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Abstract: SA-PO001

Microphysiological Model of Human Kidney Collecting Duct

Session Information

Category: Bioengineering

  • 400 Bioengineering

Authors

  • Hong, Soongweon, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Song, Minsun, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • McCracken, Kyle, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States
Background

Understanding kidney physiology is indispensable for maintaining human health, developing effective treatment strategies, implementing therapeutic interventions, and advancing personalized medicine approaches. However, much of our current knowledge of kidney physiology relies on non-human models, which do not accurately reflect human cell and system responses. To overcome this challenge, human stem cell-derived cells can be employed within a physiological microenvironment to achieve advanced physiological functions.

Methods

We developed a physiologically relevant human kidney collecting (CD) duct model using human stem cell-derived CD cells on the Epithelial Microphysiological Analysis Platform (Epi-MAP). scRNA-Seq analysis identifies the ureteric bud organoids as highly enriched in inner medullary CD principal epithelial cells We designed physiological media with compositions resembling intraluminal and basolateral conditions in vivo and used physiologically relevant tubular flow rates. Moreover, our Epi-MAP is integrated with proximal surface electrodes for in-situ real-time monitoring of physiological dynamics, enabling simultaneous tracking of optical microscopy and electrophysiological records.

Results

Compared to stationary cultures without flow, our Epi-MAP culture conditions significantly enhanced various aspects of the CD physiology. This includes improved epithelial morphology and enhanced mRNA expression of genes related to ion transport, tight junctions, water and urea transport, and receptor signaling. Our electrophysiological monitoring shows that CD-specific functions of vectorial transport and epithelial tight junction are further advanced in the physiological Epi-MAP culture. We also observed the conversion of CD principal cells to intercalated cells, resulting in a more physiological model. With our high-precision, continuous electrophysiological characterization, we also comprehensively studied the CD responses to vasopressin and aldosterone signaling, particularly on ion and water flux and tight junction integrity.

Conclusion

This human cell-derived, physiologically relevant model represents a powerful model in vitro for understanding human kidney biology, increasing drug modeling precision, understanding disease processes, and potentially serving to help create an important functional component of a biohybrid artificial kidney.

Funding

  • NIDDK Support