9%、16.5%±2.2%,均P<0.01),而Involucrin和P21表达阳性率(12.3%±1.9%、11.0%±1.7%)均明显低于对照组(29.3%±4.6%、44.3%±3.5%,均P <0.01)。
结论阻断Notch信号可以抑制表皮细胞的过度分化,从而抑制兔耳增生性瘢痕的形成。
Objective To investigate the effects of Notch signaling on scars in a rabbit ear model of hypertrophic scarring.
Methods The hypertrophic scar of rabbits' ears was reproduced. The left rabbit's ear wounds as the N-[N-(3,5-difluorophenacetyl-L-alanyl)]-(S)- phenylglycine t-butyl ester (DAPT) treated group were treated intradermally with theγ-secretase inhibitor DAPT to inhibit the activation of Notch at 1, 3, 7 and 14 day time points. The right ears as the control group were treated with normal saline at the same time points. Experimental and control wounds were harvested on days 14, 21, 28 and 35 post wounding, and then examined histologically to quantify hypertrophic index and fibroblasts. The expression of epidermal differentiation markers-keratin 14 (K14), keratin 19 (K19), Involucrin and Notch downstream molecules-P21, P63 were examined and analyzed with immunohistochemistry staining.
Results Both hypertrophic index(1.93±0.32、1.82±0.36、1.79±0.25)and number of fibroblasts [(4.08±0.88)、(3.30±0.53)、(3.19±0.73)×103/mm2]in the DAPT treated group were significantly reduced on days 21, 28 and 35, compared with the control group [2.56±0.29、2.61±0.30、2.58±0.39 and(5.45±0.99)、(4.80±1.13)、(4.43±1.17)×103/mm2, P<0.01)]. The K19、K14 and P63 increased their expression in the DAPT treated group (28.6%±5.7%、53.1%±4.5%、57.0%±5.8%) relative to the control group (10.1%±2.8%、30.8%±4.9%、16.5%±2.2%, P<0.01) on day 14 post wounding, while the Involucrin and P21 decreased their expression in the DAPT treated group (12.3%±1.9%、11.0%±1.7%) relative to the control group (29.3%±4.6%、44.3%±3.5%, P<0.01).
Conclusion Inactivation of Notch signaling will inhibit scar epidermis to over-differentiation, and thereby inhibit proliferation of hypertrophic scars in the rabbit ears.
引文
1. Al-Attar A,Mess S,Thomassen JM,et al.Keloid pathogenesis and treatment. Plast Reconstr Surg,2006,117:286-300.
2. Adolphe C, Wainwright B. Pathways to improving skin regeneration. Exp Rex Mol Med,2005,7:1-14.
3. Alonso L,Fuchs E.Stem cells of the skin epithelium. Proc Natl Acad Sci U S A,2003,100 Suppl 1:11830-11835.
4. Fuchs E.Skin stem cells: rising to the surface. J Cell Biol,2008,180:273-284.
5. Patel GK,Wilson CH,Harding KG,et al. Numerous keratinocyte subtypes involved in wound re-epithelialization. J Invest Dermatol , 2006 ,126:497-502.
6. Diao JS, Xia W, Guo SZ. Resume normal structure of epidermis and prevent hypertrophic scars formation. Med Hypotheses,2010,74:205-206.
7.赵志力,付小兵,孙同柱,等.成人正常皮肤和瘢痕组织表皮干细胞定位与表达特征的研究.中华烧伤杂志, 2003, 1:12-14.
8.贺肖洁,韩春茂,彭佳萍.瘢痕疙瘩和增生性瘢痕表皮异常的实验研究.中华外科杂志,2004,42:845-848.
9.沈丹蓓,夏隆庆.角质形成细胞与皮肤创面愈合瘢痕形成.中华整形外科杂志,2005,21:69-71.
10. Niessen FB,Andriessen MP,Schalkwijk J,et al.Keratinocyte-derived growth factors play a role in the formation of hypertrophic scars. J Pathol,2001,194:207-216.
11. Xia W,Phan TT,Lim IJ,et al. Differential transcriptional responses of keloid and normal keratinocytes to serum stimulation. J Surg Res,2006,135:156-163.
12. Lim IJ,Phan TT,Song C,et al.Investigation of the influence of keloid-derived keratinocytes on fibroblast growth and proliferation in vitro.Plast Reconstr Surg,2001,107:797-808.
13. Phan TT,Lim IJ,Bay BH,et al.Differences in collagen production between normal and keloid-derived fibroblasts in serum-media co-culture with keloid-derived keratinocytes.J Dermatol Sci,2002,29:26-34.
14. Lim IJ,Phan TT,Bay BH,et al.Fibroblasts cocultured with keloid keratinocytes:normal fibroblasts secrete collagen in a keloid like manner Am J Physiol Cell Physiol,2002,283:C212-222.
15. Funayama E ,Chodon T ,Oyama A, et al. Keratinocytes promote proliferation and inhibit apoptosis of the underlying fibroblasts: an important role in the pathogenesis of keloid. J Invest Dermatol, 2003,121:1326-1331.
16. Mukhopadhyay A,Tan EK,Khoo YT,et al. Conditioned medium from keloid keratinocyte/keloid fibroblast coculture induces contraction of fibroblast-populated collagen lattices. Br J Dermatol,2005,152:639-645.
17. 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, 12:546-556.
18. Phan TT,Lim IJ,Bay BH,et al.Role of IGF system of mitogens in the induction of fibroblast proliferation by keloid-derived keratinocytes in vitro.Am J Physiol Cell Phvsiol,2003,284:C860-869.
19. Ong CT,Khoo YT,Tan EK,et al. Epithelial-mesenchymal interactions in keloid pathogenesis modulate vascular endothelial growth factor expression and secretion. J Pathol, 2007, 211:95-108.
20.郭树忠,张琳西,王臻,等.培养的正常和瘢痕角质形成细胞上清液对瘢痕成纤维细胞增殖和胶原合成的影响.中华整形外科杂志,2002,18:82-85.
21.张曦,郭树忠,张琳西,等.增生性瘢痕表皮细胞双向电泳图谱的建立及差异蛋白展示.中华整形外科杂志,2005,21:135-138.
22.张曦,郭树忠,张琳西,等.增生性瘢痕表皮细胞差异蛋白的初步分析.中华实验外科杂志,2005,22:1565-1567.
23. Fehon RG,Kooh PJ,Rebay I,et al. Molecular interactions between the protein products of the neurogenic loci Notch and Delta , two EGF-homologous genes in Drosophila. Cell,1990,61:523-534.
24. Artavanis-Tsakonas S,Rand M D,Lake R J. Notch signaling: cell fate control and signal integration in development. Science,1999,284:770-776.
25. Yancopoulos GD,Davis S,Gale NW,et al. Vascular-specific growth factors and blood vessel formation. Nature, 2000,407:242-248.
26. Hofmann JJ,Iruela-Arispe ML. Notch signaling in blood vessels: who is talking to whom about what? Circ Res,2007,100:1556-1568.
27. Apelqvist A,Li H,Sommer L, et al. Notch signalling controls pancreatic cell differentiation. Nature,1999,400:877-881.
28. Milner LA,Bigas A. Notch as a mediator of cell fate determination in hematopoiesis: evidence and speculation. Blood,1999,93:2431-2448.
29. Sestan N,Artavanis-Tsakonas S,Rakic P. Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science,1999,286:741-746.
30. del Amo FF,Gendron-Maguire M,Swiatek PJ,et al. Cloning,analysis,and chromosomal localization of Notch-1,a mouse homolog of Drosophila Notch. Genomics,1993,15:259-264.
31. Lardelli M,Dahlstrand J,Lendahl U. The novel Notch homologue mouseNotch 3 lacks specific epidermal growth factorrepeats and is expressed in proliferating neuroepithelium. Mech Dev,1994,46:123-136.
32. Uyttendaele H,Marazzi G,Wu G,et al. Notch4/int-3,a mammary proto-oncogene,is an endothelial cell-specific mammalian Notch gene. Development,1996,122:2251-2259.
33. Weinmaster G,Roberts VJ, Lemke G. Notch 2: a second mammalian Notch gene. Development,1992,116:931-941.
34. Bettenhausen B,Hrabe de Angelis M,Simon D,et al. Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development,1995,121:2407-2418.
35. Dunwoodie SL,Henrique D,Harrison SM,et al.Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development,1997,124:3065-3076.
36. Lindsell CE,Shawber CJ,Boulter J,et al. Jagged: a mammalian ligand that activates Notch1. Cell,1995,80:909-917.
37. Shawber C,Boulter J,Lindsell CE,et al. Jagged 2: a serrate-like gene expressed during rat embryogenesis. Dev Biol,1996,180:370-376.
38. Shutter JR,Scully S, Fan W,et al. Dll4,a novel Notch ligand expressed in arterial endothelium. Genes Dev,2000,14:1313-1318.
39. Brou C,Logeat F,Gupta N,et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrinmetalloprotease TACE. Mol Cell,2000,5:207-216.
40. Iso T,Kedes L,Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol,2003,194:237-255.
41. Kageyama R,Ohtsuka T,Hatakeyama J,et al. Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res,2005,306:343-348.
42. Lai EC. Keeping a good pathway down: transcriptional repression of Notch pathway target genes by CSL proteins.EMBO,2002,3:840-845.
43. Mumm JS,Kopan R. Notch signaling: from the outside in. Dev Biol 2000,228:151-165.
44. Grego-Bessa J, Luna-Zurita L,del Monte G,et al. Notch signalling is essential for ventricular chamber development. Dev Cell,2007,12:415-429.
45. Iso T,Maeno T,Oike Y,et al. Dll4-selective Notch signalling induces ephrinB2 gene expression in endothelial cells. Biochem Biophys Res Commun,2006,341:708-714.
46. Iso T,Hamamori Y,Kedes L. Notch signalling in vascular development. Arterioscler Thromb Vasc Biol,2003,23:543-553.
47. Limbourg A,Ploom M, Elligsen D,et al. Notch ligand Delta-like 1 is essential for postnatal arteriogenesis. Circ Res,2007,100:363-371.
48. Brennan K,Gardner P. Notching up another pathway. Bioessays,2002,24:405-410.
49. Martinez Arias A,Zecchini V,Brennan K. CSL-independent Notch signalling: a checkpoint in cell fate decisions during development? Curr Opin Genet Dev,2002,12:524-433.
50. Wilson A,Radtke F. Multiple functions of Notch signaling in self-renewing organs and cancer. FEBS Lett,2006,580:2860-2868.
51. Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer,2003,3:756-767.
52. Lowell S,Jones P,Le Roux I, et al. Stimulation of human epidermal differentiation by delta-notch signaling at the boundaries of stem-cell clusters. Curr Biol,2000,10:491-500.
53. Nickoloff BJ,Qin JZ,Chaturvedi V,et al. Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytesthrough NF-kappaB and PPARgamma. Cell Death Differ,2002,9:842-855.
54. Mammucari C,Tommasi di Vignano A,Sharov AA,et al. Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control. Dev Cell,2005,8:665-676.
55. Okuyama R, LeFort K, Dotto GP. A dynamic model of keratinocyte stem cell renewal and differentiation: role of the p21WAF1/Cip1 and Notch1 signaling pathways. J Investig Dermatol Symp Proc,2004,9:248-252.
56. Devgan V, Nguyen BC, Oh H , et al. p21WAF1/Cip1 suppresses keratinocyte differentiation independently of the cell cycle through transcriptional up-regulation of the IGF-I gene. J Biol Chem,2006,281:30463-30470.
57. Osada M,Ohba M,Kawahara C,et al. Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Nat Med,1998,4:839-843.
58. Yang A,Kaghad M,Wang Y,et al. p63,a p53 homolog at 3q27-29, encodes multiple products with transactivating, deathinducing, and dominant- negative activities. Mol Cell,1998,2:305-316.
59. Mills AA,Zheng B,Wang XJ,et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature,1999,398:708-713.
60. Yang A,Schweitzer R,Sun D,et al. p63 is essential for regenerative proliferation in limb,craniofacial and epithelial development. Nature,1999,398:714-718.
61. Koster MI,Kim S,Mills AA,et al. p63 is the molecular switch for initiation of an epithelial stratication program. Genes Dev,2004,18:465-469.
62. Okuyama R,Ogawa E,Nagoshi H,et al. p53 homologue,p51/ p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity. Oncogene,2007,26:4478-4488.
63. Nguyen BC, Lefort K, Mandinova A, et al. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev, 2006, 20:1028-1042.
64. Okuyama R,Nguyen BC,Talora C,et al. High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism. Dev Cell,2004,6:551-562.
65. Lu L,Saulis AS,Liu WR,et al. The temporal effects of anti-TGF-beta1, 2 and 3 monoclonal antibody on wound healing and hypertrophic scar formation. J Am Coll Surg,2005,201:391-397.
66. Rolfe KJ,Richardson J,Vigor C,et al. A role of TGF-beta1 induced cellular responses during wound healing of the non-scarring early human fetus? J Invest Dermatol,2007,127:2656-2667.
67. Kretschmer A,Moepert K,Dames S,et al. Different regulation of TGF-beta signaling through Smad2, Smad3 and Smad4. Oncogene,2003, 22:6748- 6763.
68. Wang JF,Jiao H,Stewart TL,et al. Fibrocytes from burn patients regulate the activities of fibroblasts. Wound Repair Regen,2007,15:113-121.
69. Yang L,Chan T,Demare J,et al. Healing of burn wounds in mice overexpressing transforming growth factor-beta1 in the epidermis. Am J Pathol,2001,159:2147-2157.
70. Blokzijl A,Dahlqvist C,Reissmann E,et al. Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. J Cell Biol,2003, 163:723-728.
71. Hogan BL. Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev,1996,10:1580-1594.
72. Takizawa T,Ochiai W,Nakashima K,et al. Enhanced gene activation by Notch and BMP signaling cross-talk. Nucleic Acids Res. 2003, 31:5723- 5731.
73. Tang Y,Urs S,Boucher J,et al. Notch and TGF{beta} signaling pathways cooperatively regulate vascular smooth muscle cell differentiation. J Biol Chem,2010,doi/10.1074/jbc.M109.076414.
74. Kurpinski K,Lam H,Chu J,et al.TGF-beta and Notch Signaling Mediate Stem Cell Differentiation into Smooth Muscle Cells.Stem Cells,2010,doi: 10.1002/stem.319.
75. Hunt TK,Hopf H,Hussain Z. Physiology of wound healing. Adv Skin Wound Care,2000,13:6-11.
76. Martin P. Wound healing-aiming for perfect skin regeneration. Science,1997,276:75-81.
77. Martin P,Leibovich SJ. Inflammatory cells during wound repair: the good,the bad and the ugly. Trends Cell Biol,2005,15:599-607.
78. Monsalve E,Perez MA,Rubio A,et al. Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity. J Immunol,2006,176:5362-5373.
79. Ostroukhova M,Qi Z,Oriss TB,et al. Tregmediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-beta. J Clin Invest,2006,116:996-1004.
80. Lindner V,Booth C,Prudovsky I,et al. Members of the Jagged/Notch gene families are expressed in injured arteries and regulate cell phenotype via alterations in cell matrix and cell-cell interaction. Am J Pathol,2001,159:875-883.
81. Zimrin AB,Pepper MS,McMahon GA,et al. An antisense oligonucleotide to the notch ligand jagged enhances fibroblast growth factor-induced angiogenesis in vitro. J Biol Chem,1996,271:32499-32502.
82. Uyttendaele H,Closson V,Wu G,et al. Notch4 and Jagged-1 inducemicrovessel differentiation of rat brain endothelial cells.Microvasc Res,2000,60:91-103.
83. Dorsch M,Zheng G,Yowe D,et al. Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease. Blood,2002,100:2046-2055.
84. Savill NJ , Sherratt JA. Control of epidermal stem cell clusters by Notchmediated lateral induction. Dev Biol,2003,258:141-153.
85. Cereseto A,Tsai S. Jagged2 induces cell cycling in confluent fibroblasts susceptible to density-dependent inhibition of cell division. J Cell Physiol,2000,185:425-431.
86. Six EM,Ndiaye D,Sauer G,et al. The notch ligand Delta1 recruits Dlg1 at cell-cell contacts and regulates cell migration. J Biol Chem,2004,279: 55818-55826.
87. Thelu J, Rossio P, Favier B. Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing. BMC Dermatol, 2002, 29:1-12.
88. Chigurupati S,Arumugam TV,Son TG,et al. Involvement of Notch Signaling in Wound Healing. PLoS One,2007,2:e1167.
89. Kared H,Adle-Biassette H,Fois E,et al. Jagged2-expressing hematopoietic progenitors promote regulatory T cell expansion in the periphery through notch signaling. Immunity,2006,25:823-834.
90. Wang Y,Chan SL,Miele L,et al. Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci USA,2004,101: 9458-9462.
91. Arumugam TV,Chan SL,Jo DG,et al. Gamma secretase-mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke. Nat Med,2006,12:621-623.
92. Favier B,Flignaux I,Thélu J,et al. The notch system and the differentiation of vibrissa hair follicule: receptors , ligands and fringe modulators. Developmental Dynamics,2000,218:426-437.
93. Kopan R,Weintraub H. Mouse notch: expression in hair follicles correlates with cell fate determination. J Cell Biol,1993,121:631-641.
94. Powell BC,Passmore EA,Nesci A,et al. The Notch signaling pathway in hair growth. Mech Dev,1998,78:189-192.
95. Limbourg FP,Takeshita K,Radtke F,et al. Essential role of endothelial Notch1 in angiogenesis. Circulation,2005,111:1826-1832.
96. Krebs LT,Xue Y,Norton CR,et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev,2000,14:1343-1352.
97. Xue Y,Gao X,Lindsell CE,et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet,1999,8:723-730.
98. Swiatek PJ,Lindsell CE,del Amo FF,et al. Notch1 is essential for postimplantation development in mice. Genes Dev,1994,8:707-719.
99. Sainson RC,Aoto J,Nakatsu MN,et al. Cellautonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J,2005,19:1027-1029.
100.Takeshita K,Satoh M,Ii M,et al. Critical role of endothelial Notch1 signaling in postnatal angiogenesis. Circ Res,2007,100:70-78.
101.Paris D,Quadros A,Patel N,et al. Inhibition of angiogenesis and tumor growth by beta and gamma-secretase inhibitors. Eur J Pharmacol,2005,514:1-15.
102.Nakajima M,Yuasa S,Ueno M,et al. Abnormal blood vessel development in mice lacking presenilin-1. Mech Dev,2003,120:657-667.
103.Noguera-Troise I,Daly C,Papadopoulos NJ,et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature,2006,444:1032-1037.
104.Ridgway J,Zhang G,Wu Y,et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature,2006,444:1083-1087.
105.Li J,Zhang YP,Kirsner RS. Angiogenesis in wound repair: angiogenic growth factors and the extracellular matrix. Microsc Res Tech,2003,60:107-114.
106.Carmeliet P,Jain RK. Angiogenesis in cancer and other diseases. Nature,2000,407:249-257.
107.Risau W. Mechanisms of angiogenesis. Nature,1997,386: 671-674.
108.Yancopoulos GD,Klagsbrun M,Folkman J. Vasculogenesis,angiogenesis,and growth factors: ephrins enter the fray at the border. Cell,1998,93:661-664.
109.Joutel A, Corpechot C,Ducros A,et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature,1996,383:707-710.
110.Li L,Krantz ID,Deng Y,et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet,1997,16:243-251.
111.Oda T,Elkahloun AG,Pike BL,et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet,1997,16:235-242.
112.Krantz ID,Colliton RP,Genin A,et al.Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet,1998,62:1361-1369.
113.McCright B,Gao X,Shen L,et al. Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2mutation. Development,2001,128:491-502.
114.McCright B,Lozier J,Gridley T. A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development,2002,129:1075-1082.
115.Murphy PA,Lu G,Shiah S,et al. Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease. Lab Invest,2009,89:971-982.
116.Nicolas M,Wolfer A,Raj K,et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet,2003,33:416-421.
117.Lin MH,Leimeister C,Gessler M,et al. Activation of the Notch pathway in the hair cortex leads to aberrant differentiation of the adjacent hair-shaft layers. Development,2000,127:2421-2432.
118.Uyttendaele H,Panteleyev AA,de Berker D,et al. Activation of Notch1 in the hair follicle leads to cell-fate switch and Mohawk alopecia. Differentiation,2004,72:396-409.
119.Pan Y,Lin MH,Tian X,et al. Gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell,2004,7:731-743.
120.Vauclair S,Nicolas M,Barrandon Y,et al. Notch1 is essential for postnatal hair follicle development and homeostasis.Dev Biol,2005,284:184-193.
121.Moriyama M,Osawa M,Mak SS,et al. Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells. J Cell Biol,2006,173:333-339.
122.Alexeev V,Yoon K. Distinctive role of the cKit receptor tyrosine kinase signaling in mammalian melanocytes. J Invest Dermatol , 2006 ,126:1102-1110.
123.Raafat A,Zoltan-Jones A,Strizzi L,et al. Kit and PDGFR-alpha activitiesare necessary for Notch4/Int3-induced tumorigenesis. Oncogene,2007,26:662-672.
124.Diao JS,Zhang X,Xia WS,et al. Aberrant Notch signaling: a potential pathomechanism of vitiligo. Med Hypotheses,2009,73:70-72.
125.Nickoloff BJ,Hendrix MJ,Pollock PM,et al. Notch and NOXA-related pathways in melanoma cells. J Investig Dermatol Symp Proc,2005,10:95-104.
126.Massi D,Tarantini F,Franchi A,et al. Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma. Mod Pathol,2006,19:246-254.
127.Balint K,Xiao M,Pinnix CC,et al. Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression. J Clin Invest,2005,115:3166-3176.
128.Liu ZJ,Xiao M,Balint K,et al. Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N–cadherin expression. Cancer Res,2006,66:4182-4190.
129.夏炜,潘宝华,刘宾,等. Notch信号在增生性瘢痕表皮中的表达.中华整形外科杂志, 2009, 25:49-53.
130.Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation following burns and trauma:new approaches to treatment. PLoS Med,2007,4:e234.
131.Roseborough IE,Grevious MA,Lee RC. Prevention and treatment of excessive dermal scarring. J Natl Med Assoc,2004,96:108-116.
132.Khoo YT,Ong CT,Mukhopadhyay A,et al. Upregulation of secretory connective tissue growth factor (CTGF) in keratinocyte-fibroblast coculture contributes to keloid pathogenesis. J Cell Physiol,2006,208:336-343.
133.Blanpain C,Lowry WE,Pasolli HA,et al. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev,2006,20:3022-3035.
134.Okuyama R, Tagami H, Aiba S. Notch signaling: its role in epidermal homeostasis and in the pathogenesis of skin diseases. J Dermatol Sci,2008,49:187-194.
135.Morris DE,Wu I,Zhao LL,et al. Acute and chronic animal models for excessive dermal scarring: quantitative studies. Plast Reconstr Surg,1997,100:674-681.
136.李荟元,刘建波,夏炜,等.增生性瘢痕动物实验模型的建立与应用.中华整形外科杂志,2001,17:276-278.
137.李荟元主编.创伤研究动物模型-兔耳瘢痕模型的建立与应用西安:第四军医大学出版社,2005,1:42-45.
138.Singer AJ,Clark RA.Cutaneous wound healing.N Engl J Med,1999,341:738-746.
139.Gailit J,Welch MP,Clark RA.TGF-beta 1 stimulates expression of keratinocyte integnns during re-epithelialization of cutaneous wounds.J Invest Dermatol,1994,103:221-227.
140.Alonso L,Fuchs E. Stem cells of the skin epithelium. PANS,2003,100:11830-11835.
141.Fuchs E,Horsley V. More than one way to skin. Genes Dev,2008,22:976-985.
142.Lowell S,Watt FM. Delta regulates keratinocyte spreading and motility independently of differentiation. Mech Dev,2001,107:133-140.
143.Rangarajan A,Talora C, Okuyama R,et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J,2001,20:3427-3436.
144.Watt FM , Estrach S , Ambler CA. Epidermal Notch signalling: differentiation, cancer and adhesion. Curr Opin Cell Biol , 2008 ,20:171-179.
2. Adolphe C, Wainwright B. Pathways to improving skin regeneration. Exp Rex Mol Med,2005,7:1-14.
3. Alonso L,Fuchs E.Stem cells of the skin epithelium. Proc Natl Acad Sci U S A,2003,100 Suppl 1:11830-11835.
4. Fuchs E.Skin stem cells: rising to the surface. J Cell Biol,2008,180:273-284.
5. Patel GK,Wilson CH,Harding KG,et al. Numerous keratinocyte subtypes involved in wound re-epithelialization. J Invest Dermatol , 2006 ,126:497-502.
6. Diao JS, Xia W, Guo SZ. Resume normal structure of epidermis and prevent hypertrophic scars formation. Med Hypotheses,2010,74:205-206.
7.赵志力,付小兵,孙同柱,等.成人正常皮肤和瘢痕组织表皮干细胞定位与表达特征的研究.中华烧伤杂志, 2003, 1:12-14.
8.贺肖洁,韩春茂,彭佳萍.瘢痕疙瘩和增生性瘢痕表皮异常的实验研究.中华外科杂志,2004,42:845-848.
9.沈丹蓓,夏隆庆.角质形成细胞与皮肤创面愈合瘢痕形成.中华整形外科杂志,2005,21:69-71.
10. Niessen FB,Andriessen MP,Schalkwijk J,et al.Keratinocyte-derived growth factors play a role in the formation of hypertrophic scars. J Pathol,2001,194:207-216.
11. Xia W,Phan TT,Lim IJ,et al. Differential transcriptional responses of keloid and normal keratinocytes to serum stimulation. J Surg Res,2006,135:156-163.
12. Lim IJ,Phan TT,Song C,et al.Investigation of the influence of keloid-derived keratinocytes on fibroblast growth and proliferation in vitro.Plast Reconstr Surg,2001,107:797-808.
13. Phan TT,Lim IJ,Bay BH,et al.Differences in collagen production between normal and keloid-derived fibroblasts in serum-media co-culture with keloid-derived keratinocytes.J Dermatol Sci,2002,29:26-34.
14. Lim IJ,Phan TT,Bay BH,et al.Fibroblasts cocultured with keloid keratinocytes:normal fibroblasts secrete collagen in a keloid like manner Am J Physiol Cell Physiol,2002,283:C212-222.
15. Funayama E ,Chodon T ,Oyama A, et al. Keratinocytes promote proliferation and inhibit apoptosis of the underlying fibroblasts: an important role in the pathogenesis of keloid. J Invest Dermatol, 2003,121:1326-1331.
16. Mukhopadhyay A,Tan EK,Khoo YT,et al. Conditioned medium from keloid keratinocyte/keloid fibroblast coculture induces contraction of fibroblast-populated collagen lattices. Br J Dermatol,2005,152:639-645.
17. 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, 12:546-556.
18. Phan TT,Lim IJ,Bay BH,et al.Role of IGF system of mitogens in the induction of fibroblast proliferation by keloid-derived keratinocytes in vitro.Am J Physiol Cell Phvsiol,2003,284:C860-869.
19. Ong CT,Khoo YT,Tan EK,et al. Epithelial-mesenchymal interactions in keloid pathogenesis modulate vascular endothelial growth factor expression and secretion. J Pathol, 2007, 211:95-108.
20.郭树忠,张琳西,王臻,等.培养的正常和瘢痕角质形成细胞上清液对瘢痕成纤维细胞增殖和胶原合成的影响.中华整形外科杂志,2002,18:82-85.
21.张曦,郭树忠,张琳西,等.增生性瘢痕表皮细胞双向电泳图谱的建立及差异蛋白展示.中华整形外科杂志,2005,21:135-138.
22.张曦,郭树忠,张琳西,等.增生性瘢痕表皮细胞差异蛋白的初步分析.中华实验外科杂志,2005,22:1565-1567.
23. Fehon RG,Kooh PJ,Rebay I,et al. Molecular interactions between the protein products of the neurogenic loci Notch and Delta , two EGF-homologous genes in Drosophila. Cell,1990,61:523-534.
24. Artavanis-Tsakonas S,Rand M D,Lake R J. Notch signaling: cell fate control and signal integration in development. Science,1999,284:770-776.
25. Yancopoulos GD,Davis S,Gale NW,et al. Vascular-specific growth factors and blood vessel formation. Nature, 2000,407:242-248.
26. Hofmann JJ,Iruela-Arispe ML. Notch signaling in blood vessels: who is talking to whom about what? Circ Res,2007,100:1556-1568.
27. Apelqvist A,Li H,Sommer L, et al. Notch signalling controls pancreatic cell differentiation. Nature,1999,400:877-881.
28. Milner LA,Bigas A. Notch as a mediator of cell fate determination in hematopoiesis: evidence and speculation. Blood,1999,93:2431-2448.
29. Sestan N,Artavanis-Tsakonas S,Rakic P. Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science,1999,286:741-746.
30. del Amo FF,Gendron-Maguire M,Swiatek PJ,et al. Cloning,analysis,and chromosomal localization of Notch-1,a mouse homolog of Drosophila Notch. Genomics,1993,15:259-264.
31. Lardelli M,Dahlstrand J,Lendahl U. The novel Notch homologue mouseNotch 3 lacks specific epidermal growth factorrepeats and is expressed in proliferating neuroepithelium. Mech Dev,1994,46:123-136.
32. Uyttendaele H,Marazzi G,Wu G,et al. Notch4/int-3,a mammary proto-oncogene,is an endothelial cell-specific mammalian Notch gene. Development,1996,122:2251-2259.
33. Weinmaster G,Roberts VJ, Lemke G. Notch 2: a second mammalian Notch gene. Development,1992,116:931-941.
34. Bettenhausen B,Hrabe de Angelis M,Simon D,et al. Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development,1995,121:2407-2418.
35. Dunwoodie SL,Henrique D,Harrison SM,et al.Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development,1997,124:3065-3076.
36. Lindsell CE,Shawber CJ,Boulter J,et al. Jagged: a mammalian ligand that activates Notch1. Cell,1995,80:909-917.
37. Shawber C,Boulter J,Lindsell CE,et al. Jagged 2: a serrate-like gene expressed during rat embryogenesis. Dev Biol,1996,180:370-376.
38. Shutter JR,Scully S, Fan W,et al. Dll4,a novel Notch ligand expressed in arterial endothelium. Genes Dev,2000,14:1313-1318.
39. Brou C,Logeat F,Gupta N,et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrinmetalloprotease TACE. Mol Cell,2000,5:207-216.
40. Iso T,Kedes L,Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol,2003,194:237-255.
41. Kageyama R,Ohtsuka T,Hatakeyama J,et al. Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res,2005,306:343-348.
42. Lai EC. Keeping a good pathway down: transcriptional repression of Notch pathway target genes by CSL proteins.EMBO,2002,3:840-845.
43. Mumm JS,Kopan R. Notch signaling: from the outside in. Dev Biol 2000,228:151-165.
44. Grego-Bessa J, Luna-Zurita L,del Monte G,et al. Notch signalling is essential for ventricular chamber development. Dev Cell,2007,12:415-429.
45. Iso T,Maeno T,Oike Y,et al. Dll4-selective Notch signalling induces ephrinB2 gene expression in endothelial cells. Biochem Biophys Res Commun,2006,341:708-714.
46. Iso T,Hamamori Y,Kedes L. Notch signalling in vascular development. Arterioscler Thromb Vasc Biol,2003,23:543-553.
47. Limbourg A,Ploom M, Elligsen D,et al. Notch ligand Delta-like 1 is essential for postnatal arteriogenesis. Circ Res,2007,100:363-371.
48. Brennan K,Gardner P. Notching up another pathway. Bioessays,2002,24:405-410.
49. Martinez Arias A,Zecchini V,Brennan K. CSL-independent Notch signalling: a checkpoint in cell fate decisions during development? Curr Opin Genet Dev,2002,12:524-433.
50. Wilson A,Radtke F. Multiple functions of Notch signaling in self-renewing organs and cancer. FEBS Lett,2006,580:2860-2868.
51. Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer,2003,3:756-767.
52. Lowell S,Jones P,Le Roux I, et al. Stimulation of human epidermal differentiation by delta-notch signaling at the boundaries of stem-cell clusters. Curr Biol,2000,10:491-500.
53. Nickoloff BJ,Qin JZ,Chaturvedi V,et al. Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytesthrough NF-kappaB and PPARgamma. Cell Death Differ,2002,9:842-855.
54. Mammucari C,Tommasi di Vignano A,Sharov AA,et al. Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control. Dev Cell,2005,8:665-676.
55. Okuyama R, LeFort K, Dotto GP. A dynamic model of keratinocyte stem cell renewal and differentiation: role of the p21WAF1/Cip1 and Notch1 signaling pathways. J Investig Dermatol Symp Proc,2004,9:248-252.
56. Devgan V, Nguyen BC, Oh H , et al. p21WAF1/Cip1 suppresses keratinocyte differentiation independently of the cell cycle through transcriptional up-regulation of the IGF-I gene. J Biol Chem,2006,281:30463-30470.
57. Osada M,Ohba M,Kawahara C,et al. Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Nat Med,1998,4:839-843.
58. Yang A,Kaghad M,Wang Y,et al. p63,a p53 homolog at 3q27-29, encodes multiple products with transactivating, deathinducing, and dominant- negative activities. Mol Cell,1998,2:305-316.
59. Mills AA,Zheng B,Wang XJ,et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature,1999,398:708-713.
60. Yang A,Schweitzer R,Sun D,et al. p63 is essential for regenerative proliferation in limb,craniofacial and epithelial development. Nature,1999,398:714-718.
61. Koster MI,Kim S,Mills AA,et al. p63 is the molecular switch for initiation of an epithelial stratication program. Genes Dev,2004,18:465-469.
62. Okuyama R,Ogawa E,Nagoshi H,et al. p53 homologue,p51/ p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity. Oncogene,2007,26:4478-4488.
63. Nguyen BC, Lefort K, Mandinova A, et al. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev, 2006, 20:1028-1042.
64. Okuyama R,Nguyen BC,Talora C,et al. High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism. Dev Cell,2004,6:551-562.
65. Lu L,Saulis AS,Liu WR,et al. The temporal effects of anti-TGF-beta1, 2 and 3 monoclonal antibody on wound healing and hypertrophic scar formation. J Am Coll Surg,2005,201:391-397.
66. Rolfe KJ,Richardson J,Vigor C,et al. A role of TGF-beta1 induced cellular responses during wound healing of the non-scarring early human fetus? J Invest Dermatol,2007,127:2656-2667.
67. Kretschmer A,Moepert K,Dames S,et al. Different regulation of TGF-beta signaling through Smad2, Smad3 and Smad4. Oncogene,2003, 22:6748- 6763.
68. Wang JF,Jiao H,Stewart TL,et al. Fibrocytes from burn patients regulate the activities of fibroblasts. Wound Repair Regen,2007,15:113-121.
69. Yang L,Chan T,Demare J,et al. Healing of burn wounds in mice overexpressing transforming growth factor-beta1 in the epidermis. Am J Pathol,2001,159:2147-2157.
70. Blokzijl A,Dahlqvist C,Reissmann E,et al. Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. J Cell Biol,2003, 163:723-728.
71. Hogan BL. Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev,1996,10:1580-1594.
72. Takizawa T,Ochiai W,Nakashima K,et al. Enhanced gene activation by Notch and BMP signaling cross-talk. Nucleic Acids Res. 2003, 31:5723- 5731.
73. Tang Y,Urs S,Boucher J,et al. Notch and TGF{beta} signaling pathways cooperatively regulate vascular smooth muscle cell differentiation. J Biol Chem,2010,doi/10.1074/jbc.M109.076414.
74. Kurpinski K,Lam H,Chu J,et al.TGF-beta and Notch Signaling Mediate Stem Cell Differentiation into Smooth Muscle Cells.Stem Cells,2010,doi: 10.1002/stem.319.
75. Hunt TK,Hopf H,Hussain Z. Physiology of wound healing. Adv Skin Wound Care,2000,13:6-11.
76. Martin P. Wound healing-aiming for perfect skin regeneration. Science,1997,276:75-81.
77. Martin P,Leibovich SJ. Inflammatory cells during wound repair: the good,the bad and the ugly. Trends Cell Biol,2005,15:599-607.
78. Monsalve E,Perez MA,Rubio A,et al. Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity. J Immunol,2006,176:5362-5373.
79. Ostroukhova M,Qi Z,Oriss TB,et al. Tregmediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-beta. J Clin Invest,2006,116:996-1004.
80. Lindner V,Booth C,Prudovsky I,et al. Members of the Jagged/Notch gene families are expressed in injured arteries and regulate cell phenotype via alterations in cell matrix and cell-cell interaction. Am J Pathol,2001,159:875-883.
81. Zimrin AB,Pepper MS,McMahon GA,et al. An antisense oligonucleotide to the notch ligand jagged enhances fibroblast growth factor-induced angiogenesis in vitro. J Biol Chem,1996,271:32499-32502.
82. Uyttendaele H,Closson V,Wu G,et al. Notch4 and Jagged-1 inducemicrovessel differentiation of rat brain endothelial cells.Microvasc Res,2000,60:91-103.
83. Dorsch M,Zheng G,Yowe D,et al. Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease. Blood,2002,100:2046-2055.
84. Savill NJ , Sherratt JA. Control of epidermal stem cell clusters by Notchmediated lateral induction. Dev Biol,2003,258:141-153.
85. Cereseto A,Tsai S. Jagged2 induces cell cycling in confluent fibroblasts susceptible to density-dependent inhibition of cell division. J Cell Physiol,2000,185:425-431.
86. Six EM,Ndiaye D,Sauer G,et al. The notch ligand Delta1 recruits Dlg1 at cell-cell contacts and regulates cell migration. J Biol Chem,2004,279: 55818-55826.
87. Thelu J, Rossio P, Favier B. Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing. BMC Dermatol, 2002, 29:1-12.
88. Chigurupati S,Arumugam TV,Son TG,et al. Involvement of Notch Signaling in Wound Healing. PLoS One,2007,2:e1167.
89. Kared H,Adle-Biassette H,Fois E,et al. Jagged2-expressing hematopoietic progenitors promote regulatory T cell expansion in the periphery through notch signaling. Immunity,2006,25:823-834.
90. Wang Y,Chan SL,Miele L,et al. Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci USA,2004,101: 9458-9462.
91. Arumugam TV,Chan SL,Jo DG,et al. Gamma secretase-mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke. Nat Med,2006,12:621-623.
92. Favier B,Flignaux I,Thélu J,et al. The notch system and the differentiation of vibrissa hair follicule: receptors , ligands and fringe modulators. Developmental Dynamics,2000,218:426-437.
93. Kopan R,Weintraub H. Mouse notch: expression in hair follicles correlates with cell fate determination. J Cell Biol,1993,121:631-641.
94. Powell BC,Passmore EA,Nesci A,et al. The Notch signaling pathway in hair growth. Mech Dev,1998,78:189-192.
95. Limbourg FP,Takeshita K,Radtke F,et al. Essential role of endothelial Notch1 in angiogenesis. Circulation,2005,111:1826-1832.
96. Krebs LT,Xue Y,Norton CR,et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev,2000,14:1343-1352.
97. Xue Y,Gao X,Lindsell CE,et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet,1999,8:723-730.
98. Swiatek PJ,Lindsell CE,del Amo FF,et al. Notch1 is essential for postimplantation development in mice. Genes Dev,1994,8:707-719.
99. Sainson RC,Aoto J,Nakatsu MN,et al. Cellautonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J,2005,19:1027-1029.
100.Takeshita K,Satoh M,Ii M,et al. Critical role of endothelial Notch1 signaling in postnatal angiogenesis. Circ Res,2007,100:70-78.
101.Paris D,Quadros A,Patel N,et al. Inhibition of angiogenesis and tumor growth by beta and gamma-secretase inhibitors. Eur J Pharmacol,2005,514:1-15.
102.Nakajima M,Yuasa S,Ueno M,et al. Abnormal blood vessel development in mice lacking presenilin-1. Mech Dev,2003,120:657-667.
103.Noguera-Troise I,Daly C,Papadopoulos NJ,et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature,2006,444:1032-1037.
104.Ridgway J,Zhang G,Wu Y,et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature,2006,444:1083-1087.
105.Li J,Zhang YP,Kirsner RS. Angiogenesis in wound repair: angiogenic growth factors and the extracellular matrix. Microsc Res Tech,2003,60:107-114.
106.Carmeliet P,Jain RK. Angiogenesis in cancer and other diseases. Nature,2000,407:249-257.
107.Risau W. Mechanisms of angiogenesis. Nature,1997,386: 671-674.
108.Yancopoulos GD,Klagsbrun M,Folkman J. Vasculogenesis,angiogenesis,and growth factors: ephrins enter the fray at the border. Cell,1998,93:661-664.
109.Joutel A, Corpechot C,Ducros A,et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature,1996,383:707-710.
110.Li L,Krantz ID,Deng Y,et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet,1997,16:243-251.
111.Oda T,Elkahloun AG,Pike BL,et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet,1997,16:235-242.
112.Krantz ID,Colliton RP,Genin A,et al.Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet,1998,62:1361-1369.
113.McCright B,Gao X,Shen L,et al. Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2mutation. Development,2001,128:491-502.
114.McCright B,Lozier J,Gridley T. A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development,2002,129:1075-1082.
115.Murphy PA,Lu G,Shiah S,et al. Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease. Lab Invest,2009,89:971-982.
116.Nicolas M,Wolfer A,Raj K,et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet,2003,33:416-421.
117.Lin MH,Leimeister C,Gessler M,et al. Activation of the Notch pathway in the hair cortex leads to aberrant differentiation of the adjacent hair-shaft layers. Development,2000,127:2421-2432.
118.Uyttendaele H,Panteleyev AA,de Berker D,et al. Activation of Notch1 in the hair follicle leads to cell-fate switch and Mohawk alopecia. Differentiation,2004,72:396-409.
119.Pan Y,Lin MH,Tian X,et al. Gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell,2004,7:731-743.
120.Vauclair S,Nicolas M,Barrandon Y,et al. Notch1 is essential for postnatal hair follicle development and homeostasis.Dev Biol,2005,284:184-193.
121.Moriyama M,Osawa M,Mak SS,et al. Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells. J Cell Biol,2006,173:333-339.
122.Alexeev V,Yoon K. Distinctive role of the cKit receptor tyrosine kinase signaling in mammalian melanocytes. J Invest Dermatol , 2006 ,126:1102-1110.
123.Raafat A,Zoltan-Jones A,Strizzi L,et al. Kit and PDGFR-alpha activitiesare necessary for Notch4/Int3-induced tumorigenesis. Oncogene,2007,26:662-672.
124.Diao JS,Zhang X,Xia WS,et al. Aberrant Notch signaling: a potential pathomechanism of vitiligo. Med Hypotheses,2009,73:70-72.
125.Nickoloff BJ,Hendrix MJ,Pollock PM,et al. Notch and NOXA-related pathways in melanoma cells. J Investig Dermatol Symp Proc,2005,10:95-104.
126.Massi D,Tarantini F,Franchi A,et al. Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma. Mod Pathol,2006,19:246-254.
127.Balint K,Xiao M,Pinnix CC,et al. Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression. J Clin Invest,2005,115:3166-3176.
128.Liu ZJ,Xiao M,Balint K,et al. Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N–cadherin expression. Cancer Res,2006,66:4182-4190.
129.夏炜,潘宝华,刘宾,等. Notch信号在增生性瘢痕表皮中的表达.中华整形外科杂志, 2009, 25:49-53.
130.Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation following burns and trauma:new approaches to treatment. PLoS Med,2007,4:e234.
131.Roseborough IE,Grevious MA,Lee RC. Prevention and treatment of excessive dermal scarring. J Natl Med Assoc,2004,96:108-116.
132.Khoo YT,Ong CT,Mukhopadhyay A,et al. Upregulation of secretory connective tissue growth factor (CTGF) in keratinocyte-fibroblast coculture contributes to keloid pathogenesis. J Cell Physiol,2006,208:336-343.
133.Blanpain C,Lowry WE,Pasolli HA,et al. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev,2006,20:3022-3035.
134.Okuyama R, Tagami H, Aiba S. Notch signaling: its role in epidermal homeostasis and in the pathogenesis of skin diseases. J Dermatol Sci,2008,49:187-194.
135.Morris DE,Wu I,Zhao LL,et al. Acute and chronic animal models for excessive dermal scarring: quantitative studies. Plast Reconstr Surg,1997,100:674-681.
136.李荟元,刘建波,夏炜,等.增生性瘢痕动物实验模型的建立与应用.中华整形外科杂志,2001,17:276-278.
137.李荟元主编.创伤研究动物模型-兔耳瘢痕模型的建立与应用西安:第四军医大学出版社,2005,1:42-45.
138.Singer AJ,Clark RA.Cutaneous wound healing.N Engl J Med,1999,341:738-746.
139.Gailit J,Welch MP,Clark RA.TGF-beta 1 stimulates expression of keratinocyte integnns during re-epithelialization of cutaneous wounds.J Invest Dermatol,1994,103:221-227.
140.Alonso L,Fuchs E. Stem cells of the skin epithelium. PANS,2003,100:11830-11835.
141.Fuchs E,Horsley V. More than one way to skin. Genes Dev,2008,22:976-985.
142.Lowell S,Watt FM. Delta regulates keratinocyte spreading and motility independently of differentiation. Mech Dev,2001,107:133-140.
143.Rangarajan A,Talora C, Okuyama R,et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J,2001,20:3427-3436.
144.Watt FM , Estrach S , Ambler CA. Epidermal Notch signalling: differentiation, cancer and adhesion. Curr Opin Cell Biol , 2008 ,20:171-179.