Andrew T Bruce1,2, Roger M Ilagan1,2, Kelly I Guthrie1,2, Elias Rivera2,3, Sumana Choudhury2,4, Namrata Sangha2,5, Thomas Spencer2,6, Timothy A Bertram2,6, Deepak Jain2,6, Russell W Kelley2,7, Joydeep Basu2,6. 1. Regenerative Medicine, United Therapeutics, 55 TW Alexander Drive, Research Triangle Park, NC 27709, USA. 2. Tengion, Inc., 3929 Westpoint Blvd, Ste G, Winston-Salem, NC 27103, USA. 3. Infinium Pathology Consultants LLC, 1805 Wild Fern Dr., Oak Ridge, NC 27310, USA. 4. Gene Therapy Center, Vector Core, University of North Carolina at Chapel Hill, NC 27617, USA. 5. Wake Forest Institute for Regenerative Medicine, Medical Centre Boulevard, Winston-Salem, NC 27157, USA. 6. RegenMedTX LLC, 3929 Westpoint Blvd, Ste G, Winston-Salem, NC 27103, USA. 7. Burroughs Wellcome Fund, 21 TW Alexander Drive, Research Triangle Park, NC 27709, USA.
Abstract
AIM: Identification of mechanistic pathways for selected renal cell (SRC) therapeutic bioactivity in rodent models of chronic kidney disease. MATERIALS & METHODS: In vivo and in vitro functional bioassays applied to investigate regenerative outcomes associated with delivery of SRC to diseased rodent kidney. RESULTS: In vivo, SRC reduces chronic infiltration by monocytes/macrophages. SRC attenuates NF-κB and PAI-1 responses while simultaneously promoting host tubular cell expansion through trophic cues. In vitro, SRC-derived conditioned media attenuates TNF-α-induced NF-κB response, TGF-β-mediated PAI-1 response and increases expression of transcripts associated with cell cycle regulation. Observed bioactive responses were from vesicle and nonvesicle-associated factors, including specific miRNAs. CONCLUSION: We identify a paracrine mechanism for SRC immunomodulatory and trophic cues on host renal tissues, catalyzing long-term functional benefits in vivo.
AIM: Identification of mechanistic pathways for selected renal cell (SRC) therapeutic bioactivity in rodent models of chronic kidney disease. MATERIALS & METHODS: In vivo and in vitro functional bioassays applied to investigate regenerative outcomes associated with delivery of SRC to diseased rodent kidney. RESULTS: In vivo, SRC reduces chronic infiltration by monocytes/macrophages. SRC attenuates NF-κB and PAI-1 responses while simultaneously promoting host tubular cell expansion through trophic cues. In vitro, SRC-derived conditioned media attenuates TNF-α-induced NF-κB response, TGF-β-mediated PAI-1 response and increases expression of transcripts associated with cell cycle regulation. Observed bioactive responses were from vesicle and nonvesicle-associated factors, including specific miRNAs. CONCLUSION: We identify a paracrine mechanism for SRC immunomodulatory and trophic cues on host renal tissues, catalyzing long-term functional benefits in vivo.
Authors: Peter Stenvinkel; Jonas Wadström; Tim Bertram; Randal Detwiler; David Gerber; Torkel B Brismar; Pontus Blomberg; Torbjörn Lundgren Journal: Kidney Int Rep Date: 2016-07-16