Single-Cell Spatial Transcriptomics Unveil Platelet-Fueled Cycling Macrophages for Kidney Fibrosis

Background: With the increasing incidence of kidney diseases, there is an urgent need to develop therapeutic strategies to combat post-injury fibrosis. Immune cells, including platelet, play a pivotal role in this repair process. However, the specific role of platelet in kidney injury and subsequent repair remains underexplored. Methods: The surgery of bilateral I/R-induced kidney injury was performed on Wild-type and Thbs1 knock-out mice to induce kidney injury and fibrosis. Single-cell and spatial transcriptomics and Magnetic Resonance Imaging (MRI) scanning were applied. Results: We show that depleting platelet accelerates injury resolution and significantly reduces fibrosis. We identify a novel subset of macrophages, termed"cycling M2", which exhibit an M2 phenotype combined with enhanced proliferative activity. This subset emerges in the injured kidney during the resolution phase and is modulated by platelet-derived THBS1 signaling, acquiring profibrotic characteristics. Targeted inhibition of THBS1 reduces the cycling M2 macrophage, thereby mitigating fibrotic progression. Conclusion: Our findings highlight the adverse role of platelet THBS1-boosted cycling M2 macrophages in renal injury repair and suggest platelet THBS1 as a promising therapeutic target for alleviating kidney fibrosis. Funding: Government Support – Non-U.S.