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Abstract: SA-PO028

Perfusable Human Tubule Chip System to Model Polycystic Kidney Disease

Session Information

  • Bioengineering
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Bioengineering

  • 300 Bioengineering

Authors

  • Karp, Sophie, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Subramanian, Balaji karthick, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Group or Team Name

  • Pollak Lab
Background

Ex-vivo systems modeling human kidney tubules may be used for high-throughput drug screening and mechanistic disease studies. Polycystic kidney disease (PKD) is an important tubular disease to model, as it is responsible for 2% of worldwide renal failure. Proximal and distal tubules are affected differently in PKD settings in terms of fluid-activated transport and inflammation, leading to GFR changes and ultimately renal failure. It is thus important to establish a system in which segment-specific human-derived PKD tubules may be studied in physiologically relevant conditions, such as fluid flow.

Methods

Using photolithography, we created a microfluidic chip with a channel insert and ports for media delivery. We then derived kidney organoids from both normal and PKD patient-sourced induced pluripotent stem cells (iPSCs). We extracted proximal and distal tubule cells from these organoids, and delivered them to our chip system. Unidirectional fluid flow for various time frames was introduced through the system and changes in the tubule structure and function were examined. Tubule volume changes, marker protein expression and localization, and transport properties were assessed and compared between normal and PKD disease tubular chips.

Results

Kidney organoids formed tubular structures which mimicked human kidney structures and replicated PKD-like cyst formation. Kidney organoid-harvested cells exhibited nephron segment-specific marker protein localization and function, and formed tubular structures when introduced to the chip-system. Normal tubule chip systems exhibited human kidney-relevant structure and function, while PKD systems showed aberration in tubule volume. Diseased systems exhibited altered localization of marker proteins such as E-cadherin, as well as diminished transport capacity of solutes (e.g., 6-Carboxy fluorescein). More importantly, diseased tubules showed aberrations in structure and function in a segment-specific manner, mimicking in vivo disease pathology.

Conclusion

We have developed and validated a model system to study the effects of PKD ex vivo. Our platform will allow both mechanistic studies and drug testing in a nephron-segment specific way. Its conductivity to both distal and proximal human iPSC-derived tubules allows researchers to study disease in a personalized manner.

Funding

  • NIDDK Support