期刊
PLOS ONE
卷 5, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0009543
关键词
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资金
- Canadian Institutes of Health Research (CIHR
- Physicians' Services Incorporated Foundation of Ontario
- KRESCENT
- Heart and Stroke Foundation of Ontario
- Canadian Diabetes Association.
- Ministry of Research and Innovation, Ontario, Canada
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 antifibrotic effects of bone marrow-derived culture modified cells (CMCs) and stromal cells (SCs). Methodology/Principal Findings: 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 mu mol/L), urinary protein excretion (9x/41 v 646/41 mg/day), and diastolic cardiac stiffness (left ventricular end-diastolic pressure-volume relationship: 0.030 +/- 0.003 v 0.058 +/- 0.011 mm Hg/mu L, 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/Significance: 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).
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