Hepatic Progenitor Cell Proliferation and Liver Injury in α‐1‐Antitrypsin Deficiency

Abstract

Homozygous, ZZ, alpha-1-antitrypsin (a1AT) deficiency is a common genetic liver disease, which causes liver injury and hepatocellular carcinoma (HCC) in children and adults. The a1AT mutant Z gene encodes a mutant protein which accumulates within hepatocytes leading to hepatocellular death, and a hepatic regenerative response. However, the mechanisms linking hepatocellular injury to these responses are poorly understood. In this study, we examined liver injury and response in human liver and in transgenic mice and found involvement of hepatic progenitor cells. Liver biopsy specimens of low grade, early stage human ZZ liver exhibiting minimal inflammation and minimal fibrosis (grade 1 and stage 1) were examined for hepatic progenitor cell (HPC) proliferation using immunoreactivity for cytokeratin-7 (CK7). The results showed increased CK7 positive HPC proliferation in human ZZ liver above normal liver, but five-fold less HPC proliferation than in grade and stage-matched disease control specimens of hepatitis C infected liver. Livers from PiZ mice, a model transgenic for the human a1AT mutant Z gene which recapitulates features of the human injury, also showed HPC proliferation. Human ZZ liver and PiZ mice are both known to develop dysplasia in the liver and HCC. HCC in PiZ mice was also characterized by HPC proliferation. Progressive hepatic fibrosis with age in the PiZ mice is demonstrated for the first time in these studies. In conclusion, the chronic injury in both ZZ human and PiZ mouse liver is associated with hepatic fibrosis, and a unique magnitude of HPC proliferation associated with the hepatic proliferative response.

Prostate progenitor cells proliferate in response to castration

“…An alternative explanation for proliferation and migration of LRCs and 4-marker cells following castration would be the response to injury. Progenitor cells play a primary role in the regenerative response to injury in a variety of adult tissues [37, 38, 39, 40, 41] and it has been postulated that factors released by injured tissues stimulate stem cell proliferation and attract stem cells to the sites of injury [43, 44]. The effects of castration on the adult prostate are a combination of ischemic injury due to vascular disruption, epithelial apoptosis and acute inflammation [45; 46; 47].…”

Immunohistochemical Analysis of the Stem Cell Marker Lgr5 in Pediatric Liver Disease

“…When we further compared neonatal liver biopsies and childhood explants from the same patients with A1ATD, we found increased expression of LGR5 at time of biopsy, suggesting recruitment of a predominantly LGR5+ regenerative response early on, before end-stage cirrhosis. Interestingly, HPCs have been identified in pediatric liver diseases prior to the development of significant fibrosis, suggesting an early response to liver injury (29,30). Recently, Kou et al showed by immunohistochemistry that the regenerative compartment is expanded in patients undergoing liver transplantation for BA, compared to patients with an earlier stage of disease undergoing Kasai hepatoportoenterostomy (31).…”

Alpha-1-Antitrypsin Deficiency Presenting as Neonatal Cholestasis: Predictors of Outcome and Effect of Ursodeoxycholic Acid

“…Yet, only 10% of homozygote ZZ individuals will present neonatal cholestasis [2]. This indicates that other factors (environmental and/or genetic modifiers) are involved in liver disease pathogenesis [4,[9][10][11], influencing clinical presentation and prognosis.…”

“…The recent advances in the knowledge of the liver disease pathogenesis in AAT deficiency opened the field for development of new therapy strategies [11,12]. In summary, AAT deficiency is characterized by accumulation of misfolded ZAAT within hepatocytes The abnormal protein polymerizes and is being kept held in the ER.…”

“…Although recent advances in the knowledge of the liver disease pathogenesis in AAT deficiency had opened the field for development of new therapy strategies [9][10][11][12][13], currently there are still no prevention options, and liver transplantation [14] is the only therapy when it becomes irreversible. Ursodeoxycholic acid (UDCA) is currently the most widely used therapeutic option for the treatment of cholestatic hepatopathies [15].…”