Kidney Week

Abstract: SA-PO335

The Transcription Factor TCF21 Protects Stromal Cell Precursors During Kidney Development

Session Information

• Development, Organoids, Vascularized Kidneys, Nephrons, and More
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 600 Development, Stem Cells, and Regenerative Medicine

Authors

• Finer, Gal, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Gal Finer,

• Zhou, Yalu, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Yalu Zhou,

• Winter, Deborah R., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Deborah R. Winter,

• Gomez, Roberto Ariel, UVA Health, Charlottesville, Virginia, United States

Roberto Ariel Gomez,

• Sequeira Lopez, Maria Luisa S., UVA Health, Charlottesville, Virginia, United States

Maria Luisa S. Sequeira Lopez,

• Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Susan E. Quaggin,

Background

Normal kidney development requires coordinated interactions between multiple progenitor cells. Foxd1+ cells are critical for normal nephrogenesis and their heterogeneity is increasingly appreciated. However, the molecular mechanisms and trajectories that drive the differentiation of Foxd1+ cells toward the renal stroma, capsule, mesangial cells, renin cells, pericytes, and vascular smooth muscle cells (VSMCs) are poorly understood. Tcf21 is a mesoderm-specific bHLH transcription factor critical for embryogenesis.

Methods

To investigate the developmental origins of Tcf21 effects on stroma, we performed single-cell RNA sequencing (scRNA-seq) on GFP+ cells from E14.5 mTmG+;Foxd1Cre+;Tcf21^f/f kidneys and control kidneys.

Results

Clustering of the entire dataset identified a large stromal population and a smaller representation of non-stromal lineages. Subclustering of stromal cells identified eight populations: proliferating, medullary/perivascular, ‘Tcf21 mutant’, nephrogenic zone/ureter, nephrogenic zone, collecting duct, ureteric associated stroma, and metanephric mesenchyme. Loss of Tcf21 resulted in a dramatic reduction in the proliferating, medullary/perivascular, nephrogenic zone, and collecting duct associated stromal populations. Immunostaining confirmed that mutants had severe reduction in the medullary and collecting duct stromal space of mutants. A unique cluster, exclusively present in mutant kidneys and named ‘Tcf21 mutant’, expressed high levels of extracellular matrix (Spracl1, Fras1), perivascular cells (Rgs5, Akr1b7), and endothelial cells (Endomucin) genes. Mutant cells showed upregulation of pathways involved in extracellular matrix organization, VSMCs and fibroblast proliferation, and negative regulation of angiogenesis.

Conclusion

These data underscore a role for Tcf21 in the emergence of the milieu of Foxd1+ derivatives, whereas loss of Tcf21 leads to stromal cell fate change that results in abnormal kidney development.

Funding

• NIDDK Support