The renoprotective efficacy and safety of genetically-engineered human bone marrow-derived mesenchymal stromal cells expressing anti-fibrotic cargo

  • Stem Cell Res Ther. 2024 Oct 23;15(1):375. doi: 10.1186/s13287-024-03992-x.
Yifang Li  1  2 ,  Alex Hunter  1  2 ,  Miqdad M Wakeel  1  2 ,  Guizhi Sun  3  4 ,  Ricky W K Lau  3  2 ,  Brad R S Broughton  1  2 ,  Ivan E Oyarce Pino  1  2 ,  Zihao Deng  5 ,  Tingfang Zhang  3  2 ,  Padma Murthi  1  2 ,  Mark P Del Borgo  1  2 ,  Robert E Widdop  1  2 ,  Jose M Polo  3  4  6  7 ,  Sharon D Ricardo  8  9 ,  Chrishan S Samuel  10  11  12  13
Affiliations
  • 1. Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
  • 2. Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.
  • 3. Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
  • 4. Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia.
  • 5. Department of Medicine (Alfred Hospital), Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
  • 6. Adelaide Centre for Epigenetics, School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia.
  • 7. The South Australian Immunogenomics Cancer Institute, The University of Adelaide, Adelaide, SA, 5005, Australia.
  • 8. Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. [email protected].
  • 9. Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia. [email protected].
  • 10. Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. [email protected].
  • 11. Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. [email protected].
  • 12. Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia. [email protected].
  • 13. Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC, 3010, Australia. [email protected].
PMID: 39443975 DOI: 10.1186/s13287-024-03992-x
Abstract

Background: Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and compromises the viability of transplanted human bone marrow-derived mesenchymal stromal cells (BM-MSCs). Hence, BM-MSCs were genetically-engineered to express the anti-fibrotic and renoprotective hormone, human relaxin-2 (RLX) and green fluorescent protein (BM-MSCs-eRLX + GFP), which enabled BM-MSCs-eRLX + GFP delivery via a single intravenous injection.

Methods: BM-MSCs were lentiviral-transduced with human relaxin-2 cDNA and GFP, under a eukaryotic translation elongation factor-1α promoter (BM-MSCs-eRLX + GFP) or GFP alone (BM-MSCs-eGFP). The ability of BM-MSCs-eRLX + GFP to differentiate, proliferate, migrate, produce RLX and cytokines was evaluated in vitro, whilst BM-MSC-eRLX + GFP vs BM-MSCs-eGFP homing to the injured kidney and renoprotective effects were evaluated in preclinical models of ischemia reperfusion injury (IRI) and high salt (HS)-induced hypertensive CKD in vivo. The long-term safety of BM-MSCs-RLX + GFP was also determined 9-months after treatment cessation in vivo.

Results: When cultured for 3- or 7-days in vitro, 1 × 106 BM-MSCs-eRLX + GFP produced therapeutic RLX levels, and secreted an enhanced but finely-tuned cytokine profile without compromising their proliferation or differentiation capacity compared to naïve BM-MSCs. BM-MSCs-eRLX + GFP were identified in the kidney 2-weeks post-administration and retained the therapeutic effects of RLX in vivo. 1-2 × 106 BM-MSCs-eRLX + GFP attenuated the IRI- or therapeutically abrogated the HS-induced tubular epithelial damage and interstitial fibrosis, and significantly reduced the HS-induced hypertension, glomerulosclerosis and proteinuria. This was to an equivalent extent as RLX and BM-MSCs administered separately but to a broader extent than BM-MSCs-eGFP or the angiotensin-converting enzyme inhibitor, perindopril. Additionally, these renoprotective effects of BM-MSCs-eRLX + GFP were maintained in the presence of perindopril co-treatment, highlighting their suitability as adjunct therapies to ACE inhibition. Importantly, no major long-term adverse effects of BM-MSCs-eRLX + GFP were observed.

Conclusions: BM-MSCs-eRLX + GFP produced greater renoprotective and therapeutic efficacy over that of BM-MSCs-eGFP or ACE inhibition, and may represent a novel and safe treatment option for acute kidney injury and hypertensive CKD.

Keywords
BM-MSCs; Chronic kidney disease; Fibrosis; Genetic engineering; Relaxin.
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