Yuan Mengqin, Yin Zhengrong, Wang Zheng, Xiong Zhiyu, Chen Ping, Yao Lichao, Liu Pingji, Sun Muhua, Shu Kan, Li Lanjuan, Jiang Yingan
Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Wuhan 430000, China; Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Research Center for Medical Imaging in Hubei Province, Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
Department of Respiratory and Critical Care Medicine, Key Laboratory of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Biomaterials. 2025 Oct;321:123295. doi: 10.1016/j.biomaterials.2025.123295. Epub 2025 Mar 28.
Mesenchymal stem cells (MSCs) hold significant therapeutic potential for liver fibrosis but face translational challenges due to suboptimal homing efficiency and poor retention at injury sites. Activated hepatic stellate cells (aHSCs), the primary drivers of fibrogenesis, overexpress platelet-derived growth factor receptor-beta (PDGFRB), a validated therapeutic target in liver fibrosis. Here, we engineered pPB peptide-functionalized MSCs (pPB-MSCs) via hydrophobic insertion of DMPE-PEG-pPB (DPP) into the MSC membrane, creating a targeted "MSC-pPB-aHSC" delivery system. Our findings demonstrated that pPB modification preserved MSC viability, differentiation potential, and paracrine functions. pPB-MSCs exhibited higher binding affinity to TGF-β1-activated HSCs in vitro and greater hepatic accumulation in TAA-induced fibrotic mice, as quantified by in vivo imaging. Moreover, pPB-MSCs attenuated collagen deposition, suppressed α-SMA HSCs, and restored serum ALT/AST levels to near-normal ranges. Mechanistically, pPB-MSCs promoted hepatocyte regeneration via HGF upregulation, inhibited epithelial-mesenchymal transition through TGF-β/Smad pathway suppression, and polarized macrophages toward an M2 phenotype, reducing pro-inflammatory IL-6/TNF-α while elevating anti-inflammatory IL-10. Overall, our study raised a non-genetic MSC surface engineering strategy that synergizes PDGFRB-targeted homing with multifactorial tissue repair, addressing critical barriers in cell therapy for liver fibrosis. By achieving enhanced spatial delivery without compromising MSC functionality, our approach provides a clinically translatable platform for enhancing regenerative medicine outcomes.
间充质干细胞（MSCs）对肝纤维化具有显著的治疗潜力，但由于归巢效率欠佳以及在损伤部位的留存率低，面临着转化应用方面的挑战。肝星状细胞（aHSCs）被激活是纤维化形成的主要驱动因素，其过度表达血小板衍生生长因子受体-β（PDGFRB），这是肝纤维化中一个经过验证的治疗靶点。在此，我们通过将DMPE-PEG-pPB（DPP）疏水插入MSC膜中，构建了pPB肽功能化的MSCs（pPB-MSCs），创建了一个靶向性的“MSC-pPB-aHSC”递送系统。我们的研究结果表明，pPB修饰保留了MSC的活力、分化潜能和旁分泌功能。体外实验中，pPB-MSCs对转化生长因子-β1激活的肝星状细胞表现出更高的结合亲和力，在TAA诱导的纤维化小鼠体内成像显示其肝脏蓄积量更大。此外，pPB-MSCs减轻了胶原沉积，抑制了α-SMA阳性的肝星状细胞，并使血清谷丙转氨酶/谷草转氨酶水平恢复至接近正常范围。机制上，pPB-MSCs通过上调HGF促进肝细胞再生，通过抑制TGF-β/Smad信号通路抑制上皮-间质转化，并使巨噬细胞极化为M2表型，减少促炎细胞因子IL-6/TNF-α，同时提高抗炎细胞因子IL-10。总体而言，我们的研究提出了一种非基因的MSC表面工程策略，该策略将靶向PDGFRB的归巢与多因素组织修复协同起来，解决了肝纤维化细胞治疗中的关键障碍。通过在不损害MSC功能的情况下实现增强的空间递送，我们的方法为改善再生医学疗效提供了一个可临床转化的平台。
