间充质干细胞治疗在新冠肺炎的临床研究的应用（二）

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❷  精确调节多种免疫细胞功能

COVID-19肺炎患者外周血白细胞、中性粒细胞数量显著升高，CD4⁺ CD8⁺ T细胞数量显著减少，但过度激活，提示COVID-19肺炎患者免疫系统已严重受损。MSCs可精确调节多种免疫细胞功能，调节免疫应答反应。

Jelena M. Dokic等研究发现，MSCs可通过细胞间接触和分泌可溶性因子，抑制CD14＋单核细胞向树突状细胞(Dendritic , DC)的分化、成熟，减少DC活化，并影响其细胞因子的表达模式[6-8]。

Guan Wang等研究发现，MSCs可调节巨噬细胞免疫功能，如通过分泌TSG-6 抑制NF-κB信号通路[9]，以及通过外泌体转运抗炎微小RNA146a，促使其向抑炎M2型巨噬细胞转化[10]。MSCs分泌的吲哚胺２,３-双加氧酶(IDO)、前列腺素E2(PGE2)、可溶性白细胞抗原G5(sHLA-G5)等因子，可抑制NK细胞的功能[6]。

新冠肺炎患者体内，淋巴细胞异常激活其比例也严重失调。Pontikoglou C等研究发现，MSCs可下调T细胞TNF-α、IFN-γ的分泌，上调IL-4分泌，促使细胞由促炎症状态向抗炎症状态进行转变；抑制异常激活的Th1和Th17分化，诱导调节性Ｔ细胞(Tregs)扩增分化，恢复Th1/Th2比例平衡，同时抑制细胞毒性Ｔ淋巴细胞活性，改善免疫状态[8,11]。此外MSCs还可抑制Ｂ细胞过度增殖，下调转录因子表达阻止其向浆细胞分化，并降低免疫球蛋白分泌水平，同时抑制B细胞向淋巴结趋化[12]。
 

间充质干细胞对DC、NK、T、B细胞的免疫调节[6]

MSCs可抑制免疫细胞过度活化，调节免疫系统功能使其比例恢复到正常水平，降低新型冠状病毒对肺造成的损伤。

❸ 分泌多种可溶性因子改善肺部微环境

新冠病毒主要攻击机体肺部，引起急性肺部损伤，呈现弥漫性肺泡损伤，组织纤维化，最终发展成ARDS。MSCs经静脉输注后首先归巢于肺部，可分化为肺泡上皮细胞、肺血管内皮细胞，帮助受损组织完成再生，但该作用效率较低[13]。

MSCs主要通过分泌多种细胞因子(TGF-β, HGF, LIF, GAL, NOA1, FGF, VEGF, EGF, BDNF和NGF等) 及释放大量含有微小RNA的外泌体、微囊泡改善肺部细胞微环境、保护修复细胞、改善细胞存活，抗纤维化，促进新生血管发生，更好地发挥治疗肺损伤的作用[1, 14-15]。另外，干细胞固有表达的干扰素刺激基因(ISGs)可保护干细胞免受病毒感染，具有非常强的病毒抵抗能力[16]，临床试验检测数据显示，MSCs的ACE2和TMPRSS2检测结果均为阴性，表明MSCs未受冠状病毒感染[1]。

1. Zikuan L, et al. (2020) Transplantation of ACE2- mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. ChinaXiv

2. Bing L, et al. (2020) Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells. ChinaXiv

3. AI Caplan, et,al. (1991) Mesenchymal stem cells Journal of or thopaedic research, Wiley Online Library

4. Pittenger MF, et al. (1999) Multi-lineage potential of adult human mesenchymal stem cells[J]. Science, 284: 143-147.

5. C Huang, et al. ( 2020) Clinical Features of Patients Infected With 2019 Novel Coronavirus in Wuhan, China. Lancet 395 (10223), 497-506

6. L Marino et al. (2019) Mesenchymal Stem Cells From the Wharton's Jelly of the Human Umbilical Cord: Biological Properties and Therapeutic Potential. Int J Stem Cells 12 (2), 218-226. 

7.  JM Dokic, et al. (2016) Cross-Talk Between Mesenchymal Stem/Stromal Cells and Dendritic Cells. Curr Stem Cell Res Ther, 11 (1), 51-65 2

8. A Uccelli, et al. (2015) The Immunomodulatory Function of Mesenchymal Stem Cells: Mode of Action and Pathways. Ann N Y Acad Sci 1351, 114-26. 

9. Guan W, et al. (2018) Kynurenic Acid, an IDO Metabolite, Controls TSG-6-mediated Immunosuppression of Human Mesenchymal Stem Cells Cell Death Differ, 25 (7), 1209-1223

10. Yuxian S, et al. (2017) Exosomal miR-146a Contributes to the Enhanced Therapeutic Efficacy of Interleukin-1β-Primed Mesenchymal Stem Cells Against Sepsis Stem Cells, 35 (5), 1208-1221

11. Pontikoglou C, et al. (2011) Bone marrow mesenchymal stem cells: biological properties and their role in hematopoiesis and hematopoietic stem cell transplantation. Stem Cell Rev;7:569-589

12. Che N, et al. (2012) Umbilical cord mesenchymal stem cells suppress B-cellproliferation and differentiation. Cell Immunol ;274:46-53

13. M Rojas et al. (2005) Bone Marrow-Derived Mesenchymal Stem Cells in Repair of the Injured Lung Am J Respir Cell Mol Biol 33 (2), 145-52.

14. X Fu, et al. (2019) Mesenchymal Stem Cell Migration and Tissue Repair Cells 8 (8).

15. Y Moodley et al. (2009) Human Umbilical Cord Mesenchymal Stem Cells Reduce Fibrosis of Bleomycin-Induced Lung InjuryAm J Pathol 175 (1), 303-13. Jul 2009.

16. Wu X, et al. (2018) Intrinsic Immunity Shapes Viral Resistance of Stem Cells.Cell, 172 (3), 423-438.e25