Combination therapy of mesenchymal stem cells and serelaxin effectively attenuates renal fibrosis in obstructive nephropathy.
Chronic kidney disease (CKD) results from the development of fibrosis, ultimately leading to end-stage renal disease (ESRD). Although human bone marrow-derived mesenchymal stem cells (MSCs) can accelerate renal repair following acute injury, the establishment of fibrosis during CKD may affect their potential to influence regeneration capacity. Here we tested the novel combination of MSCs with the antifibrotic serelaxin to repair and protect the kidney 7 d post-unilateral ureteral obstruction (UUO), when fibrosis is established. Male C57BL6 mice were sham-operated or UUO-inured (n = 4-6) and received vehicle, MSCs (1 × 10(6)), serelaxin (0.5 mg/kg per d), or the combination of both. In vivo tracing studies with luciferin/enhanced green fluorescent protein (eGFP)-tagged MSCs showed specific localization in the obstructed kidney where they remained for 36 h. Combination therapy conferred significant protection from UUO-induced fibrosis, as indicated by hydroxyproline analysis (P < 0.001 vs. vehicle, P < 0.05 vs. MSC or serelaxin alone). This was accompanied by preserved structural architecture, decreased tubular epithelial injury (P < 0.01 vs. MSCs alone), macrophage infiltration, and myofibroblast localization in the kidney (both P < 0.01 vs. vehicle). Combination therapy also stimulated matrix metalloproteinase (MMP)-2 activity over either treatment alone (P < 0.05 vs. either treatment alone). These results suggest that the presence of an antifibrotic in conjunction with MSCs ameliorates established kidney fibrosis and augments tissue repair to a greater extent than either treatment alone.
*Department of Anatomy and Developmental Biology and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Australia; and Australia Regenerative Medicine Institute (ARMI) and Monash University, Clayton, Victoria, Australia.
Brooke M
BM
Huuskes
*Department of Anatomy and Developmental Biology and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Australia; and Australia Regenerative Medicine Institute (ARMI) and Monash University, Clayton, Victoria, Australia.
Andrea F
AF
Wise
*Department of Anatomy and Developmental Biology and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Australia; and Australia Regenerative Medicine Institute (ARMI) and Monash University, Clayton, Victoria, Australia.
Alison J
AJ
Cox
*Department of Anatomy and Developmental Biology and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Australia; and Australia Regenerative Medicine Institute (ARMI) and Monash University, Clayton, Victoria, Australia.
Ee X
EX
Lim
*Department of Anatomy and Developmental Biology and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Australia; and Australia Regenerative Medicine Institute (ARMI) and Monash University, Clayton, Victoria, Australia.
Natalie L
NL
Payne
*Department of Anatomy and Developmental Biology and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Australia; and Australia Regenerative Medicine Institute (ARMI) and Monash University, Clayton, Victoria, Australia.
Darren J
DJ
Kelly
*Department of Anatomy and Developmental Biology and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Australia; and Australia Regenerative Medicine Institute (ARMI) and Monash University, Clayton, Victoria, Australia sharon.ricardo@monash.edu chrishan.samuel@monash.edu.
Chrishan S
CS
Samuel
*Department of Anatomy and Developmental Biology and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Australia; and Australia Regenerative Medicine Institute (ARMI) and Monash University, Clayton, Victoria, Australia sharon.ricardo@monash.edu chrishan.samuel@monash.edu.
Sharon D
SD
Ricardo
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis / Q000503:physiopathology*; D018093:Gelatinases / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology*; D007676:Kidney Failure, Chronic / Q000503:physiopathology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D012038:Regeneration; D012065:Relaxin / Q000627:therapeutic use*; D051436:Renal Insufficiency, Chronic / Q000628:therapy*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C577649:serelaxin protein, human; D049452:Green Fluorescent Proteins; D012065:Relaxin; D003094:Collagen; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
collagen deposition; interstitial kidney injury; macrophage infiltration; matrix metalloproteinase; myofibroblast differentiation; transforming growth factor-β