Human umbilical cord mesenchymal stem cells (hUC-MSCs) have shown potential as a therapeutic option for lupus nephritis (LN), particularly in patients refractory to conventional treatments. Despite extensive translational research on MSCs, the precise mechanisms by which MSCs migrate to the kidney and restore renal function remain incompletely understood. Here, we aim to clarify the spatiotemporal characteristics of hUC-MSC migration into LN kidneys and their interactions with host cells in microenvironment. This study elucidates that the migration of hUC-MSCs to the LN kidney is driven by elevated levels of CXCL10, predominantly produced by glomerular vascular endothelial cells through the IFN-γ/IRF1-KPNA4 pathway. Interestingly, the blockade of CXCL10-CXCR3 axis impedes the migration of hUC-MSCs to LN kidney and negatively impacts therapeutic outcomes. Single cell-RNA sequencing analysis underscores the importance of this axis in mediating the regulatory effects of hUC-MSCs on the renal immune environment. Furthermore, hUC-MSCs have been observed to induce and secrete interleukin 4 inducible gene 1 (IL4I1) in response to the microenvironment of LN kidney, thereby suppressing Th1 cells. Genetically ablating IL4I1 in hUC-MSCs abolishes their therapeutic effects and prevents the inhibition of CXCR3⁺ Th1 cell infiltration into LN kidneys. This study provides valuable insights into the significant involvement of CXCL10-CXCR3 axis in hUC-MSC migration to the LN kidneys and the subsequent remodeling of renal immune microenvironment. Regulating the CXCL10-CXCR3 axis and IL4I1 secretion may be developed as a novel therapeutic strategy to improve treatment outcomes of LN.

人脐带间充质干细胞 （hUC-MSCs） 已显示出作为狼疮性肾炎 （LN） 治疗选择的潜力，尤其是在常规治疗难治性患者中。尽管对 MSC 进行了广泛的转化研究，但 MSC 迁移到肾脏并恢复肾功能的确切机制仍不完全清楚。在这里，我们旨在阐明 hUC-MSC 迁移到LN肾脏的时空特征以及它们与微环境中宿主细胞的相互作用。本研究阐明，hUC-MSC 向 LN 肾脏的迁移是由 CXCL10 水平升高驱动的，CXCL10 主要由肾小球血管内皮细胞通过 IFN-γ/IRF1-KPNA4 通路产生。有趣的是，CXCL10-CXCR3 轴的阻断阻碍了 hUC-MSCs 向 LN 肾脏的迁移，并对治疗结果产生负面影响。单细胞 RNA 测序分析强调了该轴在介导 hUC-MSC 对肾脏免疫环境的调节作用中的重要性。此外，已观察到 hUC-MSCs 响应 LN 肾脏的微环境诱导和分泌白细胞介素 4 诱导基因 1 （IL4I1），从而抑制 Th1 细胞。在 hUC-MSC 中遗传消融 IL4I1 会消除其治疗作用并防止抑制 CXCR3 ⁺ Th1 细胞浸润到 LN 肾脏。本研究为 CXCL10-CXCR3 轴在 hUC-MSC 向 LN 肾脏迁移以及随后的肾脏免疫微环境重塑中的重要参与提供了有价值的见解。调节 CXCL10-CXCR3 轴和 IL4I1 分泌可被开发为一种新的治疗策略，以改善 LN 的治疗结果。