Arterially delivered mesenchymal stem cells prevent obstruction-induced renal fibrosis.
BACKGROUND
Mesenchymal stem cells (MSCs) hold promise for the treatment of renal disease. While MSCs have been shown to accelerate recovery and prevent acute renal failure in multiple disease models, the effect of MSC therapy on chronic obstruction-induced renal fibrosis has not previously been evaluated.


METHODS
Male Sprague-Dawley rats underwent renal artery injection of vehicle or fluorescent-labeled human bone marrow-derived MSCs immediately prior to sham operation or induction of left ureteral obstruction (UUO). One or 4 wk later, the kidneys were harvested and the renal cortex analyzed for evidence of stem cell infiltration, epithelial-mesenchymal transition (EMT) as evidenced by E-cadherin/α-smooth muscle actin (α-SMA) expression and fibroblast specific protein (FSP+) staining, renal fibrosis (collagen content, Masson's trichrome staining), and cytokine and growth factor activity (ELISA and real time RT-PCR).


RESULTS
Fluorescent-labeled MSCs were detected in the interstitium of the kidney up to 4 wk post-obstruction. Arterially delivered MSCs significantly reduced obstruction-induced α-SMA expression, FSP+ cell accumulation, total collagen content, and tubulointerstitial fibrosis, while simultaneously preserving E-cadherin expression, suggesting that MSCs prevent obstruction-induced EMT and renal fibrosis. Exogenous MSCs reduced obstruction-induced tumor necrosis factor-α (TNF-α) levels, but did not alter transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), fibroblast growth factor (FGF), or hepatocyte growth factor (HGF) expression.


CONCLUSIONS
Human bone marrow-derived MSCs remain viable several weeks after delivery into the kidney and provide protection against obstruction-induced EMT and chronic renal fibrosis. While the mechanism of MSCs-induced renal protection during obstruction remains unclear, our results demonstrate that alterations in TNF-α production may be involved.
Asanuma
Hiroshi
H
Department of Urology, Indiana University School of Medicine, Indianapolis, Indianapolis, Indiana 46202, USA.
Vanderbrink
Brian A
BA
Campbell
Matthew T
MT
Hile
Karen L
KL
Zhang
Hongji
H
Meldrum
Daniel R
DR
Meldrum
Kirstan K
KK
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D014183:Transplantation, Heterologous / Q000379:methods*; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D003094:Collagen