Human amniotic epithelial stem cell is a cell therapy candidate for preventing acute graft-versus-host disease  

作　　者：Peng-jie Yang Xiang-yu Zhao Yao-hui Kou Jia Liu Xiang-yi Ren Yuan-yuan Zhang Zhi-dong Wang Zhen Ge Wei-xin Yuan Chen Qiu Bing Tan Qin Liu Yan-na Shi Yuan-qing Jiang Cong Qiu Li-he Guo Jin-ying Li Xiao-jun Huang Lu-yang Yu 

机构地区：[1]MOE Laboratory of Biosystems Homeostasis&Protection of College of Life Sciences,Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province of Sir Run Run Shaw Hospital,Zhejiang University,Hangzhou,310058,China [2]Peking University Institute of Hematology,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation,Peking University People’s Hospital,Peking University,Beijing,100044,China [3]College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory,Joint Research Centre for Engineering Biology,Zhejiang University-University of Edinburgh Institute,Zhejiang University,Hangzhou,314400,China [4]School of Pharmaceutical Sciences,Hangzhou Medical College,Hangzhou,310013,China [5]Shanghai iCELL Biotechnology Co.Ltd,Shanghai,200335,China [6]Institute of Biochemistry and Cell Biology,Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai,200031,China [7]Peking-Tsinghua Center for Life Sciences,Beijing,100084,China

出　　处：《Acta Pharmacologica Sinica》2024年第11期2339-2353,共15页中国药理学报（英文版）

基　　金：supported by the Zhejiang Provincial Key R&D Program of China(2022C03097);the National Key R&D Program of China(2017YFA0104500,2018YFA0800504);the National Natural Science Foundation of China(82300296,81621001,91839104,81770444 and 81600354);Project of Health Collaborative Innovation of Guangzhou City(201704020214);the Zhejiang Provincial Natural Science Foundation of China(LZ20H020002);the Medical and Health Science and Technology Program of Health Commission of Zhejiang Province,China(2021KY633);Fundamental Research Funds for the Central Universities of China.

摘　　要：Graft-versus-host disease(GVHD),an immunological disorder that arises from donor T cell activation through recognition of host alloantigens,is the major limitation in the application of allogeneic hematopoietic stem cell transplantation(allo-HSCT).Traditional immunosuppressive agents can relieve GVHD,but they induce serious side effects.It is highly required to explore alternative therapeutic strategy.Human amniotic epithelial stem cells(hAESCs)were recently considered as an ideal source for cell therapy with special immune regulatory property.In this study,we evaluated the therapeutic role of hAESCs in the treatment of GVHD,based on our previous developed cGMP-grade hAESCs product.Humanized mouse model of acute GVHD(aGVHD)was established by injection of huPBMCs via the tail vein.For prevention or treatment of aGVHD,hAESCs were injected to the mice on day-1 or on day 7 post-PBMC infusion,respectively.We showed that hAESCs infusion significantly alleviated the disease phenotype,increased the survival rate of aGVHD mice,and ameliorated pathological injuries in aGVHD target organs.We demonstrated that hAESCs directly induced CD4+T cell polarization,in which Th1 and Th17 subsets were downregulated,and Treg subset was elevated.Correspondingly,the levels of a series of pro-inflammatory cytokines were reduced while the levels of the anti-inflammatory cytokines were upregulated in the presence of hAESCs.We found that hAESCs regulated CD4+subset polarization in a paracrine mode,in which TGFβand PGE2 were selectively secreted to mediate Treg elevation and Th1/Th17 inhibition,respectively.In addition,transplanted hAESCs preserved the graft-versus-leukemia(GVL)effect by inhibiting leukemia cell growth.More intriguingly,hAESCs infusion in HSCT patients displayed potential anti-GVHD effect with no safety concerns and confirmed the immunoregulatory mechanisms in the preclinical study.We conclude that hAESCs infusion is a promising therapeutic strategy for post-HSCT GVHD without compromising the GVL effect.The clinical trial wa

关 键 词：graft-versus-host disease hematopoietic stem cell transplantation human amniotic epithelial stem cells IMMUNOMODULATION 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]