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Abstract: PO0145

Administration of Exosomes from Mesenchymal Stem Cells Provides Effective Survival Benefits and Functional Rescue from Severe, Progressive Ischemia-Reperfusion Injury-Induced AKI in Rats

Session Information

  • AKI Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gooch, Anna, SymbioCellTech, LLC, Salt Lake City, Utah, United States
  • Skliar, Mikhail, University of Utah, Salt Lake City, Utah, United States
  • Zhang, Ping, SymbioCellTech, LLC, Salt Lake City, Utah, United States
  • Hu, Zhuma, SymbioCellTech, LLC, Salt Lake City, Utah, United States
  • Westenfelder, Christof, SymbioCellTech, LLC, Salt Lake City, Utah, United States
Background

While administration of Mesenchymal Stem Cells (MSCs) has been demonstrated clinically to prevent Acute Kidney Injury (AKI) such as that caused by cardiac bypass surgery, administration 48 hrs post-insult was found to be ineffective or potentially damaging, likely because the introduction of large cells (~50µm) into the compromised microvasculature may impair renal function. MSCs’ renoprotection is mediated by their paracrine release of anti-inflammatory and trophic cytokines and their exosomes. Exosomes signal, post uptake by target cells, through the lateral transfer of mRNAs, miRNAs, DNA, proteins, and lipids. Since MSC-derived exosomes can prevent AKI we tested whether their small size and ability to move through the compromised renal microvasculature might allow them to provide effective rescue therapy for late stage AKI.

Methods

Exosomes from Sprague Dawley (SD) rat MSCs were isolated post 24 hr culture, purified using the ExoQuick-TC kit, and characterized for size (nanosight), protein and gene expression of relevant markers. I/R AKI (52 min bilateral renal pedicle clamp) was induced in female SD rats. If the SCr value on Day 2 was greater than that on Day 1, demonstrating progressive AKI, then rats were administered via left carotid artery either 1 ml of Vehicle (PBS; n=8), Exosomes (200 μg protein-equivalent; ~4x10e10 exosomes; n=6), or MSCs (2x10e6; n=6) on Day 3.

Results

1x10e6 MSCs secrete ~ 4.9x10e10 exosomes and other microvesicles (mode 136.7 nm) and >95% express CD44 and CD29, and carry mRNAs of renoprotective genes expressed in MSCs. While both MSC and exosome administration improved survival over PBS, renal function only showed significant and sustained improvement in exosome-treated rats.

Conclusion

MSC-derived exosome therapy 3 days post progressive AKI, when renal blood flow is significantly impaired and when most clinical AKI is diagnosed, is superior to MSC therapy, likely due to their ability to deliver their renoproetective cargo into the compromised renal microcirculation. These data have, we posit, significant translational promise for the development of an effective rescue therapy for advanced AKI.
(No University of Utah resources were used for this work.)

Funding

  • Commercial Support