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Three-Dimensional Collagen Matrix Scaffold Implantation as a Liver Regeneration Strategy
Published on: June 29, 2021
A critical role for matrix metalloproteinases in liver regeneration
Ian P J Alwayn1, Jennifer E Verbesey, Sendia Kim
1Department of Surgery and The Vascular Biology Program, Children's Hospital, Boston, Massachusetts 02115, USA.
Background:
Matrix metalloproteinases (MMPs), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) are mediators of liver regeneration. To determine whether MMPs are required for normal hepatic regeneration, we performed 67% hepatectomies on mice treated with a broad-spectrum MMP-inhibitor, and assessed the effect on liver regeneration and urinary MMP activity.
Methods:
Mice were subjected to sham operations, 67% hepatectomy, or 67% hepatectomy plus treatment with the broad-spectrum MMP inhibitor Marimastat. Urine collected preoperatively and for 8 d postoperatively was tested for MMP-2 and MMP-9 activity using zymography. Serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, TNF-alpha, IL-6, and hepatocyte growth factor levels were measured. Liver sections were analyzed by CD31 immunohistochemistry and microvessel density. Mitotic index and proliferating cell nuclear antigen labeling index were determined.
Results:
The mean regenerating liver weight on postoperative day 8 was 0.72 +/- 0.01 grams for the hepatectomy Marimastat group, and 0.83 +/- 0.02 grams for the hepatectomy control group (P < 0.001). Urinary MMP-9 activity was elevated during hepatic regeneration, and decreased on postoperative day 8 when the liver returned to its preoperative mass. In contrast, urine from hepatectomy Marimastat mice, in which liver regeneration was successfully inhibited, showed consistently low levels of MMP-2 and MMP-9 activity. The hepatectomy Marimastat group also exhibited elevated serum IL-6 levels on post-operative day 8, while serum TNF-alpha soluble receptor II levels were unchanged. Hepatocyte growth factor levels were not significantly different between the control hepatectomy and hepatectomy Marimastat groups at days 2, 4, and 8. Liver microvessel density was reduced in the hepatectomy Marimastat group at day 4. Mitotic index and proliferating cell nuclear antigen index were significantly decreased in the Marimastat hepatectomy group at post-operative day 2.
Conclusions:
The broad-spectrum MMP-inhibitor Marimastat inhibits liver regeneration. Microvessel density is reduced at day 4. Furthermore, urinary MMP-9 is elevated during liver regeneration, and this effect is not observed when regeneration is inhibited by the broad-spectrum MMP-inhibitor Marimastat.
Insights
Matrix metalloproteinases (MMPs) are crucial for liver regeneration. Inhibiting MMPs with Marimastat significantly impaired liver regrowth and reduced microvessel density in mice after hepatectomy.
Area of Science:
- Hepatology
- Molecular Biology
- Regenerative Medicine
Background:
- Matrix metalloproteinases (MMPs), TNF-alpha, and IL-6 mediate liver regeneration.
- The role of MMPs in normal hepatic regeneration requires further investigation.
Purpose of the Study:
- To determine if MMPs are essential for normal liver regeneration.
- To assess the impact of a broad-spectrum MMP inhibitor on hepatic regeneration.
Main Methods:
- Mice underwent 67% hepatectomy with or without Marimastat treatment.
- Urinary MMP activity (MMP-2, MMP-9) was measured via zymography.
- Liver regeneration markers, including weight, microvessel density, and proliferation indices, were analyzed.
Main Results:
- Marimastat significantly inhibited liver regeneration, with reduced liver weight on postoperative day 8.
- Urinary MMP-9 activity increased during regeneration but was suppressed by Marimastat.
- MMP inhibition led to decreased microvessel density and reduced mitotic/proliferating cell indices.
Conclusions:
- Broad-spectrum MMP inhibition with Marimastat effectively blocks liver regeneration.
- MMP activity, particularly MMP-9, is elevated during hepatic regeneration and is necessary for the process.
- Inhibition of MMPs impacts liver regeneration by affecting microvessel formation and cell proliferation.
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