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Abstract: SA-PO024

Exposure of Mesenchymal Stromal Cells (MSCs) to INF-γ Boosts the Therapeutic Potency of Their Exosomes (Exos) in the Rescue Therapy of Severe AKI in Rats

Session Information

Category: Bioengineering

  • 400 Bioengineering

Authors

  • Westenfelder, Christof, SymbioCellTech, Salt Lake City, Utah, United States
  • Gooch, Anna, SymbioCellTech, Salt Lake City, Utah, United States
  • Skliar, Mikhail, University of Utah Dept of Chemical Engineering, Salt Lake City, Utah, United States
Background

Preclinical and clinical studies have shown MSCs and their Exos to be effective for prevention of AKI. Yet when MSCs are given 48 hrs post-insult, a time when most patients with severe AKI are diagnosed, show them to be ineffective or even detrimental due to the compromised microvasculature. MSCs’ are renoprotective by their paracrine release of anti-inflammatory, trophic cytokines and their Exos. Exos signal, post uptake, through the lateral transfer of mRNAs, miRNAs, DNA, proteins, and lipids. We tested here whether priming of human MSCs with INFγ would result in the release of a more potent Exos-based biotherapy in rats with severe IRI AKI.

Methods

(1) 12 sets of hMSCs were culture expanded, then changed to SFM. 6 were exposed ON to 10ng/ml INFγ (Expt), and the other 6 to vehicle (Control). All Exos sizes and numbers (NanoSite), mRNAs and miRNAs were determined (rtPCR, Rosalind). (2) 3 groups of anesthetized adult female Fisher rats (n=6) were subjected to I/R AKI (55 min bilateral renal pedicle clamp) and infused via left carotid artery at 48 hrs post reflow with (a) vehicle (1 ml PBS, Control), (b) Exos harvested from ~2x10e6 hMSCs (Exos), (c) Exos harvested from ~2x10e6 INF-g exposed MSCs (ExptExos). Each Exos treatment was the equivalent of ~400 mg protein or ~ 2x10e9 particles. Post injury, SCreatinine, and Uprotein/creatinine were assessed at baseline, days 1-10, then monthly x 3.

Results

(1) Exos numbers were comparable in Expt and Control groups. ExptExos were slightly larger than Controls. ExptExos’ cargo contained both significantly increased immune modulatory mRNAs (IDO-1, CCL8, CXCL9, CXCL10, PD-L1) and 4 anti-inflammatory, angiogenic and anti-apoptotic miRNAs (MiR-548-3P; MiR-548N; MiR-148-3P; MiR-877-5P). (2) In vivo, Exos therapy with both unexposed and INFg-treated MSCs reduced SCr short and long term vs. control. Only Exos from the INFg group significantly reduced both SCr and UProtein/Creatinine at 3 mos.

Conclusion

Programming of MSCs with INFγ results in the release of Exos that deliver significantly greater renoprotective activities in the compromised microvasculature of severe AKI. We posit, these data have significant clinical promise as rescue therapy in AKI.

Funding

  • Commercial Support – SymbioCellTech