Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, 21205, USA.
Stem Cell Res Ther. 2023 Jun 25;14(1):167. doi: 10.1186/s13287-023-03380-x.
Acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transplantation of immunosuppressive human mesenchymal stromal cells (hMSCs) can protect against aGvHD post-HSCT; however, their efficacy is limited by poor engraftment and survival. Moreover, infused MSCs can be damaged by activated complement, yet strategies to minimise complement injury of hMSCs and improve their survival are limited.
Human MSCs were derived from bone marrow (BM), adipose tissue (AT) and umbilical cord (UC). In vitro immunomodulatory potential was determined by co-culture experiments between hMSCs and immune cells implicated in aGvHD disease progression. BM-, AT- and UC-hMSCs were tested for their abilities to protect aGvHD in a mouse model of this disease. Survival and clinical symptoms were monitored, and target tissues of aGvHD were examined by histopathology and qPCR. Transplanted cell survival was evaluated by cell tracing and by qPCR. The transcriptome of BM-, AT- and UC-hMSCs was profiled by RNA-sequencing. Focused experiments were performed to compare the expression of complement inhibitors and the abilities of hMSCs to resist complement lysis.
Human MSCs derived from three tissues divergently protected against aGvHD in vivo. AT-hMSCs preferentially suppressed complement in vitro and in vivo, resisted complement lysis and survived better after transplantation when compared to BM- and UC-hMSCs. AT-hMSCs also prolonged survival and improved the symptoms and pathological features of aGvHD. We found that complement-decay accelerating factor (CD55), an inhibitor of complement, is elevated in AT-hMSCs and contributed to reduced complement activation. We further report that atorvastatin and erlotinib could upregulate CD55 and suppress complement in all three types of hMSCs.
CD55, by suppressing complement, contributes to the improved protection of AT-hMSCs against aGvHD. The use of AT-hMSCs or the upregulation of CD55 by small molecules thus represents promising new strategies to promote hMSC survival to improve the efficacy of transplantation therapy. As complement injury is a barrier to all types of hMSC therapy, our findings are of broad significance to enhance the use of hMSCs for the treatment of a wide range of disorders.
急性移植物抗宿主病（aGvHD）是异基因造血干细胞移植（HSCT）后的一种危及生命的并发症。移植免疫抑制性人间质基质细胞（hMSCs）可预防 HSCT 后发生 aGvHD；然而，其疗效受到植入和存活不良的限制。此外，输注的 MSC 可被激活的补体损伤，但减少 hMSC 补体损伤和提高其存活率的策略有限。
人 MSC 源自骨髓（BM）、脂肪组织（AT）和脐带（UC）。通过 MSC 与参与 aGvHD 疾病进展的免疫细胞共培养实验，确定其体外免疫调节潜力。在该疾病的小鼠模型中，检测 BM、AT 和 UC-hMSC 保护 aGvHD 的能力。监测存活和临床症状，并通过组织病理学和 qPCR 检查 aGvHD 的靶组织。通过细胞追踪和 qPCR 评估移植细胞的存活。通过 RNA-seq 对 BM、AT 和 UC-hMSC 的转录组进行分析。进行了重点实验以比较补体抑制剂的表达和 hMSC 抵抗补体溶解的能力。
源自三种组织的人 MSC 在体内以不同的方式保护免受 aGvHD。与 BM 和 UC-hMSC 相比，AT-hMSC 优先在体外和体内抑制补体，抵抗补体溶解，移植后存活更好。AT-hMSC 还延长了存活时间，并改善了 aGvHD 的症状和病理特征。我们发现补体衰变加速因子（CD55），一种补体抑制剂，在 AT-hMSC 中升高，并有助于减少补体激活。我们进一步报告阿托伐他汀和厄洛替尼可以上调 CD55 并抑制所有三种类型的 hMSC 中的补体。
CD55 通过抑制补体，有助于 AT-hMSC 改善对 aGvHD 的保护。因此，使用 AT-hMSC 或通过小分子上调 CD55 代表了促进 hMSC 存活以提高移植治疗疗效的有前途的新策略。由于补体损伤是所有类型的 hMSC 治疗的障碍，因此我们的研究结果对于增强 hMSC 治疗广泛疾病的应用具有广泛意义。
