New Research Profiles Gene Expression During Kidney Development Using Single-Cell RNA Sequencing

A team of researchers from UPMC Children’s Hospital of Pittsburgh published results from a new study in the journal Scientific Reports that details their work using single-cell RNA sequencing to characterize the gene expression and molecular signaling profiles of cells of the developing kidney in an animal model.

The team was led by senior authors Jacqueline Ho, MD, MSc, associate professor of Pediatrics in the Division of Pediatric Nephrology at UPMC Children’s Hospital of Pittsburgh and Dennis Kostka, PhD, associate professor in the Departments of Developmental Biology and Computational and Systems Biology, and the Pittsburgh Center for Evolutionary Biology and Medicine at the University of Pittsburgh School of Medicine. Collaborating with Dr. Ho on the investigation from the Pediatric Nephrology Division were research scientist Débora M. Cerqueira, PhD; Andrew Clugston, PhD (former graduate student in the Ho Laboratory), and research technician Andrew J. Bodnar.  Other study investigators include Abha S. Bais, PhD, from the Department of Developmental Biology at the University of Pittsburgh School of Medicine. 

“Kidney disease is an all-too-frequent occurrence and a disease for which there are few treatments outside of dialysis or transplant for individuals who progress to renal failure," says Dr. Ho. "While transplantation medicine has made remarkable strides in saving lives, we cannot as yet cure chronic kidney disease. Our research exploring the cellular processes that drive normal kidney development will help us explore potential ways to either reverse or repair development processes when they go awry or the damage they create after the fact.”

Study Highlights

The study was able to characterize a complete transcriptional profile at the single-cell level in more than 4,000 cells of an embryonic mouse kidney at a mid-point in kidney development. 

This developmental timepoint captures  most of the events of cellular differentiation of the developing kidney, including the self-renewal of the nephron progenitors and their differentiation into multiple cell types required for mature nephrons. This ultimately leads to the creation of an optimal number of mature functioning nephrons in the fully formed kidney. Disruptions or errors in cell signaling, differentiation and maturation introduced during this critical point in kidney development can lead to congenital kidney defects, one of the most common causes of childhood kidney disease.

The team further grouped the analyzed cells into 11 clusters based upon different cell types that were distinguished by marker genes. By capturing cell-type-specific transcriptional characteristics at a mid-point in the developmental process, the research will be incredibly valuable for further exploring how individual cell types arise in the nascent kidney and how abnormalities in the processes may ultimately contribute to poorly formed, missing, or otherwise aberrant kidney structures. These same cellular developmental processes, once more fully understood, could become targets for therapeutic intervention – early or late – to either repair or influence proper cellular development of the kidney or regenerate cellular components that become damaged.

One of the significant findings of this study confirmed that nephron progenitor cells could be distinguished as two subtypes exhibiting either self-renewing or primed characteristics, with the primed subtype showing upregulated cell cycle activity across a number of genes. 

Also of importance is the finding that one of the cell-cycle expressed genes, Birc5, was upregulated in the cells of the forming distal tubule, and in a portion of cells that comprise the ureteric bud. The significance of this finding has to do with understanding how the nephron ultimately fuses to the renal collecting system, as abnormalities in this process can lead to subsequent renal anomalies.

“This work has given our laboratory a good deal of potential new lines of investigation to further explore the mechanistic processes that drive kidney formation, as well as targets for regenerative interventions in the future,” says Dr. Ho.

Read the full study and learn more about the clinical significance of this work at the reference below.

More About Dr. Ho

Jacqueline Ho, MD, MSc, is an associate professor of Pediatrics and director of the Pediatric Nephrology Fellowship in the Division of Pediatric Nephrology at UPMC Children's Hospital of Pittsburgh. Dr. Ho also serves as the co-director of the Pediatric Scientist Development Program in the Department of Pediatrics at the University of Pittsburgh School of Medicine

Dr. Ho earned her medical degree at the University of Western Ontario in Canada. She trained in pediatrics at British Columbia Children’s Hospital and the University of British Columbia. Her fellowship in pediatric nephrology was conducted at Boston Children’s Hospital and Harvard Medical School. 

Dr. Ho’s research program is primarily focused on understanding the role of microRNAs in kidney development and disease. Her laboratory has previously shown that microRNAs are involved in regulating the proliferation and survival of nephron progenitors in the developing kidney, which has important implications for congenital nephron endowment and subsequent kidney health in children and adults.

Reference

Bais AS, Cerqueira DM, Clugston A, Bodnar AJ, Ho J, Kostka D. Single-Cell RNA Sequencing Reveals Differential Cell Cycle Activity in Key Cell Populations During Nephrogenesis. Sci Rep. 2021; 11: 22434. Epub ahead of print.