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

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Abstract

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 TGFβ and 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 was registered at www.clinicaltrials.gov as #NCT03764228.

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Fig. 1: The identification of cGMP-grade hAESCs isolated and cultured in a serum-free system.
Fig. 2: hAESCs inhibit the development of aGVHD in humanized mouse model.
Fig. 3: hAESCs ameliorate the pathological injuries of aGVHD.
Fig. 4: hAESCs modulate cytokines production and CD4+ subsets polarization in mouse aGVHD model.
Fig. 5: hAESCs regulate CD4+ subsets polarization by secreting TGFβ and PGE2 independent of cell contact.
Fig. 6: hAESCs infusion does not impair the GVL effect.
Fig. 7: Reconstitution of immune cell subsets in HRD-HSCT patients with hAESCs engraftment.
Fig. 8: Plasma cytokine levels in HRD-HSCT patients receiving hAESCs infusion.

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Acknowledgements

We thank Dr. She-long Zhang and Dr. Fang-liang Huang (Equipment and Technology Service Platform, College of Life Sciences, Zhejiang University) for their excellent technical support with microscopy and flow cytometry. This work was 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) and Fundamental Research Funds for the Central Universities of China.

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  1. These authors contributed equally: Peng-jie Yang, **ang-yu Zhao, Yao-hui Kou

Authors and Affiliations

  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

    Peng-jie Yang, Yao-hui Kou, Jia Liu, **ang-yi Ren, Chen Qiu, Bing Tan, Yuan-qing Jiang, Cong Qiu, **-ying Li & Lu-yang Yu

  2. Peking University Institute of Hematology, Bei**g Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Peking University, Bei**g, 100044, China

    **ang-yu Zhao, Yuan-yuan Zhang, Zhi-dong Wang & **ao-jun Huang

  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

    Yao-hui Kou, Jia Liu, **ang-yi Ren, Wei-xin Yuan, Chen Qiu, Bing Tan, Yan-na Shi, Yuan-qing Jiang, Cong Qiu, **-ying Li & Lu-yang Yu

  4. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310013, China

    Zhen Ge

  5. Shanghai iCELL Biotechnology Co. Ltd, Shanghai, 200335, China

    Wei-xin Yuan, Qin Liu & Li-he Guo

  6. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Li-he Guo

  7. Peking-Tsinghua Center for Life Sciences, Bei**g, 100084, China

    **ao-jun Huang

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  1. Peng-jie Yang
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Contributions

PJY, XYZ, LHG, JYL, XJH, and LYY designed research; PJY, XYZ, YHK, JL, YYZ, ZDW, WXY, BT, QL, XYR, and YNS performed research; PJY, XYZ, YHK, ZG, JYL, Chen Qiu, YQJ, Cong Qiu, XYR, and YNS analyzed and interpreted data; PJY, XYZ, YHK, JYL, XJH, and LYY drafted and revised manuscript; JYL, XJH and LYY approved the manuscript submission.

Corresponding authors

Correspondence to **-ying Li, **ao-jun Huang or Lu-yang Yu.

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Competing interests

LYY, PJY, WXY, JYL, LHG, JL authored a China patent (No. ZL 2019 1 0310688.6) held by Zhejiang University and Shanghai iCELL Biotechnology Co. Ltd for the “Use of hAESCs for the treatment of GVHD”. WXY and QL are employees of Shanghai iCELL Biotechnology Co. Ltd. The remaining authors declare no competing financial interests.

Ethics approval and consent to participate

The hAESCs were derived from placenta amniotic membrane of unrelated, unmatched healthy donors with informed patient consent approved by the Institutional Patients and Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (Ethics Code: 2020-799). All animal studies were approved by the Institutional Animal Care and Use Committee of Zhejiang University (ZJU20210127) and adhered to the Guide for the Care and Use of Laboratory Animals. The clinical trial was approved by the institutional review board of Peking University People’s Hospital (2018PHD006-01) and conducted under an investigational new stem cells application from the National Health Commission of China. All patients and donors provided written informed consent according to the Declaration of Helsinki. The trial was registered at www.clinicaltrials.gov as #NCT03764228.

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Yang, Pj., Zhao, Xy., Kou, Yh. et al. Human amniotic epithelial stem cell is a cell therapy candidate for preventing acute graft-versus-host disease. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01283-y

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