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  3. Targeting ECM-producing cells with CAR-T therapy alleviates fibrosis in chronic kidney disease

Targeting ECM-producing cells with CAR-T therapy alleviates fibrosis in chronic kidney disease

  • Cell Stem Cell. 2025 Sep 4;32(9):1390-1402.e9. doi: 10.1016/j.stem.2025.07.014.
Songbo Zhao 1,  Rongkun Li 1,  Yuan Xia 2,  Xiaojie Wang 1,  Zhiyong Liu 1,  Qingqing Chu 1,  Jiman He 1,  Jiaying Zhang 1,  Yixuan Guo 3,  Youzhao Wang 1,  Jichao Wu 1,  Yan Zhang 1,  Ziying Wang 1,  Zhiyue Zhang 3,  Rui Zeng 4,  Chun Zhang 5,  Jicheng Lv 6,  Jinpeng Sun 7,  Wei Tang 8,  Fan Yi 9
Affiliations

Affiliations

  • 1 Department of Pharmacology, The Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
  • 2 Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 3 Department of Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
  • 4 Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 5 Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 6 Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing 100034, China.
  • 7 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China. Electronic address: sunjinpeng@sdu.edu.cn.
  • 8 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 Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China. Electronic address: weitang@sdu.edu.cn.
  • 9 Department of Pharmacology, The Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan 250012, China; National Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan 250012, China. Electronic address: fanyi@sdu.edu.cn.
PMID: 40848726 DOI: 10.1016/j.stem.2025.07.014
Abstract

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.

Keywords

PDGFRβ; cell therapy; extracellular matrix; kidney fibrosis; organoids.

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