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中华细胞与干细胞杂志(电子版)

中华细胞与干细胞杂志(电子版) ›› 2023, Vol. 13 ›› Issue (02) : 101 -107. doi: 10.3877/cma.j.issn.2095-1221.2023.02.006

综述

骨形态发生蛋白在皮肤创面修复中的研究进展
王湘, 陈良熠, 虞烽伟, 王正熙, 李秋彤, 李玉红†()   
  1. 400038　重庆，陆军军医大学基础医学院细胞生物学教研室
    400038　重庆，陆军军医大学基础医学院外语教研室
  • 收稿日期:2022-10-14 出版日期:2023-04-01
  • 通信作者: 李玉红
  • 基金资助:
    国家自然科学基金(82173446)

Development of bone morphogenetic protein in skin wound repair

Xiang Wang, Liangyi Chen, Fengwei Yu, Zhengxi Wang, Qiutong Li, Yuhong Li†()   

  1. Department of Cell Biology, Amy Medical University, Chongqing 400038, China
    Department of Foreign Languages, Amy Medical University, Chongqing 400038, China
  • Received:2022-10-14 Published:2023-04-01
  • Corresponding author: Yuhong Li
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引用本文：

王湘, 陈良熠, 虞烽伟, 王正熙, 李秋彤, 李玉红. 骨形态发生蛋白在皮肤创面修复中的研究进展[J]. 中华细胞与干细胞杂志(电子版), 2023, 13(02): 101-107.

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.

在创伤修复过程中，各类细胞因子与信号通路对于创伤修复的调控精密而复杂，长久以来一直是人们关注和探索的领域。其中转化生长因子-β （TGF-β），P38/MAPK，Wnt/β-catenin，PI3K/AKT等信号通路，在创伤修复中都有重要作用。TGF-β家族中的骨形态发生蛋白（BMP）是一组具有类似结构的高度保守的功能蛋白，既往研究发现其主要在诱导骨、软骨的形成和促进成骨细胞的生长等方面发挥作用。近年来，有研究发现，BMP可以通过信号通路促进或抑制另一种信号分子来调节各种皮肤相关细胞（如表皮干细胞、毛囊干细胞、成纤维细胞等）的活动，进而调节皮肤创伤修复过程。BMP作用于不同的细胞，对皮肤创伤修复的机制也不同。本文对BMP在创伤修复中的作用及最新研究进展予以综述。

关键词: 骨形态发生蛋白, 信号通路, 皮肤创伤修复

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
图1 骨形态发生蛋白分子结构图[4] （来源：RCSB PDB，PDB ID：6OML）
表1 各类细胞在皮肤创伤修复中的作用
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
表2 BMP与皮肤创伤修复之间的作用关系
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]
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