Culture-modified bone marrow cells attenuate cardiac and renal injury in a chronic kidney disease rat model via a novel antifibrotic mechanism.
BACKGROUND
Most forms of chronic kidney disease are characterized by progressive renal and cardiac fibrosis leading to dysfunction. Preliminary evidence suggests that various bone marrow-derived cell populations have antifibrotic effects. In exploring the therapeutic potential of bone marrow derived cells in chronic cardio-renal disease, we examined the anti-fibrotic effects of bone marrow-derived culture modified cells (CMCs) and stromal cells (SCs).


RESULTS
In vitro, CMC-conditioned medium, but not SC-conditioned medium, inhibited fibroblast collagen production and cell signalling in response to transforming growth factor-beta. The antifibrotic effects of CMCs and SCs were then evaluated in the 5/6 nephrectomy model of chronic cardio-renal disease. While intravascular infusion of 10(6) SCs had no effect, 10(6) CMCs reduced renal fibrosis compared to saline in the glomeruli (glomerulosclerosis index: 0.8+/-0.1 v 1.9+/-0.2 arbitrary units) and the tubulointersitium (% area type IV collagen: 1.2+/-0.3 v 8.4+/-2.0, p<0.05 for both). Similarly, 10(6) CMCs reduced cardiac fibrosis compared to saline (% area stained with picrosirius red: 3.2+/-0.3 v 5.1+/-0.4, p<0.05), whereas 10(6) SCs had no effect. Structural changes induced by CMC therapy were accompanied by improved function, as reflected by reductions in plasma creatinine (58+/-3 v 81+/-11 micromol/L), urinary protein excretion (9x/divided by 1 v 64x/divided by 1 mg/day), and diastolic cardiac stiffness (left ventricular end-diastolic pressure-volume relationship: 0.030+/-0.003 v 0.058+/-0.011 mm Hg/microL, p<0.05 for all). Despite substantial improvements in structure and function, only rare CMCs were present in the kidney and heart, whereas abundant CMCs were detected in the liver and spleen.


CONCLUSIONS
Together, these findings provide the first evidence suggesting that CMCs, but not SCs, exert a protective action in cardio-renal disease and that these effects may be mediated by the secretion of diffusible anti-fibrotic factor(s).
Yuen
Darren A
DA
Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Connelly
Kim A
KA
Advani
Andrew
A
Liao
Christine
C
Kuliszewski
Michael A
MA
Trogadis
Judy
J
Thai
Kerri
K
Advani
Suzanne L
SL
Zhang
Yuan
Y
Kelly
Darren J
DJ
Leong-Poi
Howard
H
Keating
Armand
A
Marsden
Philip A
PA
Stewart
Duncan J
DJ
Gilbert
Richard E
RE
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000473:pathology; D003094:Collagen / Q000737:chemistry; D003404:Creatinine / Q000097:blood; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000473:pathology*; D005921:Glomerulonephritis / Q000473:pathology; D006335:Heart Injuries / Q000473:pathology*; D007668:Kidney / Q000293:injuries* / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000473:pathology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D017154:Stromal Cells / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D017077:Culture Media, Conditioned; D016212:Transforming Growth Factor beta; D003094:Collagen; D003404:Creatinine