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

ABSTRACT: With the increasing incidence of kidney diseases, there is an urgent need to develop therapeutic strategies to combat post-injury fibrosis. Immune cells, including platelets, play a pivotal role in this repair process, primarily through their released cytokines. However, the specific role of platelets in kidney injury and subsequent repair remains underexplored. Here, our research underscores the detrimental role of platelets in renal recovery following ischemia/reperfusion injury. We show that depleting platelets accelerates injury resolution and significantly reduces fibrosis. Employing advanced single-cell and spatial transcriptomic techniques, we identify macrophages as the primary mediators modulated by platelet signals. We uncover 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 shaped by platelet-derived thrombospondin 1 (THBS1) signaling, acquiring profibrotic characteristics. Conversely, strategic inhibition of THBS1, achieved through either genetic deletion or pharmacologic suppression, markedly downregulates the cycling M2 macrophage, thereby mitigating fibrotic progression. Overall, 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 inflammation and kidney fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE271934 | GEO | 2025/07/15

REPOSITORIES: GEO

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