Single cell profiling in COVID-19 associated acute kidney injury reveals patterns of tubule injury and repair in human

Abstract

The cellular mechanisms of kidney tubule repair are poorly characterized in human. Here, we applied single-nucleus RNA sequencing to analyze the kidney in the first days after acute injury in 5 critically ill patients with COVID-19. We identified abnormal proximal tubule cell states associated with injury, characterized by altered functional and metabolic profiles and by pro-fibrotic properties. Tubule repair involved the plasticity of mature tubule cells in a process of cell de-differentiation and re-differentiation, which displayed substantial similarities between mouse and man. In addition, in man we identified a peculiar tubule reparative response determining the expansion of progenitor-like cells marked by PROM1 and following a differentiation program characterized by the sequential activation of the WNT, NOTCH and HIPPO signaling pathways. Taken together, our analyses reveal cell state transitions and fundamental cellular hierarchies underlying kidney injury and repair in critically ill patients.

Urinary single-cell sequencing captures intrarenal injury and repair processes in human acute kidney injury

“…Our current understanding of TEC injury reaction assumes a dedifferentiation and redifferentiation after successful repair, which has been demonstrated for PT cells in several mouse models (5,8,9) and cells in human AKI biopsies have been reported to mirror this process (8). A central question is how this repair takes place and why it can fail.…”

“…Transcriptomic analyses in mouse AKI models on the single-cell level have rapidly enhanced and transformed our understanding of injured and recovering TEC states (5,6,(8)(9)(10). Recently the first biopsy-based human single-cell studies of the kidney and AKI have been reported (8,11,12). However, the invasive nature of kidney biopsies limits scalability and represents a hurdle for translation into clinical routine.…”

“…Transcriptomic analyses in mouse AKI models on the single-cell level have rapidly enhanced and transformed our understanding of injured and recovering TEC states (5,6,(8)(9)(10).…”

“…Recently the first biopsy-based human single-cell studies of the kidney and AKI have been reported (8,11,12). However, the invasive nature of kidney biopsies limits scalability and represents a hurdle for translation into clinical routine.…”

“…Transcriptomic analyses in mouse AKI models on the single-cell level have rapidly enhanced and transformed our understanding of injured and recovering TEC states (5, 6, 8–10). Recently the first biopsy-based human single-cell studies of the kidney and AKI have been reported (8, 11, 12). However, the invasive nature of kidney biopsies limits scalability and represents a hurdle for translation into clinical routine.…”