Redefining kidney developmental origins

Investigations of embryonic development are critical for understanding congenital anomalies that arise from altered development. Additionally, the derivation of tissues in vitro from pluripotent cells relies on directed differentiations along developmental pathways. However, this has proven challenging for organs such as the mammalian kidney which proceeds through three different phases of development along the anterior to posterior axis before the third phase induces development of the final, metanephric kidney. Questions remain about whether cellular programs of the metanephric kidney are actually induced in vitro or whether they represent earlier phases of development. The intermediate mesoderm, which is thought to derive independently of the adjacent paraxial and lateral plate mesoderm from the primitive streak, generates the kidney tissues, gonads, and adrenals. The metanephric kidney is induced to form caudally at the hindlimb level. However, despite over a century of research into the intermediate mesoderm and metanephric kidney development, the origins remain clouded by studies focusing on anterior intermediate mesoderm, conflicting results, and building evidence that may suggest alternate mesodermal origins. Our own imaging of early embryos as well as a thorough consideration of previous findings has led us to hypothesize that the intermediate mesoderm which gives rise to the metanephric kidney is derived from paraxial mesoderm. Therefore, it is imperative that we reexamine the intermediate mesoderm and kidney origins considering these findings. Advances in tools and methodology available will enable us to interrogate intermediate mesoderm and metanephric kidney development and shed new light onto the cellular origins. In Aim 1 we will perform novel lineage traces of paraxial mesoderm and utilize whole embryo light-sheet and live imaging to examine the paraxial, intermediate, and kidney cell populations at critical developmental timepoints to ascertain their identity and origins. In Aim 2, we will utilize directed differentiations from induced pluripotent stem cells (iPSCs) to test whether in vitro derived paraxial mesoderm is competent to generate intermediate mesoderm and kidney tissue. Together, we predict that these novel and innovative studies will redefine and refine the cellular origins of intermediate mesoderm and its derivatives. These findings will contribute essential foundational knowledge to the field of developmental biology and aid the development of effective tissue replacement and regenerative strategies, as well as further our understanding of developmental anomalies which significantly affect human health. Project Number: 1R21HD117223-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Lori O'Brien | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $427,625 | Activity Code: R21 | Study Section: Development - 2 Study Section[DEV2] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21HD11722301