Chen Zesong, Yang Chen, Ji Jiang, Chen Miao, Han Bing
Department of Hematology Peking Union Medical College Hospital Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China.
Department of Oncology Cancer Hospital Chinese Academy of Medical Sciences Shenzhen Hospital, Shenzhen, China.
Stem Cells Int. 2024 Aug 12;2024:4095268. doi: 10.1155/2024/4095268. eCollection 2024.
To explore the efficacy and the mechanism of the umbilical cord-derived cells combined with cyclosporine A (CsA) in treating aplastic anemia (AA) in mice.
Immune-mediated AA model mice were treated with CsA + UC mesenchymal stem cells (UC-MSC), CsA + umbilical cord blood regulatory T cells (UCB-T), UC-MSC, UCB-T, CsA alone, or blank control, respectively ( = 9 mice/group). CsA and the cell infusion was administered on d0. Routine peripheral blood testing was performed once weekly; bone marrow colony culture, bone marrow cell flow cytometry, peripheral blood T cell subsets, and serum inflammatory cytokines tests were performed on d14. Transcriptome sequencing was performed for cells from CsA + UC-MSC, CsA + UCB-T, and CsA groups to detect the possible related genes. Gene function cluster and signal pathway enrichment analysis were also performed.
Blank control mice died due to pancytopenia within 21 days, whereas mice in other groups survived for >28 days. On d14, the CsA + UC-MSC and CsA + UCB-T groups had higher white blood cell (WBC) counts than the other groups ( < 0.05), along with higher burst-forming unit (BFU) and colony-forming unit-granulocyte, macrophage (CFU-GM) counts ( < 0.01). The CsA + UC-MSC group had the highest BFU count ( < 0.01). The CsA + UC-MSC and CsA + UCB-T groups exhibited the highest bone marrow CD34 cell proportion (9.68% ± 1.35% and 8.17% ± 0.53%, respectively; < 0.01). Tumor necrosis factor (TNF)- and interleukin (IL)-2 levels in the CsA + UC-MSC group ( < 0.05) and TNF-, interleukin-2, and interferon (INF)- levels in the CsA + UC-T group ( < 0.01) were lower than those in the CsA group. Compared with CsA treatment, CsA + UC-MSC significantly downregulated the histone methylation pathway ( < 0.05), whereas CsA + UCB-T significantly upregulated energy metabolism processes ( < 0.05). Treatment with CsA + UC-MSC upregulated superoxide dismutase activity compared with CsA + UCB-T treatment.
Adding UC-MSC or UCB-T to CsA markedly enhanced the reconstruction of hematopoiesis in AA mice, with UC-MSC eliciting greater efficiency than UCB-T. Accordingly, the addition of these cells could further improve immune abnormalities.
探讨脐带源细胞联合环孢素A（CsA）治疗小鼠再生障碍性贫血（AA）的疗效及机制。
将免疫介导的AA模型小鼠分别用CsA +脐带来源间充质干细胞（UC-MSC）、CsA +脐带血调节性T细胞（UCB-T）、UC-MSC、UCB-T、单独CsA或空白对照进行治疗（每组n = 9只小鼠）。在第0天给予CsA和细胞输注。每周进行一次常规外周血检测；在第14天进行骨髓集落培养、骨髓细胞流式细胞术、外周血T细胞亚群及血清炎性细胞因子检测。对CsA + UC-MSC、CsA + UCB-T和CsA组的细胞进行转录组测序以检测可能的相关基因。还进行了基因功能聚类和信号通路富集分析。
空白对照小鼠在21天内死于全血细胞减少，而其他组小鼠存活超过28天。在第14天，CsA + UC-MSC组和CsA + UCB-T组的白细胞（WBC）计数高于其他组（P < 0.05），同时爆式集落形成单位（BFU）和粒-巨噬细胞集落形成单位（CFU-GM）计数也更高（P < 0.01）。CsA + UC-MSC组的BFU计数最高（P < 0.01）。CsA + UC-MSC组和CsA + UCB-T组的骨髓CD34 +细胞比例最高（分别为9.68% ± 1.35%和8.17% ± 0.53%；P < 0.01）。CsA + UC-MSC组的肿瘤坏死因子（TNF）-α和白细胞介素（IL）-2水平（P < 0.05）以及CsA + UCB-T组的TNF-α、白细胞介素-2和干扰素（INF）-γ水平（P < 0.01）低于CsA组。与CsA治疗相比，CsA + UC-MSC显著下调组蛋白甲基化途径（P < 0.05），而CsA + UCB-T显著上调能量代谢过程（P < 0.05）。与CsA + UCB-T治疗相比，CsA + UC-MSC治疗上调了超氧化物歧化酶活性。
在CsA基础上添加UC-MSC或UCB-T可显著增强AA小鼠的造血重建，其中UC-MSC的效率高于UCB-T。因此，添加这些细胞可进一步改善免疫异常。
