Integrating collecting systems in kidney organoids through fusion of distal nephron to ureteric bud.

Autor:	Shi M; Division of Nephrology and Hypertension, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Crouse B; Division of Nephrology and Hypertension, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Sundaram N; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Pode Shakked N; Division of Nephrology and Hypertension, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Current address: Faculty of Medicine and Health Sciences, Tel Aviv University, Tel Aviv, Israel., Ester L; Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA., Zhang W; Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA., Janakiram V; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Kopan R; Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Helmrath MA; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Bonventre JV; Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA., McCracken KW; Division of Nephrology and Hypertension, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Lead contact.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 20. Date of Electronic Publication: 2024 Sep 20.
DOI:	10.1101/2024.09.19.613645
Abstrakt:	The kidney maintains homeostasis through an array of parallel nephrons, which all originate in development as isolated epithelial structures that later fuse through their distal poles to a system of collecting ducts (CD). This connection is required to generate functional nephrons by providing a pathway for excretion of metabolic waste and byproducts. Currently, methods for differentiating human pluripotent stem cells into kidney organoids generate nephrons that lack CDs and instead terminate as blind-ended tubules. Here we describe a developmentally inspired system that addresses this deficiency through assembly of induced nephrogenic mesenchyme with ureteric bud (UB) tissues, the embryonic building blocks of the kidney's collecting system. The UB progenitors grow and develop into a network of CDs within the organoid, and importantly, they functionally integrate with the nephrons through recapitulating fusion between the distal tubule and CD to create a continuous epithelial lumen. We further showed that proximal-distal nephron specification, fusion frequency, and maturation of the CD can be augmented through temporal manipulation of developmental signaling pathways. This work provides a platform for interrogating the principles and mechanisms underlying nephron-UB fusion and a framework for engineering unobstructed nephrons with patterned collecting systems, an important step toward the de novo generation of functional kidney tissue. Competing Interests: Declaration of Interests M.S., K.W.M., and J.V.B. are co-inventors on pending UB organoid patents, and M.S. and K.W.M. are coinventors on pending integrated organoid technologies described herein. The other authors have no competing financial interests to declare.
Databáze:	MEDLINE
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