Serum from patients with fulminant hepatic failure causes hepatocyte detachment and apoptosis by a β1-integrin pathway

Abstract

Hepatocyte transplantation is restricted by the impaired ability of hepatocytes to engraft and survive in the damaged liver. Understanding the mechanisms that control this process will permit the development of strategies to improve engraftment. We studied changes in liver matrix during acute injury and delineated the mechanisms that perturb the successful adhesion and engraftment of hepatocytes. Collagen IV expression was increased in sinusoidal endothelium and portal tracts of fulminant hepatic failure explants, whereas there were minimal changes in the expression of fibronectin, tenascin, and laminin. Using an in vitro model of cellular adhesion, hepatocytes were cultured on collagen-coated plates and exposed to serum from patients with liver injury to ascertain their subsequent adhesion and survival. There was a rapid, temporally progressive decrease in the adhesive properties of hepatocytes exposed to such serum that occurred within 4 hours of exposure. Loss of activity of the ␤1-integrin receptor, which controls adhesion to collagen, was seen to precede this loss of adhesive ability. Addition of the ␤1-integrin activating antibody (TS2/16) to cells cultured with liver injury serum significantly increased their adhesion to collagen, and prevented significant apoptosis. In conclusion, we have identified an important mechanism that underpins the failure of infused hepatocytes to engraft and survive in liver injury. Pretreating cells with an activating antibody can improve their engraftment and survival, indicating that serum from patients with liver injury exerts a defined nontoxic biological effect. This finding has important implications in the future of cellular transplantation for liver and other organ diseases. (HEPATOLOGY 2004;40:636 -645.)

Characterization of Pro‐apoptotic Effect of Liver Failure Plasma on Primary Human Hepatocytes and Its Modulation by Molecular Adsorbent Recirculation System Therapy

“…There was considerable variation in the extent of apoptosis induced by different LFP samples, not surprisingly reflecting the variability in the clinical status of the patients, and indeed some samples showed a similar level of apoptosis to normal plasma. This report enhances the observation of Newsome et al (5) who used a single pool of serum from a panel of liver failure patients to show enhanced in vitro apoptosis on primary human hepatocytes after loss of adhesion. There are important differences between the techniques used, however.…”

“…These toxic factors affect many systems (e.g., systemic vasculature and brain) and may have deleterious effects on liver cells themselves, by inhibiting regeneration and via induction of cytotoxicity (4)(5)(6)(7)(8). Potentially, this initiates a downhill cycle with further reduction in liver-specific function, persisting long after withdrawal of the insult that precipitated liver failure.…”

PolyHEMA spheroids are an inadequate model for the drug resistance of the intractable solid tumors

“…Further, several previous studies had shown that, in vitro, integrins are involved in resistance to cytotoxins. [36][37][38][39][40][41][42] Again, we used the chemotherapeutic compounds cisplatin, daunorubicin, doxorubicin and romidepsin, but now together with a 25 amino-acid long polypeptide, derived from netrin-1, which had been shown to interact with α6β4 integrin and block adhesion-mediated signaling. 43 We reasoned that if the netrin-1 derived peptide reduced cell adhesion, it should diminish drug resistance.…”

Disturbance of Apoptosis and DNA Synthesis by Helicobacter pylori Infection of Hepatocytes

“…Once the bacteria initiate the process of internalization, contact between the extracellular matrix (ECM) and integrin are broken, allowing endocytotic factors to concentrate receptors at the site of bacterial binding [34]. Loss of adherence of integrin to ECM then induces apoptosis [35,36].…”