Zhao Songbo, Li Rongkun, Xia Yuan, Wang Xiaojie, Liu Zhiyong, Chu Qingqing, He Jiman, Zhang Jiaying, Guo Yixuan, Wang Youzhao, Wu Jichao, Zhang Yan, Wang Ziying, Zhang Zhiyue, Zeng Rui, Zhang Chun, Lv Jicheng, Sun Jinpeng, Tang Wei, Yi Fan
Department of Pharmacology, The Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Cell Stem Cell. 2025 Sep 4;32(9):1390-1402.e9. doi: 10.1016/j.stem.2025.07.014. Epub 2025 Aug 22.
Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and a potential therapeutic target. However, clinical interventions and therapies targeting kidney fibrosis remain conceptual and practical challenges due to the complex origin, functional heterogeneity, and regulation of scar-forming cells. Here, we define fibroblasts, pericytes, and myofibroblasts as the major extracellular matrix (ECM)-producing cells in the kidney, highlighting their primary contribution to kidney fibrosis. We then identify platelet-derived growth factor receptor β (PDGFRβ) as a potential targeting surface antigen for anti-fibrotic chimeric antigen receptor (CAR)-T against CKD. In multiple mouse CKD models, both adoptive transfer and CD5-lipid nanoparticle (LNP)-mediated in vivo generation of PDGFRβ CAR-T cells significantly ameliorate fibrosis-associated pathologies, including kidney, myocardial interstitial, and perivascular fibrosis without notable toxicity, evoking an integrated therapeutic strategy for multi-organ fibrosis in mice with CKD and its cardiovascular complications. The anti-fibrotic effects are also demonstrated in the human kidney organoid CKD, further strongly supporting the therapeutic potential for the treatment of patients with CKD.
肾纤维化是慢性肾脏病（CKD）的一个标志，也是一个潜在的治疗靶点。然而，由于瘢痕形成细胞的起源复杂、功能异质性和调控机制，针对肾纤维化的临床干预和治疗仍然面临概念和实践上的挑战。在此，我们将成纤维细胞、周细胞和平滑肌肌成纤维细胞定义为肾脏中主要的细胞外基质（ECM）产生细胞，强调它们对肾纤维化的主要贡献。然后，我们将血小板衍生生长因子受体β（PDGFRβ）鉴定为针对CKD的抗纤维化嵌合抗原受体（CAR）-T细胞的潜在靶向表面抗原。在多个小鼠CKD模型中，过继转移和CD5-脂质纳米颗粒（LNP）介导的体内生成PDGFRβ CAR-T细胞均能显著改善纤维化相关病变，包括肾脏、心肌间质和血管周围纤维化，且无明显毒性，为患有CKD及其心血管并发症的小鼠的多器官纤维化引出了一种综合治疗策略。在人肾类器官CKD中也证实了抗纤维化作用，进一步有力地支持了治疗CKD患者的治疗潜力。
