Tracing the origin of myofibroblasts in kidney fibrosis

Area of Science:

• Nephrology
• Cell Biology
• Fibrosis Research

Background:

• Kidney fibrosis, a hallmark of chronic kidney disease (CKD), involves myofibroblast accumulation.
• The cellular origins of these myofibroblasts, particularly through mesenchymal transition processes like EMT, EndoMT, and MMT, have been debated.
• Understanding myofibroblast origins is crucial for developing effective CKD therapies.

Purpose of the Study:

• To systematically investigate the cellular origin of myofibroblasts during kidney fibrosis.
• To differentiate between established mesenchymal transition pathways and other cellular contributions.
• To identify the precise cell types involved in myofibroblast generation in fibrotic kidneys.

Main Methods:

• Utilized advanced renal cell lineage tracing tools to track cell origins during kidney fibrosis.
• Developed and applied novel dual recombinase-mediated lineage tracing systems: EMTracer, EndoMTracer, and MMTracer.
• Analyzed cell transitions including epithelial-mesenchymal transition (EMT), endothelial-mesenchymal transition (EndoMT), and macrophage-mesenchymal transition (MMT).

Main Results:

• Found no evidence of EMT, EndoMT, or MMT contributing to myofibroblast populations in kidney fibrosis.
• Identified resident fibroblasts as the primary source of myofibroblasts.
• Observed reversible partial mesenchymal transition predominantly in renal urothelial cells (UroCs) and parietal epithelial cells (PECs).

Conclusions:

• Resident fibroblasts are the principal source of myofibroblasts in kidney fibrosis.
• Mesenchymal transition is not a significant contributor to myofibroblast formation via EMT, EndoMT, or MMT in this context.
• Partial mesenchymal transition occurs in urothelial and parietal epithelial cells, offering new perspectives for CKD diagnosis and treatment strategies.