Chilmi Syahrul, Fauziah Dina, Khrisna Matthew Brian, Fauziah Ifa, Supriyanto Friska, Handono Kusworini, Sunjaya Kevin Reinaldo, Wijaya Wimardy Leonard, Aidid Mustofa, Susianti Hani
Clinical Pathology Department, Faculty of Medicine Brawijaya University/Dr. Saiful Anwar General Hospital, Malang, Indonesia.
J Blood Med. 2025 Jun 4;16:269-277. doi: 10.2147/JBM.S499999. eCollection 2025.
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by damaged and dysregulated immune system due to breakdown in the selection process during clonal growth of immune cells. Studies have shown that patients with systemic lupus erythematosus (SLE) display altered gene expression patterns and increased double-stranded DNA breaks within their hematopoietic stem and progenitor cells (HSPC). However, the current animal models for SLE found in the existing literature predominantly emphasize the use of peripheral blood mononuclear cells (PBMC) over HSPC for the creation of humanized mouse models. Nevertheless, these prior models were constrained by the limited efficiency of human cell engraftment and limited PBMC ability to replicate the capacity of HSPC to generate human SLE cells that can engraft host mice, thus making the transplant protocol inadequate.
Transplantation was initiated by extracting HSPC from stable SLE patients by leukapheresis. The collected cells were assessed for purity before storage at -80 °C. Humanized mice were conditioned with cyclophosphamide and total-body irradiation before receiving the HSPC transplant. After transplantation, the mice were administered human granulocyte-colony stimulating factor and sacrificed to evaluate autoantibodies and HSPC in their bone marrow and blood samples. Statistical analysis was performed using Student's -test and one-way ANOVA.
Upon human stem cells engravement into mice, we found a noteworthy presence of HSPC, as evidenced by the positive expression of hCD45, hCD34, and/or hCD44, and the production of human antinuclear antibodies. The results indicated that the transplanted mice generated reactive autoantibodies against human cells, similar to that observed in the human donor patient. These findings shed light on the survival and behavior of transplanted human stem cells in a mouse model.
In this study, we successfully induced immunodeficiency in mice for xenotransplantation with human peripheral stem cells.
系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是由于免疫细胞克隆生长过程中选择过程的破坏，导致免疫系统受损和失调。研究表明，系统性红斑狼疮（SLE）患者的造血干细胞和祖细胞（HSPC）中基因表达模式改变，双链DNA断裂增加。然而，现有文献中发现的当前SLE动物模型主要强调使用外周血单核细胞（PBMC）而非HSPC来创建人源化小鼠模型。尽管如此，这些先前的模型受到人类细胞植入效率有限以及PBMC复制HSPC产生可植入宿主小鼠的人类SLE细胞能力的限制，因此使得移植方案不充分。
通过白细胞分离术从稳定的SLE患者中提取HSPC开始移植。收集的细胞在储存在-80°C之前评估纯度。在接受HSPC移植之前，用人源化小鼠进行环磷酰胺和全身照射预处理。移植后，给小鼠注射人粒细胞集落刺激因子，并处死以评估其骨髓和血液样本中的自身抗体和HSPC。使用学生t检验和单因素方差分析进行统计分析。
当人类干细胞植入小鼠体内时，我们发现HSPC显著存在，hCD45、hCD34和/或hCD44的阳性表达以及人类抗核抗体的产生证明了这一点。结果表明，移植的小鼠产生了针对人类细胞的反应性自身抗体，类似于在人类供体患者中观察到的情况。这些发现揭示了移植的人类干细胞在小鼠模型中的存活和行为。
在本研究中，我们成功地诱导了小鼠的免疫缺陷，用于与人外周干细胞的异种移植。
