Development of bone morphogenetic protein in skin wound repair

doi:10.3877/cma.j.issn.2095-1221.2023.02.006

Abstract

Abstract:

In trauma repair, regulating various cytokines and signaling pathways for trauma repair is sophisticated and complex, which has long been the field of attention and exploration. Among them, transforming growth factor-β (TGF-β), P38/MAPK, Wnt/β-catenin, PI3K/AKT and other signaling pathways play important roles in wound repair. Bone morphogenetic proteins (BMP) in the TGF-β family is a group of highly conserved functional proteins with similar structures. The previous research mainly focused on its function in inducing bone and cartilage formation and promoting osteoblast growth. However, recently ongoing studies have found BMP can promote or inhibit another signal molecule through the signaling pathways to regulate the activities of various skin-related cells, such as epidermal stem cells, hair follicle stem cells, fibroblasts, etc., to regulate the process of skin wound repair. In this process, the mechanisms of BMP differ as it acts on different cells. This article reviews the role of BMP in wound repair and some latest findings.

Key words: Bone morphogenetic protein, Signaling pathway, Skin wound healing

Xiang Wang, Liangyi Chen, Fengwei Yu, Zhengxi Wang, Qiutong Li, Yuhong Li. Development of bone morphogenetic protein in skin wound repair[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(02): 101-107.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhxbygxbzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2095-1221.2023.02.006

https://zhxbygxbzz.cma-cmc.com.cn/EN/Y2023/V13/I02/101

Figures/Tables 3

References 108

1	方勇. 创面修复机制及技术研究进展[J]. 上海交通大学学报（医学版） [J]. 2009, 29(12): 1403-1406.
2	Mu Y, Gudey SK, Landström M. Non-Smad signaling pathways[J]. Cell Tissue Res, 2012, 347(1): 11-20.
3	韩虎. 10个地方山羊品种群体遗传结构及羊绒性状选择进化研究 [D]; 中国科学院大学, 2020.
4	Seeherman HJ, Berasi SP, Brown CT, et al. A BMP/activin A chimera is superior to native BMPs and induces bone repair in nonhuman primates when delivered in a composite matrix[J]. Sci Transl Med, 2019, 11(489):eaar4953. doi: 10.1126/scitranslmed.aar4953.
5	Lowery JW, Rosen V. The BMP pathway and its inhibitors in the skeleton[J]. Physiol Rev, 2018, 98(4): 2431-2452.
6	王燕妮. BMPs蛋白对烫伤创面愈合及疤痕疙瘩形成的影响[D].中南大学, 2007.
7	Herford AS, Lowe I, Jung P. Titanium mesh grafting combined with recombinant human bone morphogenetic protein 2 for alveolar reconstruction [J]. Oral and maxillofacial surgery clinics of North America, 2019, 31(2): 309-315.
8	Li H, Zou X, Baatrup A, et al. Cytokine profiles in conditioned media from cultured human intervertebral disc tissue. Implications of their effect on bone marrow stem cell metabolism [J]. Acta Orthop, 2005, 76(1): 115-121.
9	Roberts RM, Ezashi T, Sheridan MA, et al. Specification of trophoblast from embryonic stem cells exposed to BMP4[J]. Biol Reprod, 2018, 99(1): 212-224.
10	Cole AE, Murray SS, Xiao J. Bone Morphogenetic protein 4 signalling in neural stem and progenitor cells during development and after injury[J]. Stem Cells Int, 2016, 2016:9260592. doi: 10.1155/2016/9260592.
11	Baboota RK, Blüher M, Smith U. Emerging role of bone morphogenetic protein 4 in metabolic disorders[J]. Diabetes, 2021, 70(2): 303-312.
12	Sun B, Huo R, Sheng Y, et al. Bone morphogenetic protein-4 mediates cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy[J]. Hypertension, 2013, 61(2):352-360.
13	Hu H, Wang S, He Y, et al. The role of bone morphogenetic protein 4 in corneal injury repair[J]. Exp Eye Res, 2021, 212:108769. doi: 10.1016/j.exer.2021.108769.
14	Xi G, Best B, Mania-Farnell B, et al. Therapeutic Potential for Bone Morphogenetic Protein 4 in Human Malignant Glioma [J]. Neoplasia, 2017, 19(4): 261-270.
15	Wang JF, Lee MS, Tsai TL, et al. Bone morphogenetic protein-6 attenuates type 1 diabetes mellitus-associated bone loss[J]. Stem cells translational medicine, 2019, 8(6):522-534.
16	Verhamme FM, De Smet EG, Van Hooste W, et al. Bone morphogenetic protein 6 (BMP-6) modulates lung function, pulmonary iron levels and cigarette smoke-induced inflammation [J]. Mucosal immunology, 2019, 12(2):340-351.
17	Zhang Y, Zhang Q. Bone morphogenetic protein-7 and Gremlin: new emerging therapeutic targets for diabetic nephropathy[J]. Biochemical and biophysical research communications, 2009, 383(1):1-3.
18	Cortez MA, Masrorpour F, Ivan C, et al. Bone morphogenetic protein 7 promotes resistance to immunotherapy[J]. Nat Commun, 2020, 11(1):4840. doi: 10.1038/s41467-020-18617-z.
19	Desroches-Castan A, Tillet E, Ricard N, et al. Bone morphogenetic protein 9 is a paracrine factor controlling liver sinusoidal endothelial cell fenestration and protecting against hepatic fibrosis[J]. Hepatology, 2019, 70(4): 1392-1408.
20	Schmierer B, Hill CS. TGF beta-SMAD signal transduction:molecular specificity and functional flexibility[J]. Nat Rev Mol Cell Biol, 2007, 8(12):970-982.
21	Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins[J]. Nature, 1997, 390(6659): 465-471.
22	Murakami G, Watabe T, Takaoka K, et al. Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads [J]. Mol Biol Cell, 2003, 14(7):2809-2817.
23	Grada A, Mervis J, Falanga V. Research techniques made simple: animal models of wound healing[J]. J Invest Dermatol, 2018, 138(10):2095-2105.e1.
24	Zeng R, Lin C, Lin Z, et al. Approaches to cutaneous wound healing: basics and future directions [J]. Cell Tissue Res, 2018, 374(2): 217-232.
25	Li M, Sun L, Liu Z, et al. 3D bioprinting of heterogeneous tissue-engineered skin containing human dermal fibroblasts and keratinocytes[J]. Biomater Sci, 2023, 11(7):2461-2477.
26	Lukomskyj AO, Rao N, Yan L, et al. Stem cell-based tissue engineering for the treatment of burn wounds: a systematic review of preclinical studies [J]. Stem Cell Rev Rep, 2022, 18(6):1926-1955.
27	Al-Masawa ME, Alshawsh MA, Ng CY, et al. Efficacy and safety of small extracellular vesicle interventions in wound healing and skin regeneration: A systematic review and meta-analysis of animal studies [J]. Theranostics, 2022, 12(15):6455-6508.
28	Działo E, Czepiel M, Tkacz K, et al. WNT/β-catenin signaling promotes TGF-β-mediated activation of human cardiac fibroblasts by enhancing IL-11 production[J]. Int J Mol Sci, 2021, 22(18):10072. doi: 10.3390/ijms221810072.
29	Sun Q, Guo S, Wang C-C, et al. Cross-talk between TGF-β/Smad pathway and Wnt/β-catenin pathway in pathological scar formation[J]. Int J Clin Exp Pathol, 2015, 8(6):7631-7639.
30	Chen X, Zankl A, Niroomand F, et al. Upregulation of ID protein by growth and differentiation factor 5 (GDF5) through a smad-dependent and MAPK-independent pathway in HUVSMC[J]. J Mol Cell Cardiol, 2006, 41(1):26-33.
31	Bochenek ML, Schäfer K. Role of endothelial cells in acute and chronic thrombosis [J]. Hamostaseologie, 2019, 39(2):128-139.
32	Pool JG. Normal hemostatic mechanisms:a review[J]. Am J Med Technol, 1977, 43(8):776-780.
33	Furie B, Furie BC. Mechanisms of thrombus formation[J]. N Engl J Med, 2008, 359(9):938-949.
34	Levin R, Grinstein S, Canton J. The life cycle of phagosomes: formation, maturation, and resolution [J]. Immunol Rev, 2016, 273(1): 156-179.
35	Yipp BG, Kubes P. NETosis: how vital is it?[J]. Blood, 2013, 122(16): 2784-2794.
36	Sorokin L. The impact of the extracellular matrix on inflammation[J]. Nat Rev Immunol, 2010, 10(10):712-723.
37	Savill J, Fadok V. Corpse clearance defines the meaning of cell death[J]. Nature, 2000, 407(6805):784-788.
38	Leibovich SJ, Polverini PJ, Shepard HM, et al. Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha[J]. Nature, 1987, 329(6140):630-632.
39	Fantin A, Vieira JM, Gestri G, et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction [J]. Blood, 2010, 116(5):829-840.
40	Weller K, Foitzik K, Paus R, et al. Mast cells are required for normal healing of skin wounds in mice[J]. FASEB J, 2006, 20(13):2366-2368.
41	Garbuzenko E, Nagler A, Pickholtz D, et al. Human mast cells stimulate fibroblast proliferation, collagen synthesis and lattice contraction: a direct role for mast cells in skin fibrosis[J]. Clin Exp Allergy, 2002, 32(2):237-246.
42	Talbott HE, Mascharak S, Griffin M, et al. Wound healing, fibroblast heterogeneity, and fibrosis [J]. Cell Stem Cell, 2022, 29(8):1161-1180.
43	Tomasek JJ, Gabbiani G, Hinz B, et al. Myofibroblasts and mechano-regulation of connective tissue remodelling[J]. Nat Rev Mol Cell Biol, 2002, 3(5):349-363.
44	Eilken HM, Adams RH. Dynamics of endothelial cell behavior in sprouting angiogenesis[J]. Curr Opin Cell Biol, 2010, 22(5):617-625.
45	Murray LA, Chen Q, Kramer MS, et al. TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P[J]. Int J Biochem Cell Biol, 2011, 43(1):154-162.
46	Werner S, Krieg T, Smola H. Keratinocyte-fibroblast interactions in wound healing[J]. J Invest Dermatol, 2007, 127(5):998-1008.
47	Lange SS, Bhetawal S, Reh S, et al. DNA polymerase ζ deficiency causes impaired wound healing and stress-induced skin pigmentation [J]. Life Sci Alliance, 2018, 1(3):e201800048. doi: 10.26508/lsa.201800048.
48	Schiefer JL, Held M, Fuchs PC, et al. Growth differentiation factor 5 accelerates wound closure and improves skin quality during repair of full-thickness skin defects[J]. Adv Skin Wound Care, 2017, 30(5):223-229.
49	Hesketh M, Sahin KB, West ZE, et al. Macrophage phenotypes regulate scar formation and chronic wound healing[J]. Int J Mol Sci, 2017, 18(7):1545. doi:10.3390/ijms18071545.
50	Kim JH, Bae HC, Kim J, et al. HIF-1α-mediated BMP6 down-regulation leads to hyperproliferation and abnormal differentiation of keratinocytes in vitro[J]. Exp Dermatol, 2018, 27(11):1287-1293.
51	Theocharis A D, Skandalis S S, Gialeli C, et al. Extracellular matrix structure[J]. Adv Drug Deliv Rev, 2016, 97:4-27.
52	Plikus MV, Guerrero-Juarez CF, Ito M, et al. Regeneration of fat cells from myofibroblasts during wound healing[J]. Science, 2017, 355(6326):748-752.
53	Bin S, Li HD, Xu YB, et al. BMP-7 attenuates TGF-β1-induced fibroblast-like differentiation of rat dermal papilla cells[J]. Wound Repair Regen, 2013, 21(2): 275-281.
54	Duan M, Zhang Y, Zhang H, et al. Epidermal stem cell-derived exosomes promote skin regeneration by downregulating transforming growth factor-β1 in wound healing[J]. Stem Cell Res Ther, 2020, 11(1):452. doi: 10.1186/s13287-020-01971-6.
55	Ouji Y, Ishizaka S, Nakamura-Uchiyama F, et al. Partial maintenance and long-term expansion of murine skin epithelial stem cells by Wnt-3a in vitro[J]. J Invest Dermatol, 2015, 135(6):1598-1608.
56	Li H, Yao Z, He W, et al. P311 induces the transdifferentiation of epidermal stem cells to myofibroblast-like cells by stimulating transforming growth factor β1 expression[J]. Stem Cell Res Ther, 2016, 7(1):175. doi:10.1186/s13287-016-0421-1.
57	Zaidi SH, Huang Q, Momen A, et al. Growth differentiation factor 5 regulates cardiac repair after myocardial infarction [J]. J Am Coll Cardiol, 2010, 55(2):135-143.
58	Zhao X, Bian R, Wang F, et al. GDF-5 promotes epidermal stem cells proliferation via Foxg1-cyclin D1 signaling[J]. Stem Cell Res Ther, 2021, 12(1):42. doi: 10.1186/s13287-020-02106-7.
59	Zhang J, He XC, Tong WG, et al. Bone morphogenetic protein signaling inhibits hair follicle anagen induction by restricting epithelial stem/progenitor cell activation and expansion[J]. Stem Cells, 2006, 24(12): 2826-2839.
60	Yu H, Kumar SM, Kossenkov AV, et al. Stem cells with neural crest characteristics derived from the bulge region of cultured human hair follicles[J]. J Invest Dermatol, 2010, 130(5):1227-1236.
61	El Seady R, Huisman MA, Löwik CW, et al. Uncomplicated differentiation of stem cells into bipolar neurons and myelinating glia [J]. Biochem Biophys Res Commun, 2008, 376(2):358-362.
62	杜伟斌, 全仁夫, 郑宣, 等. 毛囊干细胞在皮肤伤口修复中的促进作用[J]. 中国组织工程研究, 2015, 19(14): 2278-2282.
63	Li B, Hu W, Ma K, et al. Are hair follicle stem cells promising candidates for wound healing?[J]. Expert Opin Biol Ther, 2019, 19(2): 119-128.
64	Kandyba E, Kobielak K. Wnt7b is an important intrinsic regulator of hair follicle stem cell homeostasis and hair follicle cycling [J]. Stem cells (Dayton, Ohio), 2014, 32(4): 886-901.
65	Oshimori N, Fuchs E. Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation[J]. Cell stem cell, 2012, 10(1): 63-75.
66	Kobielak K, Stokes N, de la Cruz J, et al. Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling[J]. Proc Natl Acad Sci U S A, 2007, 104(24):10063-10068.
67	魏兆明, 江文胜, 高艺, 等. 脂肪间充质干细胞的生物学特性及潜在临床应用[J]. 中国临床药理学与治疗学, 2019, 24(01): 116-120.
68	Dong Y, Hassan WU, Kennedy R, et al. Performance of an in situ formed bioactive hydrogel dressing from a PEG-based hyperbranched multifunctional copolymer[J]. Acta Biomater, 2014, 10(5):2076-2085.
69	Lin L, Shen Q, Wei X, et al. Comparison of osteogenic potentials of BMP4 transduced stem cells from autologous bone marrow and fat tissue in a rabbit model of calvarial defects[J]. Calcif Tissue Int, 2009, 85(1):55-65.
70	Hao W, Dong J, Jiang M, et al. Enhanced bone formation in large segmental radial defects by combining adipose-derived stem cells expressing bone morphogenetic protein 2 with nHA/RHLC/PLA scaffold[J]. Int Orthop, 2010, 34(8):1341-1349.
71	Lin CY, Wang YH, Li KC, et al. Healing of massive segmental femoral bone defects in minipigs by allogenic ASCs engineered with FLPo/Frt-based baculovirus vectors[J]. Biomaterials, 2015, 50:98-106.
72	Fan J, Im CS, Cui ZK, et al. Delivery of phenamil enhances BMP-2-induced osteogenic differentiation of adipose-derived stem cells and bone formation in calvarial defects [J]. Tissue Eng Part A, 2015, 21(13-14): 2053-2065.
73	Lee SH, Hong B, Sharabi A, et al. Embryonic stem cells and mammary luminal progenitors directly sense and respond to microbial products[J]. Stem Cells, 2009, 27(7):1604-1615.
74	Fan J, Park H, Lee MK, et al. Adipose-derived stem cells and BMP-2 delivery in chitosan-based 3D constructs to enhance bone regeneration in a rat mandibular defect model[J]. Tissue Eng Part A, 2014, 20(15-16):2169-2179.
75	Blazquez R, Sanchez-Margallo FM, de la Rosa O, et al. Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells[J]. Front Immunol, 2014, 5:556. doi:10.3389/fimmu.2014.00556.
76	Kranendonk ME Visseren FL, van Balkom BW, et al. Human adipocyte extracellular vesicles in reciprocal signaling between adipocytes and macrophages[J]. Obesity (Silver Spring), 2014, 22(5):1296-1308.
77	Zhang Y, Mei H, Chang X, et al. Adipocyte-derived microvesicles from obese mice induce M1 macrophage phenotype through secreted miR-155[J]. J Mol Cell Biol, 2016, 8(6): 505-517.
78	Chen B, Cai J, Wei Y, et al. Exosomes are comparable to source adipose stem cells in fat graft retention with up-regulating early inflammation and angiogenesis[J]. Plast Reconstr Surg, 2019, 144(5):816e-827e.
79	Zhao L, Johnson T, Liu D. Therapeutic angiogenesis of adipose-derived stem cells for ischemic diseases[J]. Stem Cell Res Ther, 2017, 8(1):125. doi:10.1186/s13287-017-0578-2.
80	Liang X, Zhang L, Wang S, et al. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a[J]. J Cell Sci, 2016, 129(11): 2182-2189.
81	Kang T, Jones TM, Naddell C, et al. Adipose-derived stem cells induce angiogenesis via microvesicle transport of miRNA-31[J]. Stem Cells Transl Med, 2016, 5(4): 440-450.
82	Choi EW, Seo MK, Woo EY, et al. Exosomes from human adipose-derived stem cells promote proliferation and migration of skin fibroblasts[J]. Exp Dermatol, 2018, 27(10):1170-1172.
83	Wang L, Hu L, Zhou X, et al. Exosomes secreted by human adipose mesenchymal stem cells promote scarless cutaneous repair by regulating extracellular matrix remodelling[J]. Sci Rep, 2017, 7(1):13321. doi: 10.1038/s41598-017-12919-x.
84	Hu L, Wang J, Zhou X, et al. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts[J]. Sci Rep, 2016, 6:32993.doi:10.1038/srep32993.
85	Yamashita H, Shimizu A, Kato M, et al. Growth/differentiation factor-5 induces angiogenesis in vivo[J]. Exp Cell Res, 1997, 235(1):218-226.
86	Tang A, Amagai M, Granger LG, et al. Adhesion of epidermal Langerhans cells to keratinocytes mediated by E-cadherin[J]. Nature, 1993, 361(6407):82-85.
87	Ratzinger G, Stoitzner P, Ebner S, et al. Matrix metalloproteinases 9 and 2 are necessary for the migration of Langerhans cells and dermal dendritic cells from human and murine skin[J]. J Immunol, 2002, 168(9): 4361-4371.
88	Zhang M, Zhang S. T cells in fibrosis and fibrotic diseases[J]. Front Immunol, 2020, 11:1142. doi:10.3389/fimmu.2020.01142.
89	Martínez VG, Hernández-López C, Valencia J, et al. The canonical BMP signaling pathway is involved in human monocyte-derived dendritic cell maturation[J]. Immunol Cell Biol, 2011, 89(5):610-618.
90	Martínez VG, Rubio C, Martínez-Fernández M, et al. BMP4 induces M2 macrophage polarization and favors tumor progression in bladder cancer[J]. Clin Cancer Res, 2017, 23(23):7388-7399.
91	Hager-Theodorides AL, Outram SV, Shah DK, et al. Bone morphogenetic protein 2/4 signaling regulates early thymocyte differentiation[J]. J Immunol, 2002, 169(10): 5496-5504.
92	Huse K, Bakkebø M, Oksvold M P, et al. Bone morphogenetic proteins inhibit CD40L/IL-21-induced Ig production in human B cells: differential effects of BMP-6 and BMP-7[J]. Eur J Immunol, 2011, 41(11):3135-3145.
93	Robson NC, Hidalgo L, Mc Alpine T, et al. Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling[J]. Cancer Res, 2014, 74(18):5019-5031.
94	Sconocchia T, Hochgerner M, Schwarzenberger E, et al. Bone morphogenetic protein signaling regulates skin inflammation via modulating dendritic cell function[J]. J Allergy Clin Immunol, 2021, 147(5):1810-1822.e9.
95	Aluganti Narasimhulu C, Singla DK. The role of bone morphogenetic protein 7 (BMP-7) in inflammation in heart diseases[J]. Cells, 2020, 9(2):280. doi:10.3390/cells9020280.
96	Milne P, Bigley V, Gunawan M, et al. CD1c+ blood dendritic cells have Langerhans cell potential [J]. Blood, 2015, 125(3):470-473.
97	Hopkins DR, Keles S, Greenspan DS. The bone morphogenetic protein 1/Tolloid-like metalloproteinases[J]. Matrix Biol, 2007, 26(7):508-523.
98	Vadon-Le Goff S, Hulmes DJ, Moali C. BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling[J]. Matrix Biol, 2015, 44-46:14-23.
99	François S, Eder V, Belmokhtar K, et al. Synergistic effect of human bone morphogenic protein-2 and mesenchymal stromal cells on chronic wounds through hypoxia-inducible factor-1 α induction [J]. Sci Rep, 2017, 7(1): 4272. doi: 10.1038/s41598-017-04496-w.
100	Bahamonde ME, Lyons KM. BMP3:to be or not to be a BMP[J]. J Bone Joint Surg Am, 2001, 83-A Suppl 1(Pt 1): S56-S62.
101	Jank M, von Niessen N, Olivier CB, et al. Platelet bone morphogenetic protein-4 mediates vascular inflammation and neointima formation after arterial injury[J]. Cells, 2021, 10(8):2027. doi: 10.3390/cells10082027.
102	Lewis CJ, Mardaryev AN, Poterlowicz K, et al. Bone morphogenetic protein signaling suppresses wound-induced skin repair by inhibiting keratinocyte proliferation and migration[J]. J Invest Dermatol, 2014, 134(3): 827-837.
103	Chai P, Yu J, Wang X, et al. BMP9 promotes cutaneous wound healing by activating Smad1/5 signaling pathways and cytoskeleton remodeling [J]. Clin Transl Med, 2021, 11(1): e271. doi: 10.1002/ctm2.271.
104	Wu R, Hu W, Chen H, et al. A Novel Human Long Noncoding RNA SCDAL Promotes Angiogenesis through SNF5-Mediated GDF6 Expression [J]. Adv Sci (Weinh), 2021, 8(18): e2004629. doi: 10.1002/advs.202004629.
105	Begam H, Nandi SK, Kundu B, et al. Strategies for delivering bone morphogenetic protein for bone healing[J]. Mater Sci Eng C Mater Biol Appl, 2017, 70(Pt 1):856-869.
106	Garrison KR, Shemilt I, Donell S, et al. Bone morphogenetic protein (BMP) for fracture healing in adults[J]. Cochrane Database Syst Rev, 2010, 2010(6): CD006950. doi: 10.1002/14651858.CD006950.pub2.
107	丁玉路, 张国芳. 首例国产rhBMP-2人工骨植入手术在成都军区昆明总医院完成[J].中国科技产业, 2014, (7): 67.
108	White KA, Olabisi RM. Spatiotemporal control strategies for bone formation through tissue engineering and regenerative medicine approaches[J]. Adv Healthc Mater, 2019, 8(2):e1801044. doi: 10.1002/adhm.201801044.

细胞类型	在皮肤创伤修复中的功能	作用阶段
内皮细胞	介导血管平滑肌的收缩^[31]	凝血止血
血小板	阻止创面的进一步出血；为后续促进伤口愈合所需细胞的渗透提供临时支架^[32,33]	凝血止血
中性粒细胞	释放颗粒物质产生氧化爆发、启动吞噬作用、产生中心粒细胞外陷阱以消灭病原体与损伤因子^[34,35]	炎症反应
巨噬细胞	（1）M1型巨噬细胞：分泌促炎因子；识别并吞噬杀灭大多数病原体；溶解细胞外基质与血栓；吞噬创面处的中心粒细胞^[36,37] （2）M2型巨噬细胞：有助于血管的萌发；融合分支血管内皮细胞，将新生血管吻合到原有血管系统^[38,39]	炎症反应
肥大细胞	刺激角质形成细胞的增殖与再上皮化；促进成纤维细胞增殖与胶原合成，有利于伤口的收缩^[40,41]	炎症反应
成纤维细胞	合成新的细胞外基质，帮助收缩伤口；作为新合成的细胞外基质、新血管和炎症细胞的支架^[42]	细胞增殖分化
肌成纤维细胞	有利于伤口的收缩，减少再上皮化的伤口面积^[43]	细胞增殖分化
内皮细胞	分解肉芽组织中的细胞外基质，形成新的细胞-细胞连接，并分支形成新的毛细血管^[44]	细胞增殖分化
巨噬细胞	诱导成纤维细胞向肌成纤维细胞的转变，增加伤口胶原与α-平滑肌肌动蛋白的沉积；转变为纤维化的细胞，有助于疤痕的形成^[45]	细胞增殖分化
角质形成细胞	与成纤维细胞之间相互作用，以双旁分泌方式刺激角质形成细胞增殖。增殖迁移的角质形成细胞迁移到肉芽组织上，发生再上皮化^[46]	细胞增殖分化
黑素细胞	与表皮的重新色素沉积密切相关^[47]	细胞增殖分化
内皮细胞	内皮细胞凋亡，新生血管退化，具体机制尚未研究清晰	组织重塑
肌成纤维细胞	重塑细胞外基质，并使基质合成显著减慢，肉芽组织中的Ⅲ型胶原逐渐被Ⅰ型胶原取代^[48]	组织重塑
巨噬细胞	重新获得吞噬表型，释放蛋白酶并吞噬伤口闭合不再需要的多余细胞与细胞基质^[49]	组织重塑

细胞类型	在皮肤创伤修复中的功能	作用阶段
内皮细胞	介导血管平滑肌的收缩^[31]	凝血止血
血小板	阻止创面的进一步出血；为后续促进伤口愈合所需细胞的渗透提供临时支架^[32,33]	凝血止血
中性粒细胞	释放颗粒物质产生氧化爆发、启动吞噬作用、产生中心粒细胞外陷阱以消灭病原体与损伤因子^[34,35]	炎症反应
巨噬细胞	（1）M1型巨噬细胞：分泌促炎因子；识别并吞噬杀灭大多数病原体；溶解细胞外基质与血栓；吞噬创面处的中心粒细胞^[36,37] （2）M2型巨噬细胞：有助于血管的萌发；融合分支血管内皮细胞，将新生血管吻合到原有血管系统^[38,39]	炎症反应
肥大细胞	刺激角质形成细胞的增殖与再上皮化；促进成纤维细胞增殖与胶原合成，有利于伤口的收缩^[40,41]	炎症反应
成纤维细胞	合成新的细胞外基质，帮助收缩伤口；作为新合成的细胞外基质、新血管和炎症细胞的支架^[42]	细胞增殖分化
肌成纤维细胞	有利于伤口的收缩，减少再上皮化的伤口面积^[43]	细胞增殖分化
内皮细胞	分解肉芽组织中的细胞外基质，形成新的细胞-细胞连接，并分支形成新的毛细血管^[44]	细胞增殖分化
巨噬细胞	诱导成纤维细胞向肌成纤维细胞的转变，增加伤口胶原与α-平滑肌肌动蛋白的沉积；转变为纤维化的细胞，有助于疤痕的形成^[45]	细胞增殖分化
角质形成细胞	与成纤维细胞之间相互作用，以双旁分泌方式刺激角质形成细胞增殖。增殖迁移的角质形成细胞迁移到肉芽组织上，发生再上皮化^[46]	细胞增殖分化
黑素细胞	与表皮的重新色素沉积密切相关^[47]	细胞增殖分化
内皮细胞	内皮细胞凋亡，新生血管退化，具体机制尚未研究清晰	组织重塑
肌成纤维细胞	重塑细胞外基质，并使基质合成显著减慢，肉芽组织中的Ⅲ型胶原逐渐被Ⅰ型胶原取代^[48]	组织重塑
巨噬细胞	重新获得吞噬表型，释放蛋白酶并吞噬伤口闭合不再需要的多余细胞与细胞基质^[49]	组织重塑

BMP类型	在皮肤创伤修复方面的功能与研究进展
BMP1	控制胶原的成熟来调控基底膜的组装，调节ECM形成，与创伤后胶原沉积和瘢痕形成相关^[97,98]
BMP2	重组人BMP2能够促进内皮血管形成，诱导真皮再生毛囊附近的微血管形成，改善皮肤愈合情况^[99]
BMP3	成骨素的主要成分，对BMP-2等有较强拮抗作用，暂未见有皮肤创伤修复方相关研究^[100]
BMP4	（1）BMP4表达缺乏能够使血小板与白细胞之间的相互作用力减弱（血小板白细胞聚集物形成减少），抑制了炎症反应的启动，抑制炎性血管的重塑^[101] （2）促进成纤维细胞向脂肪细胞转化，减少ECM生成，抑制瘢痕生成^[52] （3）通过BMPR-1b介导，抑制角质形成细胞的增殖与迁移、增加伤口上皮中该细胞的凋亡，减缓伤口愈合^[102] （4）BMP4在伤口中的过度表达导致延迟的再上皮化^[102] （5）BMP4通过BMPR-1a介导可以抑制毛囊干细胞的迁移和增殖的能力^[59]
BMP5	研究多在神经细胞、癌症、骨组织等方面，暂未见有皮肤创伤修复相关研究
BMP6	BMP6的低表达与银屑病皮肤损伤相关^[50]
BMP7	影响前体细胞向病态的LCs分化，与银屑病密切相关^[96]
BMP8	研究多存在于精子发生与发育，暂未见有皮肤创伤修复相关研究
BMP9	刺激真皮成纤维细胞和角质形成细胞的激活，从而促进皮肤修复^[103]
BMP10	研究方向广泛，暂未见有皮肤创伤修复相关研究
BMP11	研究方向广泛，暂未见有皮肤创伤修复相关研究
BMP12	研究方向多在肌腱修复方面，暂未见有皮肤创伤修复相关研究
BMP13	促进内皮血管生成^[104]
BMP14	（1）刺激成纤维细胞的迁移、增殖和机体内胶原蛋白合成^[48] （2）促进表皮干细胞的增殖并诱导表皮干细胞迁移^[48,57] （3）可诱导纤溶酶原激活剂活性，并以趋化方式加速主动脉内皮细胞的迁移^[85] （4）与皮肤细胞外基质中I型胶原丝的超微结构相互作用以形成更稳定的伤口闭合^[48]

BMP类型	在皮肤创伤修复方面的功能与研究进展
BMP1	控制胶原的成熟来调控基底膜的组装，调节ECM形成，与创伤后胶原沉积和瘢痕形成相关^[97,98]
BMP2	重组人BMP2能够促进内皮血管形成，诱导真皮再生毛囊附近的微血管形成，改善皮肤愈合情况^[99]
BMP3	成骨素的主要成分，对BMP-2等有较强拮抗作用，暂未见有皮肤创伤修复方相关研究^[100]
BMP4	（1）BMP4表达缺乏能够使血小板与白细胞之间的相互作用力减弱（血小板白细胞聚集物形成减少），抑制了炎症反应的启动，抑制炎性血管的重塑^[101] （2）促进成纤维细胞向脂肪细胞转化，减少ECM生成，抑制瘢痕生成^[52] （3）通过BMPR-1b介导，抑制角质形成细胞的增殖与迁移、增加伤口上皮中该细胞的凋亡，减缓伤口愈合^[102] （4）BMP4在伤口中的过度表达导致延迟的再上皮化^[102] （5）BMP4通过BMPR-1a介导可以抑制毛囊干细胞的迁移和增殖的能力^[59]
BMP5	研究多在神经细胞、癌症、骨组织等方面，暂未见有皮肤创伤修复相关研究
BMP6	BMP6的低表达与银屑病皮肤损伤相关^[50]
BMP7	影响前体细胞向病态的LCs分化，与银屑病密切相关^[96]
BMP8	研究多存在于精子发生与发育，暂未见有皮肤创伤修复相关研究
BMP9	刺激真皮成纤维细胞和角质形成细胞的激活，从而促进皮肤修复^[103]
BMP10	研究方向广泛，暂未见有皮肤创伤修复相关研究
BMP11	研究方向广泛，暂未见有皮肤创伤修复相关研究
BMP12	研究方向多在肌腱修复方面，暂未见有皮肤创伤修复相关研究
BMP13	促进内皮血管生成^[104]
BMP14	（1）刺激成纤维细胞的迁移、增殖和机体内胶原蛋白合成^[48] （2）促进表皮干细胞的增殖并诱导表皮干细胞迁移^[48,57] （3）可诱导纤溶酶原激活剂活性，并以趋化方式加速主动脉内皮细胞的迁移^[85] （4）与皮肤细胞外基质中I型胶原丝的超微结构相互作用以形成更稳定的伤口闭合^[48]

[1]	Hongling Fu, Hanmin Liu. Research progress on signaling pathways involved in bronchopulmonary dysplasia and pulmonary hypertension [J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2022, 18(05): 497-505.
[2]	Yimiao Wang, Peijie He. Role and regulatory factors of fibroblasts in hypertrophic scar formation [J]. Chinese Journal of Injury Repair and Wound Healing(Electronic Edition), 2023, 18(01): 78-85.
[3]	Weixia Cai, Tao Cao, Ming Zhao, Dan Xiao, Yanhui Jia, Jing Wang, Yue Zhang, Kejia Wang, Juntao Han, Dahai Hu. Effects of Notch signaling pathway on the intercellular adhesion molecule-1 of pulmonary vascular endothelial cell induced by serum in burned rats [J]. Chinese Journal of Injury Repair and Wound Healing(Electronic Edition), 2022, 17(04): 292-299.
[4]	Xinrui Yu, Hui Zeng. Complexity between the Janus kinase-signal transducer and activator of transcription proteins signaling pathway and sepsis [J]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2022, 16(06): 366-369.
[5]	Yifan Zhou, Ying Jin. Functions of the ERK signaling pathway in the regulation of pluripotency states of human pluripotent stem cells [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(01): 27-35.
[6]	Junjie Huang, Lie Wang, Hu Zhao, Yin Xia, Zaizhong Zhang. Progress in the mechanism of lncRNA as ceRNA involved in the pathogenesis and progression of infantile hemangioma [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2022, 12(06): 360-366.
[7]	Lili Yin, Chen Guan, Long Zhao, Wei Jiang, Zhenzhi Qin, Chenyu Li, Yan Xu. Potential molecular mechanism of astaxanthin regulating renal interstitial fibrosis through CCN1 [J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2022, 11(06): 318-326.
[8]	Feng Ying, Jing Wang, Xueqing Liu, Xiao Li. The effects of aquaporin 1 on the proliferation, migration, and apoptosis of human corneal endothelial cells [J]. Chinese Journal of Ophthalmologic Medicine(Electronic Edition), 2023, 13(03): 146-151.
[9]	Yu Song, Xiuli Bao. Research progress of Dickkopf-1 in ocular fibrosis [J]. Chinese Journal of Ophthalmologic Medicine(Electronic Edition), 2022, 12(06): 362-366.
[10]	Hang Wei, Mingwei Zhao, Jinfeng Qu. Text mining-based in bioinformatics analysis of key genes and signal pathways related to immunoreaction in dry age-related macular degeneration [J]. Chinese Journal of Ophthalmologic Medicine(Electronic Edition), 2022, 12(05): 262-267.
[11]	Zechao Zhu, Xinyu Yang, Youcheng Li, Pengyu Pan, Guobiao Liang. Impact of genistein on early brain injury following subarachnoid hemorrhage in mice via the SIRT1/p53 signaling pathway [J]. Chinese Journal of Neurotraumatic Surgery(Electronic Edition), 2023, 09(05): 261-269.
[12]	Gang Cui, Deliang Wang, Maowu Fu, Biming Tian, Ying Wang, Hubin Duan. Study on the relationship between RHO/ROCK signal pathway, neuroinflammatory reaction and pathological injury in rats brain after traumatic brain injury [J]. Chinese Journal of Neurotraumatic Surgery(Electronic Edition), 2022, 08(06): 324-328.
[13]	Gang Cui, Youchao Xiao, Huan Wang, Biming Tian, Ying Wang, Hubin Duan. Effects of RHO/ROCK signaling pathway on the microenvironment of nervous system after traumatic brain injury in rats [J]. Chinese Journal of Neurotraumatic Surgery(Electronic Edition), 2022, 08(04): 204-208.
[14]	Siyu Yang, Jingjing Yang, Ping Zhang, Qiao Liu, Jie Wu, Xiangjin Huang, Yijie Wang, Jingyun Fu. Leptin modulates α1-adrenergic receptor-mediated CaMKK-AMPKα signaling in GT1-7 cells [J]. Chinese Journal of Clinicians(Electronic Edition), 2023, 17(05): 569-574.
[15]	Min He, Zhen Huang. Study on the effect of modified Zhibai Dihuang pill on bone cells in idiopathic central precocious puberty mice based on BMP-Smads signaling pathway [J]. Chinese Journal of Clinical Laboratory Management(Electronic Edition), 2023, 11(04): 214-220.

Please choose a citation manager

Content to export