Kidney Week

Abstract: SA-OR10

Single-Cell Spatial Map of the Developing Human Kidney Highlights Insulin-Like Growth Factor 2-Mediated Signaling in Renewal

Session Information

• Bioengineered Model Systems and Insights in Kidney Development and Function
  October 26, 2024 | Location: Room 2, Convention Center
  Abstract Time: 04:30 PM - 04:40 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 600 Development, Stem Cells, and Regenerative Medicine

Authors

• Levinsohn, Jonathan, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

Jonathan Levinsohn, MD, PhD

• Dumoulin, Bernhard, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Bernhard Dumoulin, MD

• Abedini, Amin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Amin Abedini, MD

• Bergeson, Andi M., University of Pennsylvania, Philadelphia, Pennsylvania, United States

Andi M. Bergeson

• Kloetzer, Konstantin A., University of Pennsylvania, Philadelphia, Pennsylvania, United States

Konstantin A. Kloetzer, MD

• Ha, Eunji, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Eunji Ha, PhD

• Finn, Laura S., The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

Laura S. Finn, MD

• Pleniceanu, Oren, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel

Oren Pleniceanu, MD, PhD

• Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Katalin Susztak, MD, PhD

Background

The developing human kidney is a complex multi-lineage structure. It has long been understood that interplay between these lineages is crucial to form functional nephrons, however large gaps remain in our understanding of this process. Specifically, the mechanisms by which the nephron stem cell population is maintained are unclear.

Methods

To address this, we generated a comprehensive single cell dataset of 5 developing human kidneys and CosMx sinlge cell spatial transcriptomic map of 3 developing human kidneys. By integrating our spatial and single cell data, using a novel approach, allowing us to impute whole transcriptome expression for our spatial data.

Results

We generate an integrated atlas of spatial and single cell expression allowing is to map trajectories in space. We find that nephron progenitor renewal genes decrease in expression over gestational age, preceding nephrogenic zone exhaustion. We also use H&E histology to define neighborhoods for our spatial dataset allowing us to identify genes enriched within the blastema, early tubular structures and early glomeruli. Using this approach We identify IGF2 ligand as being specific to the blastema, where we also note increased expression of insulin signaling pathways, suggesting a specific role for in vivo human NPC renewal.

Conclusion

We identify potential mediators of NPC renewal in humans which localize to the blastema. Among these genes is IGF2. We propose that this may help explain the epidemiologic data showing that uncontrolled gestational diabetes is associated with smaller fetal kidneys and poor fetal outcomes. This analysis shows the power of an integrated approach to spatial transcriptomics.

Funding

• NIDDK Support