Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population

Michael G Michalopulos; Yan Liu; Dinesh Ravindra Raju; John T Lafin; Yanru Ma; Dhruv Gaur; Sadiksha Khadka; Chao Xing; Andrew P McMahon; Thomas J Carroll; Keri A Drake

doi:10.1242/dev.204964

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Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population

Journal article

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Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population

Michael G Michalopulos, Yan Liu, Dinesh Ravindra Raju, John T Lafin, Yanru Ma, Dhruv Gaur, Sadiksha Khadka, Chao Xing, Andrew P McMahon, Thomas J Carroll, …

Development (Cambridge), Vol.153(1), dev204964

12/08/2025

DOI: 10.1242/dev.204964

PMCID: PMC12848570

PMID: 41358813

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Abstract

The Foxd1+ stromal progenitor cells gives rise to the majority of the renal interstitium; yet, much remains to be understood about how this self-renewing progenitor population is regulated during development. Here, we demonstrate that disruption of the NPC lineage via loss of Wt1 (i.e., Six2cre;Wt1c/c) results in an expansion of Foxd1+ progenitor cells. Analyses of two additional models (i.e., Wnt4-null mutants, which fail to form nephron structures similar to Six2cre;Wt1c/c kidneys, and NPC ablation via diphtheria toxin using the Six2cre;RosaDTAc/+) phenocopy the expansion Foxd1+ cells and further confirm that mutant kidneys with defects in nephrogenesis develop an abnormal increase in the stromal progenitor population. Furthermore, single nuclei RNA-sequencing shows transcriptional changes in the Foxd1+ progenitor cells from Six2cre;Wt1c/c kidneys and identifies a distinct subcluster of the Foxd1+ stroma, which is maintained independent of signals from the nephrogenic niche in the Six2cre;RosaDTAc/+ model. Overall, these findings provide insights into the developmental regulation of the stromal progenitor population and uncover heterogeneity within the Foxd1+ cells, which undergo both cellular and molecular changes in response to defects in nephrogenesis.

Foxd1

Stromal progenitor cells

Wt1

Wnt4

Kidney development

Details

Title: Subtitle: Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population
Creators: Michael G Michalopulos - The University of Texas Southwestern Medical Center
Yan Liu - The University of Texas Southwestern Medical Center
Dinesh Ravindra Raju - The University of Texas Southwestern Medical Center
John T Lafin - The University of Texas Southwestern Medical Center
Yanru Ma - The University of Texas Southwestern Medical Center
Dhruv Gaur - The University of Texas Southwestern Medical Center
Sadiksha Khadka - The University of Texas Southwestern Medical Center
Chao Xing - The University of Texas Southwestern Medical Center
Andrew P McMahon - University of Southern California
Thomas J Carroll - The University of Texas Southwestern Medical Center
Keri A Drake - The University of Texas Southwestern Medical Center
Resource Type: Journal article
Publication Details: Development (Cambridge), Vol.153(1), dev204964
DOI: 10.1242/dev.204964
PMID: 41358813
PMCID: PMC12848570
NLM abbreviation: Development
ISSN: 1477-9129
eISSN: 1477-9129
Publisher: The Company of Biologists; CAMBRIDGE
Grant note: P30DK079328 / NIDDK NIH HHS K08DK131258 / NIDDK NIH HHS RC2DK125960 / NIDDK NIH HHS WU-20-101 / Chan Zuckerberg Initiative DK054364 / NIDDK NIH HHS
Language: English
Electronic publication date: 12/08/2025
Academic Unit: Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics
Record Identifier: 9985091803102771

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