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Culture-Modified Bone Marrow Cells Attenuate Cardiac and Renal Injury in a Chronic Kidney Disease Rat Model via a Novel Antifibrotic Mechanism

Yuen DA, Connelly KA, Advani A, Liao C, Kuliszewski MA, Trogadis J, Thai K, Advani SL, Zhang Y, Kelly DJ, Leong-Poi H, Keating A, Marsden PA, Stewart DJ, Gilbert RE - PLoS ONE (2010)

Bottom Line: 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).

Affiliation: Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT

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).

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 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/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).

Cardiac fibrosis.(a–c) Representative picrosirius red stained heart sections at 8 weeks post-surgery. Original magnification × 160. (a) Sham animal. (b) SNX animal. (c) SNX–CMC animal. (d) Quantitative cardiac fibrosis analysis. * p<0.05 vs. sham operated animals. † p<0.05 vs. SNX animals. Abbreviations: PSR: picrosirius red.
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pone-0009543-g007: Cardiac fibrosis.(a–c) Representative picrosirius red stained heart sections at 8 weeks post-surgery. Original magnification × 160. (a) Sham animal. (b) SNX animal. (c) SNX–CMC animal. (d) Quantitative cardiac fibrosis analysis. * p<0.05 vs. sham operated animals. † p<0.05 vs. SNX animals. Abbreviations: PSR: picrosirius red.

Mentions: One of the primary determinants of impaired left ventricular relaxation is the development of cardiac fibrosis. Accordingly, we examined the degree of cardiac matrix accumulation at 8 weeks post-surgery. As in the kidney, SNX lead to significant interstitial fibrosis in the heart. CMC treatment significantly attenuated the extent of cardiac fibrosis (Fig. 7). In addition, myocyte cross sectional area, indicative of cellular hypertrophy and thus worsened cardiac afterload, was increased in SNX rats and reduced by CMC administration (Fig. 8).

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Culture-Modified Bone Marrow Cells Attenuate Cardiac and Renal Injury in a Chronic Kidney Disease Rat Model via a Novel Antifibrotic Mechanism

Yuen DA, Connelly KA, Advani A, Liao C, Kuliszewski MA, Trogadis J, Thai K, Advani SL, Zhang Y, Kelly DJ, Leong-Poi H, Keating A, Marsden PA, Stewart DJ, Gilbert RE - PLoS ONE (2010)

Cardiac fibrosis.(a–c) Representative picrosirius red stained heart sections at 8 weeks post-surgery. Original magnification × 160. (a) Sham animal. (b) SNX animal. (c) SNX–CMC animal. (d) Quantitative cardiac fibrosis analysis. * p<0.05 vs. sham operated animals. † p<0.05 vs. SNX animals. Abbreviations: PSR: picrosirius red.
© Copyright Policy
pone-0009543-g007: Cardiac fibrosis.(a–c) Representative picrosirius red stained heart sections at 8 weeks post-surgery. Original magnification × 160. (a) Sham animal. (b) SNX animal. (c) SNX–CMC animal. (d) Quantitative cardiac fibrosis analysis. * p<0.05 vs. sham operated animals. † p<0.05 vs. SNX animals. Abbreviations: PSR: picrosirius red.
Mentions: One of the primary determinants of impaired left ventricular relaxation is the development of cardiac fibrosis. Accordingly, we examined the degree of cardiac matrix accumulation at 8 weeks post-surgery. As in the kidney, SNX lead to significant interstitial fibrosis in the heart. CMC treatment significantly attenuated the extent of cardiac fibrosis (Fig. 7). In addition, myocyte cross sectional area, indicative of cellular hypertrophy and thus worsened cardiac afterload, was increased in SNX rats and reduced by CMC administration (Fig. 8).

Bottom Line: 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).

Affiliation: Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT

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).

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 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/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).

View Similar Images In: Results  - Collection
View Article: PubMed Central -  PubMed
Show All Figures - Show MeSH
getmorefigures.php?pmc=2832011&rFormat=json&query=null&req=5