PDF(Pubmed)
Abstract：
BACKGROUND: The emergence of SARS-CoV-2 becomes life-threatening for the older and immunocompromised individuals, whereas limited treatment is available on these populations. Mesenchymal stromal cells (MSCs) have been reported to be useful in SARS-CoV-2 treatment and reduce SARS-CoV-2-related sequelae.
RESULTS: In this study, we developed an autonomous cellular machine to secret neutralizing antibody in vivo constantly based on the clinical-grade MSCs, to combat SARS-CoV-2 infections. First, various modified recombinant plasmids were constructed and transfected into clinical-grade MSCs by electroporation, for assembly and expression of neutralizing anti-SARS-CoV-2 antibodies. Second, the stable antibody secreting MSCs clones were screened through pseudovirus neutralization assay. Finally, we investigated the pharmacokinetics and biodistribution of neutralizing antibody secreted by engineered MSCs in vivo. The stable clinical-grade MSCs clones, expressing XGv347-10 and LY-CoV1404-5 neutralizing antibodies, exhibited their feasibility and protective efficacy against SARS-CoV-2 infection. Transplanted engineered clinical-grade MSCs effectively delivered the SARS-CoV-2 antibodies to the lung, and the immune hyperresponsiveness caused by COVID-19 was coordinated by MSC clones through inhibiting the differentiation of CD4 + T cells into Th1 and Th17 subpopulations.
CONCLUSIONS: Our data suggested that engineered clinical-grade MSCs secreting effective neutralizing antibodies as cellular production machines had the potential to combat SARS-CoV-2 infection, which provided a new avenue for effectively treating the older and immunocompromised COVID-19 patients.
RESULTS: In this study, we developed an autonomous cellular machine to secret neutralizing antibody in vivo constantly based on the clinical-grade MSCs, to combat SARS-CoV-2 infections. First, various modified recombinant plasmids were constructed and transfected into clinical-grade MSCs by electroporation, for assembly and expression of neutralizing anti-SARS-CoV-2 antibodies. Second, the stable antibody secreting MSCs clones were screened through pseudovirus neutralization assay. Finally, we investigated the pharmacokinetics and biodistribution of neutralizing antibody secreted by engineered MSCs in vivo. The stable clinical-grade MSCs clones, expressing XGv347-10 and LY-CoV1404-5 neutralizing antibodies, exhibited their feasibility and protective efficacy against SARS-CoV-2 infection. Transplanted engineered clinical-grade MSCs effectively delivered the SARS-CoV-2 antibodies to the lung, and the immune hyperresponsiveness caused by COVID-19 was coordinated by MSC clones through inhibiting the differentiation of CD4 + T cells into Th1 and Th17 subpopulations.
CONCLUSIONS: Our data suggested that engineered clinical-grade MSCs secreting effective neutralizing antibodies as cellular production machines had the potential to combat SARS-CoV-2 infection, which provided a new avenue for effectively treating the older and immunocompromised COVID-19 patients.
摘要：
背景：SARS-CoV-2的出现对老年人和免疫功能低下的个体造成生命威胁，而这些人群的治疗有限。据报道，间充质基质细胞（MSC）可用于SARS-CoV-2治疗并减少SARS-CoV-2相关后遗症。
结果：在这项研究中，我们开发了一种自主的细胞机器，以临床级MSCs为基础，不断在体内秘密中和抗体，对抗SARS-CoV-2感染.首先,构建各种修饰的重组质粒，并通过电穿孔转染临床级MSCs，用于中和抗SARS-CoV-2抗体的组装和表达。第二,通过假病毒中和试验筛选出稳定的分泌抗体的MSCs克隆。最后,我们研究了工程化MSCs分泌的中和抗体在体内的药代动力学和生物分布。稳定的临床级MSCs克隆，表达XGv347-10和LY-CoV1404-5中和抗体，显示了它们对SARS-CoV-2感染的可行性和保护作用。移植的工程化临床级MSCs有效地将SARS-CoV-2抗体递送至肺部，由COVID-19引起的免疫高反应由MSC克隆通过抑制CD4T细胞分化为Th1和Th17亚群来协调。
结论：我们的数据表明，作为细胞生产机器分泌有效中和抗体的工程化临床级MSCs具有对抗SARS-CoV-2感染的潜力，这为有效治疗老年和免疫功能低下的COVID-19患者提供了新的途径。
结果：在这项研究中，我们开发了一种自主的细胞机器，以临床级MSCs为基础，不断在体内秘密中和抗体，对抗SARS-CoV-2感染.首先,构建各种修饰的重组质粒，并通过电穿孔转染临床级MSCs，用于中和抗SARS-CoV-2抗体的组装和表达。第二,通过假病毒中和试验筛选出稳定的分泌抗体的MSCs克隆。最后,我们研究了工程化MSCs分泌的中和抗体在体内的药代动力学和生物分布。稳定的临床级MSCs克隆，表达XGv347-10和LY-CoV1404-5中和抗体，显示了它们对SARS-CoV-2感染的可行性和保护作用。移植的工程化临床级MSCs有效地将SARS-CoV-2抗体递送至肺部，由COVID-19引起的免疫高反应由MSC克隆通过抑制CD4T细胞分化为Th1和Th17亚群来协调。
结论：我们的数据表明，作为细胞生产机器分泌有效中和抗体的工程化临床级MSCs具有对抗SARS-CoV-2感染的潜力，这为有效治疗老年和免疫功能低下的COVID-19患者提供了新的途径。
