Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Hematology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Transplant Cell Ther. 2024 Feb;30(2):189.e1-189.e13. doi: 10.1016/j.jtct.2023.11.005. Epub 2023 Nov 7.
Acute graft-versus-host disease (aGVHD) represents a fatal severe complication after allogeneic hematopoietic stem cell transplantation. As a promising cell therapeutic strategy of aGVHD, the mechanism of mesenchymal stem cells (MSC) to ameliorate aGVHD has not been fully clarified, especially in the field of intestinal homeostasis including the intestinal microbiome involved in the pathogenesis of aGVHD. The present study aimed to explore the effect of MSC on intestinal homeostasis including the intestinal barrier and intestinal microbiome and its metabolites, as well as the role of intestinal microbiome in the preventive process of hAMSCs ameliorating aGVHD. The preventive effects of human amniotic membrane-derived MSC (hAMSCs) was assessed in humanized aGVHD mouse models. Immunohistochemistry and RT-qPCR were used to evaluate intestinal barrier function. The 16S rRNA sequencing and targeted metabolomics assay were performed to observe the alternation of intestinal microbiome and the amounts of medium-chain fatty acids (MCFAs) and short-chain fatty acids (SCFAs), respectively. Flow cytometry was performed to analyze the frequencies of T immune cells. Through animal experiments, we found that hAMSCs had the potential to prevent aGVHD. HAMSCs could repair the damage of intestinal barrier structure and function, as well as improve the dysbiosis of intestinal microbiome induced by aGVHD, and meanwhile, upregulate the concentration of metabolites SCFAs, so as to reshape intestinal homeostasis. Gut microbiota depletion and fecal microbial transplantation confirmed the involvement of intestinal microbiome in the preventive process of hAMSCs on aGVHD. Our findings showed that hAMSCs prevented aGVHD in an intestinal microbiome-dependent manner, which might shed light on a new mechanism of hAMSCs inhibiting aGVHD and promote the development of new prophylaxis regimes for aGVHD prevention.
急性移植物抗宿主病（aGVHD）是异基因造血干细胞移植后致命的严重并发症。间充质干细胞（MSC）作为一种有前途的 aGVHD 细胞治疗策略，其改善 aGVHD 的机制尚未完全阐明，特别是在涉及肠道微生物组的肠道内稳态领域，而肠道微生物组参与了 aGVHD 的发病机制。本研究旨在探讨 MSC 对肠道内稳态（包括肠道屏障和肠道微生物组及其代谢物）的影响，以及肠道微生物组在 hAMSCs 预防 aGVHD 中的作用。在人源化 aGVHD 小鼠模型中评估了人羊膜源性 MSC（hAMSCs）的预防作用。免疫组织化学和 RT-qPCR 用于评估肠道屏障功能。通过 16S rRNA 测序和靶向代谢组学检测分别观察肠道微生物组和中链脂肪酸（MCFAs）和短链脂肪酸（SCFAs）含量的变化。流式细胞术用于分析 T 免疫细胞的频率。通过动物实验，我们发现 hAMSCs 具有预防 aGVHD 的潜力。hAMSCs 可以修复由 aGVHD 引起的肠道屏障结构和功能的损伤，改善肠道微生物组的失调，同时上调代谢物 SCFAs 的浓度，从而重塑肠道内稳态。肠道微生物组耗竭和粪便微生物移植证实了肠道微生物组在 hAMSCs 预防 aGVHD 中的作用。我们的研究结果表明，hAMSCs 以肠道微生物组依赖的方式预防 aGVHD，这可能为 hAMSCs 抑制 aGVHD 的新机制提供了线索，并促进了预防 aGVHD 的新预防方案的发展。
