GastrointestinalA Critical Role for Matrix Metalloproteinases in Liver Regeneration1
Introduction
Liver regeneration is an essential physiological response after hepatic injury, resection, or transplantation. The liver is a unique organ in that regeneration occurs by DNA replication and mitosis, whereas most other organs simply hypertrophy [1]. Stimulators of hepatic regeneration include hepatocyte (HGF) and epidermal growth factor, transforming growth factor-alpha, and the potent stimulators of angiogenesis, fibroblast growth factor and vascular endothelial growth factor [2]. In addition, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) are associated with liver regeneration [3, 4, 5].
IL-6 and TNF-α are both considered to be priming factors for regeneration because they prepare hepatocytes for replication [6]. IL-6 initiates the acute phase response in the liver, and activates STAT3, a transcription factor that initiates hepatocyte replication [7]. Therefore, it appears that IL-6 plays both a priming and mitogenic role in hepatic regeneration. Further demonstrating the importance of this cytokine in the regenerative process, IL-6 deficient mice demonstrate abnormal regeneration after partial hepatectomy [8]. Although it has been difficult to test the result of giving mice large doses of IL-6 due to systemic toxicity, lower doses administered over a long period of time have resulted in livers that regenerate beyond their original mass [6]. While IL-6 activates STAT3, TNF-α activates nuclear factor kappa B (NF-κB) a similar transcription factor [9, 10]. The main action of TNF-α is thought to be the release of IL-6, resulting in the cascade described above. While TNF-α deficient mice do not regenerate their livers successfully, preoperative administration of IL-6 produces normal regeneration, suggesting that TNF-α affects hepatic regeneration principally through its effects on IL-6 [11]. Lastly, the metalloproteinase, ADAM 17, actively releases TNF- α from the cell surface.
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that work in concert with their endogenous inhibitors, the tissue inhibitors of metalloproteinases to control the rate and degree of extracellular matrix degradation [12, 13]. The effects of this activity are widespread and include tissue regeneration, embryologic development, ovulation, tumor growth, and metastasis [14, 15, 16]. Extracellular matrix (ECM) remodeling by MMPs is critical for the growth of new capillaries from pre-existing vessels (angiogenesis) [15, 17, 18].
In a recent study, we investigated whether urinary MMPs or tissue inhibitors of metalloproteinases could predict the status of liver regeneration after partial hepatectomy. Rodent livers are known to regenerate to their original mass 8 days after a 67% hepatectomy [19, 20]. We showed that during hepatic regeneration in mice, there is an elevation in MMP-9 activity in the urine. At postoperative day 8, loss of MMP-9 activity was consistent with the cessation of hepatic regeneration [14].
Because MMPs appear to be a key mediator of hepatic regeneration, we more recently hypothesized that a broad-spectrum MMP inhibitor would reduce the rate of organ regeneration. Successful inhibition of hepatic regeneration through this route would support the concept that liver regeneration is dependent on MMP activity and would provide additional insight into the complex mechanisms of hepatic regeneration. To test our hypothesis, mice underwent a partial hepatectomy and were subsequently treated with Marimastat, a broad-spectrum MMP inhibitor.
Section snippets
Partial Hepatectomy
Experiments were performed on 7 to 8 wk old male C57BL/6 mice (The Jackson Laboratory, Bar Harbor, ME). The mice were housed five animals to a cage in a barrier room. Mice were acclimated to their environment for at least 72 h prior to the initiation of each experiment and allowed food and water ad libitum. Animal protocols complied with the NIH Animal Research Advisory Committee guidelines and were approved by the Children’s Hospital Institutional Animal Care and Use Committee. Mice underwent
Mouse and Liver Weights
There was no statistical difference in mouse weights between any of the groups when comparing preoperative weights and post-hepatectomy day 8 weights (data not shown). There was no statistical difference in mean liver weights in the sham control and sham Marimastat mice at post operative day 4 and day 8 (data not shown). Mean post-hepatectomy liver weights after sacrifice at day 4 were 0.84 ± 0.07 grams for the hepatectomy control group and 0.74 ± 0.03 grams for the hepatectomy Marimastat
Discussion
It has become increasingly clear that organ regeneration, like tumor growth, is dependent upon angiogenesis. The endothelial cell proliferation and apoptosis that accompany hepatic regeneration, for example, can be modulated through the administration of angiogenic agents [2]. In this report we show that matrix metalloproteinases are also a critical requirement in the normal hepatic regenerative process. This hypothesis was founded on the fact that MMPs are active in both extracellular matrix
Acknowledgments
JEV is supported by the American Society of Transplant Surgeons-Roche Laboratories Scientist Research Award and the Robert E. Wise Research Foundation. MP is supported by the CHMC Surgical Foundation and by NIH grant DK069621-01. IPJA is supported by the Dutch Cancer Society. MAM is supported by P01 CA45548 and 1 P50 DK065298.
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2012, Biotechnology AdvancesCitation Excerpt :However, it is essential to understand the sequence of events leading to regeneration of hepatocytes in vivo in order to mimic these factors in vitro. Hepatocytes are known to regenerate in a series of steps (initiation, expansion, proliferation and termination) through the action of growth factors and certain cytokines in vivo (Alwayn et al., 2008). In the initiation phase, cytokines (Interleukin 6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α)) are required for hepatocytes to proliferate (Alwayn et al., 2008).
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2011, Journal of Pediatric SurgeryCitation Excerpt :Interleukin-6 also uses glycoprotein 130 (gp 130) as a receptor to induce the nuclear translocation of STAT3 as well as to activate the Ras/mitogen activated protein pathway. Glycoprotein 130/STAT3 demonstrated a protective effect against liver fibrogenesis during chronic cholestasis and controlled hepatocyte proliferation after a partial hepatectomy [5,12]. However, the underlying mechanism of liver regeneration could not be elucidated in this study.
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Ian P.J. Alwayn and Jennifer E. Verbesey contributed equally to this work.