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Abstract: SA-PO564

Adipose Stem Cell-Derived Exosomes Afford Effective Survival Benefits and Functional Rescue from Severe, Progressive IRI-Induced AKI in Rats

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gooch, Anna, SCT, Salt Lake City, Utah, United States
  • Zhang, Ping, SCT, Salt Lake City, Utah, United States
  • Hu, Zhuma, SCT, Salt Lake City, Utah, United States
  • Westenfelder, Christof, University of Utah and VA Medical Centers, Salt Lake City, Utah, United States
Background

Bone marrow and Adipose-derived Mesenchymal Stem Cells (M/ASCs) are effective for prevention of Acute Kidney Injury (AKI). Yet when MSCs are given 48 hrs post-insult, a time at which severe clinical AKI is diagnosed and when no rescue therapy is currently available, they are ineffective or potentially damaging because the introduction of large cells (~50µm) into the compromised microvasculature may impair renal function. M/ASCs’ 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 ASC-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 ASCs were isolated post 24 hr culture in SFM, purified using the ExoQuick-TC kit, and characterized for size, 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 D2 was greater than that on D1, 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 ASCs (2x10e6 ASCs; n=6) on D3.

Results

1e6 ASCs 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 ASCs. While both ASC and exosome administration improved survival over PBS, renal function only showed significant and sustained improvement in exosome-treated rats.

Conclusion

ASC-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 ASC 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.

Funding

  • Commercial Support