Modification of MSCs with aHSCs-targeting peptide pPB for enhanced therapeutic efficacy in liver fibrosis

Abstract

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.

Keywords: Hepatic stellate cell; Human umbilical cord mesenchymal stem cell; Liver fibrosis; Living cell-surface modification; Platelet-derived growth factor receptor-beta polypeptide; pPB peptide.