Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms.
Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms.
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DOI：
10.1038/s41422-021-00573-y
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发表时间：
2021-12
期刊：
影响因子：
44.1
通讯作者：
Zhao RC
中科院分区：
文献类型：
--
作者：
Zhu R;Yan T;Feng Y;Liu Y;Cao H;Peng G;Yang Y;Xu Z;Liu J;Hou W;Wang X;Li Z;Deng L;Wang S;Li J;Han Q;Li H;Shan G;Cao Y;An X;Yan J;Zhang Z;Li H;Qu X;Zhu J;Zhou S;Wang J;Zhang F;Gao J;Jin R;Xu D;Ma YQ;Huang T;Peng S;Zheng Z;Stambler I;Gilson E;Lim LW;Moskalev A;Cano A;Chakrabarti S;Ulfhake B;Su H;Xu H;Xu S;Wei F;Brown-Borg HM;Min KJ;Ellison-Hughes G;Caruso C;Jin K;Zhao RC
2019冠状病毒病（COVID-19）患者输注间充质干细胞（MSC）可能会改善临床症状，但其潜在机制仍不清楚。我们进行了一项随机、单盲、安慰剂对照（29例患者/组）的II期临床试验，以验证先前的研究结果并探索潜在的机制。与接受安慰剂治疗的患者相比，接受脐带来源的MSC治疗的患者住院时间更短（P = 0.0198），症状缓解所需的时间更短（P = 0.0194）。基于胸部图像，用MSC治疗的重度和危重患者在第7天（P = 0.0099）和第21天（P = 0.0084）均显示出改善。MSC治疗的患者不良事件较少。MSC输注降低了C反应蛋白、促炎细胞因子和中性粒细胞胞外陷阱（NET）的水平，并促进了SARS-CoV-2特异性抗体的维持。为了探索MSC如何调节免疫系统，我们采用外周血单细胞RNA测序分析。我们的分析确定了一种新的VNN 2+造血干/祖细胞样（HSPC样）细胞亚群，表达CSF 3R和PTPRE，MSC输注后动员。编码趋化因子的基因-CX 3CR 1和L-选择素-在各种免疫细胞中上调。MSC治疗还调节B细胞亚群，并增加体内和体外T细胞中共刺激CD 28的表达。此外，一项体内小鼠研究证实，MSC通过上调kindlin-3信号转导抑制NET释放并减少静脉血栓形成。总之，我们的研究结果强调了MSC通过维持免疫稳态在改善COVID-19患者预后方面的作用。
The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+ hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors — CX3CR1 and L-selectin — were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.
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