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Neuronally differentiated macula densa cells regulate tissue remodeling and regeneration in the kidney

2024; American Society for Clinical Investigation; Volume: 134; Issue: 11 Linguagem: Inglês

10.1172/jci174558

1558-8238

Georgina Gyarmati, Urvi Nikhil Shroff, Anne Riquier‐Brison, Dorinne Desposito, Wenjun Ju, Sean D. Stocker, Audrey Izuhara, Sachin Deepak, Alejandra Becerra Calderon, James L. Burford, Hiroyuki Kadoya, Ju‐Young Moon, Yibu Chen, Markus M. Rinschen, Nariman Ahmadi, Lester F. Lau, Daniel Biemesderfer, Aaron W. James, Liliana Minichiello, Berislav V. Zloković, Inderbir S. Gill, Matthias Kretzler, János Peti‐Peterdi,

Tissue Engineering and Regenerative Medicine

Tissue regeneration is limited in several organs including the kidney, contributing to the high prevalence of kidney disease globally. However, evolutionary and physiological adaptive responses and the presence of renal progenitor cells suggest existing remodeling capacity. This study uncovered endogenous tissue remodeling mechanisms in the kidney that were activated by the loss of body fluid and salt and regulated by a unique niche of a minority renal cell type called the macula densa (MD). Here we identified neuronal differentiation features of MD cells that sense the local and systemic environment, secrete angiogenic, growth and extracellular matrix remodeling factors, cytokines and chemokines, and control resident progenitor cells. Serial intravital imaging, MD nerve growth factor receptor and Wnt mouse models and transcriptome analysis revealed cellular and molecular mechanisms of these MD functions. Human and therapeutic translation studies illustrated the clinical potential of MD factors including CCN1 as a urinary biomarker and therapeutic target in chronic kidney disease. The concept that a neuronally differentiated key sensory and regulatory cell type responding to organ-specific physiological inputs controls local progenitors to remodel or repair tissues may be applicable to other organs and diverse tissue regenerative therapeutic strategies.