间充质干细胞实现心肌修复:机遇与挑战

doi:10.3969/j.issn.1674-490X.2022.05.005

摘要/Abstract

摘要： 间充质干细胞(mesenchymal stem cells, MSCs)是一类存在多种组织内的成体干细胞,主要来源于骨髓、脂肪组织和脐带血。随着对MSCs分离、培养、鉴定的程序化、标准化,使其成为实现心肌修复的理想种子细胞。MSCs植入受损心肌后可分泌多种生物活性物质,抑制心肌重构、促进新生血管形成。然而MSCs体内存活时间短、有形成肿瘤风险,使其尚未大规模应用于临床。为提高MSCs的治疗潜能、保障其治疗安全,基因修饰、药物诱导、生物工程等多种方法从基础走向了临床,使MSCs成为实现心肌修复的优质资源,为心肌梗死、终末阶段心力衰竭带来新的曙光。

关键词: 心肌梗死, 心力衰竭, 心肌修复, 旁分泌, 间充质干细胞

Abstract: Mesenchymal stem cells(MSCs)are a kind of adult stem cells residing in a variety of tissues, such as bone marrow, adipose tissue and umbilical cord. With the developments of standard procedures and protocols for isolation, culturing and characterization of these cells, MSCs have emerged as an ideal seed cell for myocardial repair. When transplanted into a injured heart, MSCs have paracrine effects that nurture the injured area, prevent adverse cardiac remodeling, and mediate angiogenesis capabilities. MSCs have short survival time and risk of tumor formation, so they have not been widely used in clinic. In order to improve the therapeutic potential of MSCs and ensure its therapeutic safety, many methods such as gene modification, drug induction and bioengineering have moved from basic research to clinical practices, making MSCs become a high-quality resource cells for myocardial repair, bring new opportunity to myocardial infarction and end-stage heart failure.

Key words: myocardial infarction, heart failure, myocardial repair, paracrine, mesenchymal stem cells

中图分类号:

张红强, 张冰, 李建奇, 瞿海龙. 间充质干细胞实现心肌修复:机遇与挑战[J]. 医学研究与教育, 2022, 39(5): 25-30.

ZHANG Hongqiang, ZHANG Bing, LI Jianqi, JU Hailong. Mesenchymal stem cells for cardiac repair: opportunities and challenges[J]. Journal of Hebei Medical College for Continuing Education, 2022, 39(5): 25-30.

参考文献

[1] 刘莉,张丹丹,邹国良,等.活血化瘀法治疗冠心病合并心力衰竭临床疗效的Meta分析[J].中西医结合心脑血管病杂志, 2021, 19(12): 2038-2044. DOI: 10.12102/j.issn.1672-1349.2021.12.017.
[2] CHIEN K R,FRISÉN J,FRITSCHE-DANIELSON R, et al. Regenerating the field of cardiovascular cell therapy[J]. Nat Biotechnol,2019,37(3): 232-237. DOI: 10.1038/s41587-019-0042-1.
[3] 瞿海龙,周英莲,张新欣,等.间充质干细胞治疗ARDS的新观点[J].医学研究与教育, 2018, 35(5): 7-11. DOI: 10.3969/j.issn.1674-490X.2018.05.002.
[4] 瞿海龙,梁璐,边剑飞,等.实现人类心肌的再生:干细胞的风雨路[J].医学研究与教育, 2015,32(4): 50-55. DOI: 10.3969/j.issn.1674-490X.2015.04.012.
[5] FU D L, JIANG H, LI C Y, et al. microRNA-338 in MSCs-derived exosomes inhibits cardiomyocyte apoptosis in myocardial infarction[J]. Eur Rev Med Pharmacol Sci, 2020, 24(19): 10107-10117. DOI: 10.26355/eurrev_202010_23230.
[6] XIAO W T, GUO S P, GAO C Y, et al. A randomized comparative study on the efficacy of intracoronary infusion of autologous bone marrow mononuclear cells and mesenchymal stem cells in patients with dilated cardiomyopathy[J]. Int Heart J, 2017, 58(2): 238-244. DOI: 10.1536/ihj.16-328.
[7] MA J, ZHAO Y Y, SUN L, et al. Exosomes derived from Akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D[J]. Stem Cells Transl Med, 2017, 6(1): 51-59. DOI: 10.5966/sctm.2016-0038.
[8] JIANG S J, HAIDER H K, IDRIS N M, et al. Stable therapeutic effects of mesenchymal stem cell-based multiple gene delivery for cardiac repair[J]. Cardiovasc Res, 2008, 77(3): 525-533. DOI: 10.1093/cvr/cvm077.
[9] NI X B, OU C W, GUO J B, et al. Lentiviral vector-mediated co-overexpression of VEGF and Bcl-2 improves mesenchymal stem cell survival and enhances paracrine effects in vitro[J]. Int J Mol Med, 2017, 40(2): 418-426. DOI: 10.3892/ijmm.2017.3019.
[10] SUN D, SONG H L, SHEN Z Y. Research progress in mesenchymal stem cells modified by Heme oxygenase 1[J]. Chin J Reparative Reconstr Surg, 2019, 33(7): 901-906. DOI: 10.7507/1002-1892.201812079.
[11] HUANG J, ZHANG Z P, GUO J, et al. Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium[J]. Circ Res, 2010, 106(11): 1753-1762. DOI: 10.1161/CIRCRESAHA.109.196030.
[12] ZENG B, LIU L, WANG S F, et al. ILK regulates MSCs survival and angiogenesis partially through AKT and mTOR signaling pathways[J]. Acta Histochem, 2017, 119(4): 400-406. DOI: 10.1016/j.acthis.2017.04.003.
[13] HU C X, LI L J. Preconditioning influences mesenchymal stem cell properties in vitro and in vivo[J]. J Cell Mol Med, 2018, 22(3): 1428-1442. DOI: 10.1111/jcmm.13492.
[14] ZHANG Z, YANG C, SHEN M Z, et al. Autophagy mediates the beneficial effect of hypoxic preconditioning on bone marrow mesenchymal stem cells for the therapy of myocardial infarction[J]. Stem Cell Res Ther, 2017, 8(1): 89. DOI: 10.1186/s13287-017-0543-0.
[15] 李佩霖,朱恒.间充质干细胞生物学特性的可塑性研究进展[J].中国实验血液学杂志, 2021, 29(2): 629-632. DOI: 10.19746/j.cnki.issn1009-2137.2021.02.051.
[16] HAN Y S, LEE J H, YOON Y M, et al. Hypoxia-induced expression of cellular prion protein improves the therapeutic potential of mesenchymal stem cells[J]. Cell Death Dis, 2016, 7(10): e2395. DOI: 10.1038/cddis.2016.310.
[17] MENG S S, XU X P, CHANG W, et al. LincRNA-p21 promotes mesenchymal stem cell migration capacity and survival through hypoxic preconditioning[J]. Stem Cell Res Ther, 2018, 9(1): 280. DOI: 10.1186/s13287-018-1031-x.
[18] 胡小武,惠杰,沈振亚,等.曲美他嗪预处理BMSCs移植对心肌缺血再灌注大鼠心功能改善的影响[J].中国老年学杂志, 2015, 35(14): 3799-3802.
[19] 裴宇,梁振兴,郝爽,等.阿托伐他汀联合人脐带间充质干细胞移植治疗猪急性心肌梗死的研究[J]. 中华实验外科杂志, 2021, 38(11): 2191-2194. DOI: 10.3760/cma.j.cn 421213-20210309-01081.
[20] 赵静苗,胡继宏,王秋萍.黄芪甲苷诱导大鼠骨髓间充质干细胞向心肌样细胞分化的研究[J]. 中国全科医学, 2017, 20(21): 2635-2639. DOI: 10.3969/j.issn.1007-9572. 2017.05.y11.
[21] LEE J, SHIN M S, KIM M O, et al. Apple ethanol extract promotes proliferation of human adult stem cells, which involves the regenerative potential of stem cells[J]. Nutr Res, 2016, 36(9): 925-936. DOI: 10.1016/j.nutres.2016.06.010.
[22] 康晓军,李燕.染料木素对大鼠骨髓间充质干细胞增殖能力的影响[J].实验与检验医学, 2019, 37(5): 819-821. DOI: 10.3969/j.issn.1674-1129.2019.05.014.
[23] LIU X B, WANG J A, JI X Y, et al. Preconditioning of bone marrow mesenchymal stem cells by prolyl hydroxylase inhibition enhances cell survival and angiogenesis in vitro and after transplantation into the ischemic heart of rats[J]. Stem Cell Res Ther, 2014, 5(5): 111. DOI: 10.1186/scrt499.
[24] 吴硕,任鹏,郭金超,等.含血小板源性生长因子的载银介孔二氧化硅对大鼠BMSCs细胞毒性及抗菌性能的影响[J].中华显微外科杂志, 2020, 43(2): 167-172.DOI: 10.3760/cma.j.cn441206-20190711-00235.
[25] LI Z D, XU X, WANG W W, et al. Modulation of the mesenchymal stem cell migration capacity via preconditioning with topographic microstructure[J]. Clin Hemorheol Microcirc, 2017, 67(3/4): 267-278. DOI: 10.3233/CH-179208.
[26] SART S, AGATHOS S N, LI Y, et al. Regulation of mesenchymal stem cell 3D microenvironment: from macro to microfluidic bioreactors[J]. Biotechnol J, 2016, 11(1): 43-57. DOI: 10.1002/biot.201500191.
[27] 思黛伟,王新涛.低能量激光照射疗法调节间充质干细胞生物学效应研究进展[J].国际骨科学杂志, 2021, 42(4): 231-235. DOI: 10.3969/j.issn.1673-7083.2021.04.009.
[28] URNUKHSAIKHAN E, CHO H, MISHIG-OCHIR T, et al. Pulsed electromagnetic fields promote survival and neuronal differentiation of human BM-MSCs[J]. Life Sci, 2016, 151: 130-138. DOI: 10.1016/j.lfs.2016.02.066.
[29] MOLONEY T C, HOBAN D B, BARRY F P, et al. Kinetics of thermally induced heat shock protein 27 and 70 expression by bone marrow-derived mesenchymal stem cells[J]. Protein Sci, 2012, 21(6): 904-909. DOI: 10.1002/pro.2077.
[30] PARK B W, JUNG S H, DAS S, et al. In vivo priming of human mesenchymal stem cells with hepatocyte growth factor-engineered mesenchymal stem cells promotes therapeutic potential for cardiac repair[J]. Sci Adv, 2020, 6(13): eaay6994. DOI: 10.1126/sciadv.aay6994.
[31] HAHN J Y, CHO H J, KANG H J, et al. Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction[J]. J Am Coll Cardiol, 2008, 51(9): 933-943. DOI: 10.1016/j.jacc.2007.11.040.
[32] 刘小刚,李甜,张舵.软骨组织工程中种子细胞选择的研究热点[J].中国组织工程研究, 2021, 25(31): 5059-5064.
[33] PARK S J, KIM R Y, PARK B W, et al. Dual stem cell therapy synergistically improves cardiac function and vascular regeneration following myocardial infarction[J]. Nat Commun, 2019, 10(1): 3123. DOI: 10.1038/s41467-019-11091-2.