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Refining the Role of Basal Urothelial Cells in Bladder Development

Refining the Role of Basal Urothelial Cells in Bladder Development 1024 683 Jessica Nye, PhD

Basal keratin 5 urothelial cells (K5-UCs) were found to be age-restricted progenitors in bladders and their progenitor potential could be rescued by exogenous proliferative cues.

 

“The identity of the bladder urothelium progenitor is controversial and confounded by slow turnover, and a low mitotic index during homeostasis,” says Ashley R. Jackson, PhD, principal investigator in the Kidney and Urinary Tract Center at Nationwide Children’s Hospital and assistant professor at The Ohio State University. “There are multiple papers that looked at bladder urothelium progenitors, but inconsistent methodologies have led to disparate or context-dependent progenitor theories.”

To refine the role of K5-UCs in bladder development and in tissue repair, Dr. Jackson, Brian Becknell, PhD, research director and principal investigator in the Kidney and Urinary Tract Center at Nationwide Children’s, and colleagues mapped the fate of K5-UCs using mice and a novel dual reporter urothelial organoid model. K5-UCs were permanently labeled at different time points during postnatal maturation and their expression profiles were assessed by transcriptomics.

Basal K5-UCs were found to have an age-delimited capacity to form intermediate and superficial cells. Compared to lineage restricted adult K5-UCs, the fate of neonate K5-UCs revealed their superior intermediate (P =.0006) and superficial (P =.0452) cell forming potential. Neonate K5-UCs reprised their role as superior progenitors in organoid forming assays. In a dual reporter in vitro model, neonatal K5-UCs formed larger (P =.0008) and more differentiated organoids (P =.0115) relative to K5-UCs from adults.

When challenged to reconstitute the urothelial barrier following cyclophosphamide injury, adult K5-UCs remained lineage restricted, a finding consistent with prior reports. However, by mapping the fate K5-UCs across postnatal maturation, they found that intermediate cells derived from neonatal K5-UCs had the greatest tissue reconstitution potential.

“The age of the urothelium matters,” says Dr. Jackson. “I think the most surprising outcome was that by accounting for age, we found evidence that unifies both of the prevailing progenitor theories.”

Limiting cell RNAseq was used to explain functional differences in K5-UCs at different ages. Transcription profiles of neonatal and adult K5-UCs revealed 645 differentially expressed genes. The most striking difference was that genes enriched in neonate K5-UCs were associated with epithelial proliferation and differentiation.

Given that K5-UC proliferation and progenitor capacity are inversely correlated with age, recombinant human fibroblast growth factor 7 (FGF7; palifermin) was used to induce adult K5-UC proliferation. With treatment, the capacity of adult K5-UCs to form superficial cells in response to injury was restored compared with control (22.63% vs 0%), respectively.

“Our data shows that adult intermediate cells are derived predominantly from neonatal K5-UCs, and those adult intermediate cells reconstitute damaged superficial cells. The most exciting finding was that palifermin, a drug used clinically to treat oral mucositis, can promote the tissue reconstitution potential of bladder K5-UCs,” says Dr. Jackson.

The novel dual reporter organoid system developed in this study will be important to the identification of additional progenitor influencing signals. With greater understanding of the developmental and repair process of basal K5-UCs, there is the potential to open new avenues of therapeutic targets or tissue engineering for conditions that disrupt the urothelial barrier.

 

Reference:

Becknell B, El-Harakeh M, Rodriguez-Tirado F, Grounds KM, Li B, Kercsmar M, Wang X, Jackson AR. Keratin 5 Basal Cells are Temporally Regulated Developmental and Tissue Repair Progenitors in Bladder Urothelium. American Journal of Physiolology – Renal Physiology. Published online April 18, 2024.

 

 

About the author

Jessica Nye, PhD, is a freelance science and medical writer based in Barcelona, Spain. She completed her BS in biology and chemistry and MS in evolutionary biology at Florida State University. Dr. Nye studied population genetics for her doctorate in biomedicine at University of Pompeu Fabra. She conducted her postdoctoral research on the inheritance of complex traits at the Autonomous University of Barcelona.

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