Trajectory Analysis of Proximal Tubule Cells Reveals a VCAM1+, THY1+, PROM1+ Transitional State in the Kidneys

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Background: Proximal tubule (PT) cells are fundamental to maintaining fluid, electrolyte, and nutrient balance in the kidney. Defining their health states and response to injury is crucial to understand the pathogenesis of kidney disease. THY1 is a stem cell marker that is highly expressed in PTs. PROM1 and VCAM1 are markers associated with kidney injury and repair. This study examines the dynamics of VCAM1, THY1 and PROM1 expression using spatial protein imaging. Methods: CODEX imaging was conducted on 49 human kidney tissues with 41 markers from KPMP and HuBMAP. Samples were scaled, integrated, and clustered using an established pipeline. Clusters with high expression of THY1, PROM1, and VCAM1 were identified. Trajectory analysis for the VCAM1 enriched cluster was performed using Slingshot package. Results: Our findings confirm the increase of PROM1 and a reduction of THY1 expression during chronic kidney disease. High expression of VCAM1 was observed in THY1+PROM1+ PT cells (figure1b-d). Trajectory analysis starting from VCAM1+ cluster reveals four paths: two towards healthy PTs (Trajectories 1 and 2), one towards PROM1+PT (Trajectory 3), and another towards THY1+PT (Trajectory 4)(figure1e). Trajectory 4 is the major lineage carrying the larger number of cells (figure 4j). Pseudotime protein expression analysis demonstrates consistent THY1 expression in Trajectory 4, transitioning from triple-positive PTs to THY1+PTs, while VCAM1 and PROM1 expression were reduced along this trajectory. Conversely, Trajectory 3 maintains high PROM1 expression leading to PROM1+PTs, with decreasing VCAM1 and THY1 expression. Conclusion: VCAM1 is expressed during a transitional injury stage in PTs, co-expressed with THY1 and PROM1. Analyzing VCAM1 in association with these markers provides a better understanding of injury states. Funding: NIDDK Support - NIDDK Support, NIDDK Support

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