Wnt’s Role in Kidney Formation Unveiled

The Wnt pathway is a collection of crucial signaling molecules that first appeared during the early stages of the evolution of multicellular life. Scientists have been studying Wnt actions for four decades to comprehend its complex roles in development and disease. Researchers from Andy McMahon’s team at USC Stem Cell conducted two separate experiments on the development of the mammalian kidney. These findings, which were published today in the journal Development, provide fresh light on the crucial role that Wnt signaling plays in triggering this process.

“Many stem and progenitor cells require Wnt signaling, and the kidney is a particularly interesting example, because the level of signaling may have profoundly different outcomes,” said corresponding author McMahon, who is the W.M. Keck Provost and University Professor of Stem Cell Biology and Regenerative Medicine, and Biological Sciences at the Keck School of Medicine of USC.

“By enhancing our knowledge of how Wnt signaling acts in the developing kidney, these two papers provide insights that can guide efforts amongst USC collaborators in the Synthetic Kidney Consortium to build kidneys from stem and progenitor cells as a new treatment option for patients.”- Andy McMahon, Keck School of Medicine of USC

The progenitor and stem cells that give rise to the kidney’s filtering units, or nephrons, in embryonic mice are the subject of both research.

“Nephron progenitor cells cease to exist by the time humans are born,” said Helena Bugacov, who is a first author on both studies and a PhD graduate from the McMahon Lab now pursuing her MD at the Icahn School of Medicine at Mount Sinai in New York. “Without NPCs, postnatal kidneys are unable to form new nephrons-;hence the need for kidney transplantation once nephron function declines. However, there are simply not enough kidneys available for those that need them. Therefore, understanding the signals required to promote the self-renewal, differentiation, and formation of the precursors to nephrons from their progenitor cells is pivotal to the creation of stem cell-based artificial kidneys.”

Nephron progenitor cells, or NPCs, were extracted and cultured in the lab. Subsequently, the NPCs were subjected to varying concentrations of a chemical known as CHIR, which modifies the Wnt signaling pathway’s activity.

In order to investigate the functions of the Wnt pathway, scientists concentrated on how Wnt signals control genes, a process that is mediated by proteins involved in DNA binding, as well as Apart from its fundamental function in Wnt-induced gene regulation, beta-catenin plays a crucial role as a mediator in cell adhesion processes, which are responsible for structuring and maintaining the integrity of the epithelium.

Genetically engineering NPCs was a novel method developed by Helena Bugacov to study the functions of these Wnt pathway components.

In the first investigation, reactions to varying degrees of Wnt pathway activation were examined by Bugacov and colleagues using the genetic modification technique.

The researchers discovered that low signaling levels control NPC self-renewal, which is essential for producing all the NPCs required to construct the 14,000 nephrons that make up the mouse kidney. NPCs begin to differentiate into mature kidney cell types at higher levels. According to past research from the McMahon Lab and others, the consequences of NPCs vary depending on the amount of beta-catenin.

When high levels of Wnt signaling induce kidney development, a crucial cellular transition occurs: separate NPCs clump together to form a tiny cell cluster known as the renal vesicle. A single nephron originates from each renal vesicle. The one million human nephrons are produced by one million renal vesicles.

The first authors of the second study, Bálint Dér, MD, a postdoc, and Bugacov from the McMahon Lab, examined how the Wnt signaling pathway controls NPC aggregation to create the condensed clusters that eventually develop into nephron precursors.

According to Dér, Bugacov, and their colleagues, Wnt activation causes NPCs to stick together, changing from a mobile, disorganized group of cells to a stationary, ordered group of cells that eventually forms the renal vesicle. This process, called the mesenchymal-epithelial transition, is a defining feature of many other developmental and pathological processes in the body, including kidney development throughout embryonic development. When a cancer spreads to distant locations from its main tumor, a mechanism known as the epithelial-mesenchymal transition is responsible. This process is known as tumor metastasis.

In order to accomplish the cellular aggregation required for the nephrons to start forming, beta-catenin connects the cadherins—adhesive proteins found on the surface of NPCs—with an internal structural scaffold via alpha-catenin.

“It’s been a pleasure and an honor to work on these research projects in a lab that has been investigating the Wnt signaling pathway since the first identification of Wnt genes and their developmental actions in mammals -; and to be able to combine the power of developmental biology, stem cell science, and genetic engineering to one day advance treatment options for people with kidney disease,” said Bugacov.

Dér, who is currently specializing in urological surgery at Semmelweis University in Budapest, Hungary, added: “Because the Wnt signaling pathway plays a role in so many organ systems throughout the body, our studies are important not only for understanding the development of the kidney, but also for gaining relevant insight into development of other organs. Furthermore, it was an honor to work in the McMahon Lab, and I am grateful for the people I have met along the way.”

For more information: Dose-dependent responses to canonical Wnt transcriptional complexes in the regulation of mammalian nephron progenitors, Development, https://doi.org/10.1242/dev.202279