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Liver-Selective MMP-9 Inhibition in the Rat Eliminates Ischemia-Reperfusion Injury and Accelerates Liver Regeneration
Xiangdong Wang1, Ana C Maretti-Mira1, Lei Wang1
1USC Division of Gastrointestinal and Liver Disease and the USC Research Center for Liver Disease, Keck Medicine of the University of Southern California, Los Angeles, CA.
Hepatology (Baltimore, Md.)
|July 19, 2018
Summary
Targeted MMP-9 inhibition in the liver boosts progenitor cell recruitment, accelerating liver regeneration and healing after injury. Systemic inhibition, however, hinders this process, highlighting the importance of localized treatment for liver repair.
Area of Science:
- Hepatology and regenerative medicine
- Molecular and cellular biology
- Vascular biology
Background:
- Liver sinusoidal endothelial cell progenitor cells (sprocs) are crucial for liver regeneration, recruited via VEGF-sdf-1 signaling.
- Matrix metalloproteinases (MMPs) can degrade VEGF, potentially inhibiting sproc recruitment.
- Systemic MMP inhibition may impede sproc mobilization from bone marrow.
Purpose of the Study:
- To investigate the effects of liver-selective versus systemic MMP-9 inhibition on liver regeneration and injury.
- To determine if liver-selective MMP-9 inhibition enhances bone marrow sproc recruitment via the VEGF-sdf-1 pathway.
- To compare the therapeutic potential of localized vs. systemic MMP inhibition in liver repair.
Main Methods:
- Partial hepatectomy and extended hepatectomy models in animals.
- Administration of liver-selective MMP-9 inhibitors and systemic MMP inhibitors.
- Assessment of liver regeneration, injury markers, and sproc recruitment and engraftment.
- Analysis of VEGF and sdf-1 protein expression and VEGF cleavage by MMP-9.
Main Results:
- Liver-selective MMP-9 inhibition accelerated liver regeneration by 40% and abolished warm ischemia-reperfusion injury.
- Systemic MMP inhibition impaired liver regeneration and sproc mobilization from bone marrow.
- Liver-selective MMP-9 inhibition increased sproc recruitment and engraftment, preventing VEGF cleavage and enhancing VEGF/sdf-1 signaling.
- Systemic MMP inhibition improved allogeneic progenitor cell engraftment when infused.
Conclusions:
- Liver-selective MMP-9 inhibition protects hepatic VEGF from degradation, promoting sproc recruitment and enhancing liver regeneration.
- Targeted inhibition of MMP-9 in the liver is a promising therapeutic strategy for vascular damage and liver injury.
- Systemic MMP inhibition may augment the efficacy of endothelial progenitor cell-based stem cell therapies.
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