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

TY - JOUR

T1 - Neuronally differentiated macula densa cells regulate tissue remodeling and regeneration in the kidney

AU - Gyarmati, Georgina

AU - Shroff, Urvi Nikhil

AU - Riquier-Brison, Anne

AU - Desposito, Dorinne

AU - Ju, Wenjun

AU - Stocker, Sean D

AU - Izuhara, Audrey

AU - Deepak, Sachin

AU - Becerra Calderon, Alejandra

AU - Burford, James L

AU - Kadoya, Hiroyuki

AU - Moon, Ju-Young

AU - Chen, Yibu

AU - Rinschen, Markus M

AU - Ahmadi, Nariman

AU - Lau, Lester

AU - Biemesderfer, Daniel

AU - James, Aaron W

AU - Minichiello, Liliana

AU - Zlokovic, Berislav V

AU - Gill, Inderbir S

AU - Kretzler, Matthias

AU - Peti-Peterdi, János

PY - 2024/4/10

Y1 - 2024/4/10

N2 - 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 an 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 and 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.

AB - 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 an 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 and 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.

KW - Animals

KW - Mice

KW - Humans

KW - Regeneration

KW - Cell Differentiation

KW - Kidney/metabolism

KW - Neurons/metabolism

KW - Renal Insufficiency, Chronic/pathology

KW - Male

U2 - 10.1172/JCI174558

DO - 10.1172/JCI174558

M3 - SCORING: Journal article

C2 - 38598837

VL - 134

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 11

M1 - e174558

ER -