Abstract
BackgroundMost 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).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-ß. 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 106 SCs had no effect, 106 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, 106 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 106 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 µmol/L), urinary protein excretion (9×/÷1 v 64×/÷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/µL, 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/SignificanceTogether, 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).
Highlights
Repair by connective tissue formation is a fundamental response to acute injury
To determine the structural correlates of the improved kidney function seen with culture modified cells (CMCs) therapy, we examined the extent of glomerulosclerosis and tubulointerstitial fibrosis in SNX animal treated with phosphate-buffered saline (SNX) animals treated with syngeneic CMCs
We show that declining glomerular filtration rate (GFR) and worsening proteinuria, two of the cardinal laboratory indicators of progression towards end-stage kidney disease, were substantially attenuated by the administration of culture modified bone marrow derived cells in a widely used model of non-immune chronic kidney disease
Summary
Repair by connective tissue formation is a fundamental response to acute injury. If unchecked, the resulting fibrotic response leads to parenchymal replacement and organ dysfunction, estimated to account for nearly 45% of all deaths in the industrialized world [1]. Chronic kidney disease (CKD), for instance, estimated to affect almost 20 million adults in the United States alone, is characterized by progressive renal fibrosis with attendant reduction in glomerular filtration that results in the need for dialysis or transplantation to preserve life [2]. In addition to its profibrotic effects, TGF-ß has been implicated in microvascular loss [7], cardiomyocyte hypertrophy [8], and podocyte dysfunction [9] that characterize cardio-renal disease. Most forms of chronic kidney disease are characterized by progressive renal and cardiac fibrosis leading to dysfunction. 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)
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