Journal Article

Identification of a Novel ECM Remodeling Macrophage Subset in AKI to CKD Transition by Integrative Spatial and Single‐Cell Analysis

Wu, Min, Crowley, Steven D., Zhang, Yi‐Lin, Feng, Ye, Jiang, Wei, Wu, Qiu‐Li, Liu, Bi‐Cheng, Lv, Lin‐Li, Wang, Bin, Yin, Qing, Li, Zuo‐Lin, Tang, Tao‐Tao, Zhang, Yue, Lan, Hui‐Yao, Song, Jing, Wen, Yi

2024

Overview

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is a critical clinical issue. Although previous studies have suggested macrophages as a key player in promoting inflammation and fibrosis during this transition, the heterogeneity and dynamic characterization of macrophages are still poorly understood. Here, we used integrated single‐cell RNA sequencing and spatial transcriptomic to characterize the spatiotemporal heterogeneity of macrophages in murine AKI‐to‐CKD model of unilateral ischemia‐reperfusion injury. A marked increase in macrophage infiltration at day 1 was followed by a second peak at day 14 post AKI. Spatiotemporal profiling revealed that injured tubules and macrophages co‐localized early after AKI, whereas in late chronic stages had spatial proximity to fibroblasts. Further pseudotime analysis revealed two distinct lineages of macrophages in this transition: renal resident macrophages differentiated into the pro‐repair subsets, whereas infiltrating monocyte‐derived macrophages contributed to chronic inflammation and fibrosis. A novel macrophage subset, extracellular matrix remodeling‐associated macrophages (EAMs) originating from monocytes, linked to renal fibrogenesis and communicated with fibroblasts via insulin‐like growth factors (IGF) signalling. In sum, our study identified the spatiotemporal dynamics of macrophage heterogeneity with a unique subset of EAMs in AKI‐to‐CKD transition, which could be a potential therapeutic target for preventing CKD development. This study sheds new light on the heterogeneous roles of macrophages in the complex and cumbersome pathological process of AKI to CKD. Integrating high‐throughput spatial and single‐cell transcriptomic data, the study identifies distinct macrophage lineages, with renal resident macrophages promoting repair and monocyte‐derived ECM remodeling macrophages (EAMs) contributing to renal fibrogenesis. These findings pave the way for the development of innovative therapeutic strategies to halt disease progression.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Acute Kidney Injury - metabolism / Acute Kidney Injury - pathology / AKI / Angiogenesis / Animals / Cells / CKD / Cytokines / Disease Models, Animal / Disease Progression / Extracellular Matrix - metabolism / Fibroblasts / Fibrosis - metabolism / Inflammation / Ischemia / Kidney diseases / macrophage / Macrophages - metabolism / Male / Mice / Mice, Inbred C57BL / Renal Insufficiency, Chronic - metabolism / Renal Insufficiency, Chronic - pathology / Single-Cell Analysis - methods / single‐cell RNA‐seq / spatial transcriptomic / Wound healing