Current status and future of treatment of pulmonary fibrosis by mesenchymal stem cells and extracellular vesicles

doi:10.12307/2024.193

Chinese Journal of Tissue Engineering Research ›› 2024, Vol. 28 ›› Issue (25): 4079-4086.doi: 10.12307/2024.193

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Current status and future of treatment of pulmonary fibrosis by mesenchymal stem cells and extracellular vesicles

Wang Yanyang1, 2, Liu Chan1, 2, Yu Limei1, 2, He Zhixu1, 2, 3

1Key Cell Engineering Laboratory, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China; 2Ministry of Tissue Damage Repair and Regenerative Medicine Jointly Established a Collaborative Innovation Center, Zunyi Medical University, Zunyi 563000, Guizhou Province, China; 3Guizhou Children’s Hospital; Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China

Received:2023-07-08 Accepted:2023-08-24 Online:2024-09-08 Published:2023-11-24
Contact: He Zhixu, Chief physician, Professor, Doctoral supervisor, Key Cell Engineering Laboratory, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China; Ministry of Tissue Damage Repair and Regenerative Medicine Jointly Established a Collaborative Innovation Center, Zunyi Medical University, Zunyi 563000, Guizhou Province, China; Guizhou Children’s Hospital; Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
About author:Wang Yanyang, Master candidate, Key Cell Engineering Laboratory, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China; Ministry of Tissue Damage Repair and Regenerative Medicine Jointly Established a Collaborative Innovation Center, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
Supported by:
2022 National Natural Science Foundation (General Program), No. 32270848 (to HZX); 2020 Ministry of Education Collaborative Innovation Center Construction Project: Ministry of Tissue Damage Repair and Regenerative Medicine Jointly Established a Collaborative Innovation Center, No. [2020]39 (to HZX); 2020 Guizhou Provincial Science and Technology Support Plan Project, No. [2020]4Y192 (to HZX)

Abstract

Abstract: BACKGROUND: Despite a series of clinical treatment measures, the treatment of pulmonary fibrosis still faces challenges. In recent years, mesenchymal stem cells and their extracellular vesicles have attracted extensive attention as an emerging therapeutic strategy and are considered to be a promising means of treating pulmonary fibrosis.
OBJECTIVE: To systematically review the application of mesenchymal stem cells and their extracellular vesicles in the treatment of pulmonary fibrosis, to comprehensively understand their therapeutic mechanism, efficacy evaluation and problems, and provide reference and guidance for further research and clinical application in the future.
METHODS: Using Chinese and English search terms “mesenchymal stem cells”, “ mesenchymal stem cell extracellular vesicles”, “pulmonary fibrosis”, we searched the CNKI and PubMed electronic journal databases. By means of manual reading and eliminating duplicate articles, 112 articles were selected, but 58 Chinese and English articles were finally included for summary.
RESULTS AND CONCLUSION: (1) Mesenchymal stem cells and their extracellular vesicles have shown great potential in the treatment of pulmonary fibrosis, such as regulating inflammatory responses, inhibiting fibroblast proliferation, and promoting damaged tissue repair. Preliminary results from clinical trials have also shown some effects of the treatment, including improved lung function and quality of life in patients. (2) However, mesenchymal stem cells and extracellular vesicles in the treatment of pulmonary fibrosis still face some challenges. During treatment, technical challenges such as cell migration and intrachistological localization need to be addressed for it to accurately reach the damaged lung tissue. Furthermore, its long-term safety also needs to be further studied and improved. For translational medicine development, standardized procedures such as cell collection, cell isolation, cell culture, cell harvesting, and cell identification need to be refined. (3) Despite these challenges, through the joint efforts of scientific researchers and medical personnel, these problems are expected to be gradually solved. In the future, we can further improve treatment outcomes by optimizing treatment regimens and exploring individualized treatments. At the same time, in-depth research on the therapeutic mechanism of stem cells and their extracellular vesicles is expected to develop more efficient and safe therapeutic strategies.

Key words: pulmonary fibrosis, mesenchymal stem cell, extracellular vesicle, review

CLC Number:

Wang Yanyang, Liu Chan, Yu Limei, He Zhixu. Current status and future of treatment of pulmonary fibrosis by mesenchymal stem cells and extracellular vesicles[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(25): 4079-4086.

Figures/Tables 4

2.1.1 免疫微环境改变肺纤维化最初被描述为一种以炎症反应为始的疾病[19]，研究证明炎症反应几乎参与了所有的伤口愈合发生与纤维化进程[20]，其中在纤维化进程中炎症微环境发生的主要变化包括：①免疫细胞群与炎症因子。新近研究通过单细胞测序技术揭示肺纤维化过程中免疫细胞群的主要改变以巨噬细胞与T细胞为主[21]。巨噬细胞分为促进炎症的M1型巨噬细胞和抗炎的M2型巨噬细胞，M1型巨噬细胞负责肺泡上皮损伤后的调节过程，分泌肿瘤坏死因子α等肺纤维化相关炎症因子。M2型巨噬细胞主要在伤口愈合过程、肺部炎症反应中发挥关键作用，分泌白细胞介素10等肺纤维化过程的重要因子。各种调节细胞因子、趋化因子、递质和免疫调节细胞通过改变M1、M2型巨噬细胞的极化过程来作用于肺部疾患，从而影响肺纤维化的发展过程[22-23]。在T细胞群中，Th1细胞参与吞噬细胞依赖性炎症，分泌大量白细胞介素2等，Th2细胞参与慢性炎症疾病和组织修复，分泌大量白细胞介素4等[24]。正常伤口有效愈合通常以占主导地位的Th1反应为特征，而免疫平衡转为以Th2细胞为主导会导致慢性炎症，最终导致纤维化[25]，不平衡的Th1/Th2免疫反应被认为是特发性肺纤维化发病机制的核心。研究发现，Th17分化受阻可以减轻博莱霉素诱导的肺纤维化[24，26]。②Toll样受体与炎性小体等免疫活性物质。Toll样受体是参与非特异性免疫(天然免疫)的一类重要蛋白质分子，表达在巨噬细胞、树突状细胞和上皮细胞表面。研究表明，Toll样受体3、Toll样受体4缺乏会促进肺纤维化中异常的炎症反应和纤维增殖反应，Toll样受体2、Toll样受体5在肺纤维化动物模型中表达增加[27-30]。在肺纤维化发生中现有研究比较多的炎性小体是NLRP3与AIM2炎性小体，NLRP3在肺泡上皮细胞中被激活，可以通过转化生长因子β1调节上皮-间质转化参与肺纤维化进程[31-32]。CHO等[33]通过临床试验证明，AIM2炎性小体在特发性肺纤维化患者的外周血单核细胞中会增加，AIM2炎性小体激活有助于产生和释放促纤维化递质。 2.1.2 上皮、间质细胞群改变导致的间质沉积肺纤维化过程中，肌成纤维细胞大量产生导致间质沉积的途径包括：①间质细胞种群发生变化：成纤维细胞向肌成纤维细胞的过渡是伤口愈合过程中的正常事件，其特征是平滑肌肌动蛋白达增加。肌成纤维细胞是产生闭合伤口收缩力所必需的要素，这与胶原蛋白沉积有关[34]，肌成纤维细胞数量的增加会导致纤维化的进展，单细胞测序结果揭示了在肺纤维化发生发展中，肌成纤维细胞特异性表面标志物表达在平滑肌细胞等多种细胞中，所有间充质细胞中与细胞外基质相关的基因都上调[35]。②肺上皮细胞发生上皮-间质转化。临床样本与实验动物肺部组织病理染色中间充质与上皮细胞标志物的共定位证实了上皮-间质转化的发生[36-38] ，单细胞测序揭示肺纤维化肺上皮细胞的特点是气道上皮细胞比例增加，肺泡上皮细胞大幅下降，出现的异常基底细胞表达上皮-间质转化的标志物[21]，肺纤维化过程中，转化生长因子β、血小板衍生生长因子受体、成纤维细胞生长因子和多种信号通路都能促进间充质基因的表达和上皮基因的下调[4，39]。 2.1.3 血管生成血管生成是伤口修复的正常特征，能够提供组织愈合所需的细胞和营养。研究发现，在肺纤维化过程中，纤维化区域内出现广泛新生血管[40]。血管生成的稳态由血管生成促进和抑制因素共同调节，例如血管生成趋化因子5、血管生成趋化因子8与血管生成趋化因子10的表达不平衡，可以使血管生成增加，抑制血管生成趋化因子受体2可以减弱博莱霉素诱导的肺纤维化程度[41-42]；也有研究证明血管生成素生物轴与肺纤维化血管重塑的调节明确相关[43]；血管内皮生长因子、血小板衍生生长因子和成纤维细胞生长因子也都与肺纤维化的发病机制相关[44]，血管内皮生长因子是最有效的血管生成刺激因素之一，在肺纤维化发生发展过程中发挥重要作用[45-46]。 2.2 MSCs治疗肺纤维化的研究进展在中国知网、PubMed数据库筛选出近5年内涉及MSCs治疗肺纤维化的相关研究37篇[47-83]，其中包括34个临床前研究，3个临床研究，研究所涉及的具体细节按照MSCs种类进行分类，造模方法、细胞移植途径、剂量、时间等具体细节见表1。关于MSCs治疗肺纤维化的机制，迄今为止研究最充分的是炎症改善，不同来源MSCs可以通过调整中性粒细胞比例、T细胞数量、Treg平衡来对抗炎症[47-50]，现有的通路研究包含SMAD-3/TGF-β信号通路、PD-1/PD-L1通路、AKT通路、IL-6/IL-10/TGF-β轴、Wnt/β-catenin通路[51-55]，通过不同的作用机制最终使得促炎因子下调，抗炎因子上调；其次是上皮间质细胞群的改善[56]：其中包括肺上皮细胞的凋亡减轻[57-59]，成纤维细胞的激活或增殖被抑制[60]，上皮-间质转化的改善[61]，现有研究多数集中在通过Wnt/β-catenin信号通路减缓上皮-间质转化的发生[62-63]；最后是氧化应激过程的改善[64-65]。大多数情况下，上述改变并不单一发生，多种机制发生综合作用[66]，最终完成纤维化的改善。"

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Current status and future of treatment of pulmonary fibrosis by mesenchymal stem cells and extracellular vesicles

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