Decoding myofibroblast origins in human kidney fibrosis

Area of Science:

• Nephrology
• Cell Biology
• Genomics

Background:

• Kidney fibrosis is a primary driver of chronic kidney disease (CKD) progression.
• Current therapeutic options for kidney fibrosis are limited, highlighting an unmet clinical need.
• The cellular sources and regulation of scar-forming cells in human kidney fibrosis are not well understood.

Purpose of the Study:

• To comprehensively map cellular populations in healthy and fibrotic human kidneys.
• To identify the specific cell types responsible for myofibroblast differentiation during kidney fibrosis.
• To discover potential therapeutic targets for antifibrotic treatments.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of human kidney cells.
• Genetic fate-tracing and time-course scRNA-seq in mouse models.
• Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) in mice.
• Spatial transcriptomics of human fibrotic kidney tissue.

Main Results:

• High-resolution mapping of matrix-producing cells in the human kidney.
• Identification of distinct pericyte and fibroblast subpopulations as major sources of myofibroblasts.
• Elucidation of the cellular origins and differentiation pathways of myofibroblasts.
• Discovery of NKD2 as a myofibroblast-specific target.

Conclusions:

• Pericytes and fibroblasts are key cellular precursors of myofibroblasts in human kidney fibrosis.
• Understanding these cellular dynamics provides insights into fibrosis mechanisms.
• NKD2 represents a promising therapeutic target for treating kidney fibrosis.