Dr. Bell is a member of the Division of Experimental Pathology.
My research interest lies in understanding the role of transcription factors in control and regulation of liver growth, regeneration, differentiation and carcinogenesis. In particular my studies focus on how growth factors, extra-cellular matrix, or chemicals alter the transcriptional program and affect cellular differentiation and fate. Of particular interest are the liver-enriched transcription factors, especially Hepatic Nuclear Factor-4, a key liver transcription factor required for liver development and function. We have established an in-vitro cell culture model in which primary hepatocytes grow and de-differentiate then can be induced to re-differentiate upon addition of extra-cellular matrix, DMSO or Phenobarbital. This system has many similarities to the embryonic development of the liver and may garner significant insights into the molecular events involved in hepatocyte differentiation and liver development. Results from these studies have shown that HNF4 expression and function are highly regulated during de-differentiation and re-differentiation of hepatocytes. We continue to investigate the mechanisms regulating hepatic differentiation, as these have a role in liver development, regeneration and cancer.
α-1-Antitrypsin (A1AT) deficiency (ATD) is the most common cause of pediatric metabolic liver disease and can lead to cirrhosis and hepatocellular carcinoma in adults. A1AT deficiency has a range of complications affecting liver, lungs and other tissues. The hepatocellular injury is caused by toxicity associated with accumulation of A1AT-Z mutant protein (ATZ). The ATZ protein cannot be properly processed, resulting in misfolding and accumulation in the endoplasmic reticulum of hepatocytes. The availability of a transgenic mouse model, PiZ mice, harboring the human ATZ gene along with a large part of the A1AT promoter, has provided an excellent murine model for the study of the human liver disease. The livers of PiZ mice harbor PAS/D positive intrahepatic globules composed of aggregated and polymerized ATZ protein, fibrosis, mild steatosis, hepatocyte proliferation and eventually carcinomas. Interestingly, these livers show spontaneous emergence of hepatocytes free of globules. Using cell culture and invivo administration of viral vectors, we seek to understand the mechanisms by which GF cells proliferate and replace GC cells, and to manipulate these mechanisms to affect therapeutic resolution of liver damage in A1AT deficiency.
TGF-β is a multifunctional cytokine that is cytotoxic to hepatocytes. It plays key roles in fibrogenesis which is found in many chronic liver diseases which ultimately result in cirrhosis. We have found that TGF-β regulates HNF4 expression in hepatocyte cultures, HCC cell lines and have evidence that it does so in fibrosis of many etiologies in rodents and humans. The mechanisms by which TGF-β regulates HNF4 in fibrosis are currently being investigated in rodent models of fibrosis and carcinogenesis.
NIH Research
View Dr. Bell's NIH RePORT on nih.gov.
View Dr. Bell's publications on PubMed.
- Nishikawa T, Bell A, Brooks JM, Setoyama K, Melis M, Han B, Fukumitsu K, Handa K, Tian J, Kaestner KH, Vodovotz Y, Locker J, Soto-Gutierrez A, Fox IJ. Resetting the transcription factor network reverses terminal chronic hepatic failure. The Journal of Clinical Investigation. 2015 Apr 1; 125 (4):1533-1544. PMID: PMID: 25774505. doi: 10.1172/JCI73137.
- Donthamsetty S, Bhave VS, Kliment CS, Bowen WC, Mars WM, Bell AW, Stewart RE, Orr A, Wu C, Michalopoulos GK. Excessive hepatomegaly of mice with hepatocyte-targeted elimination of integrin linked kinase following treatment with 1,4-bis [2-(3,5-dichaloropyridyloxy)] benzene. Hepatology (Baltimore, Md.). 2011 Feb; 53 (2):587-95. PMCID: PMC3062106. PMID: 21274879.
- Lin CW, Mars WM, Paranjpe S, Donthamsetty S, Bhave VS, Kang LI, Orr A, Bowen WC, Bell AW, Michalopoulos GK. Hepatocyte proliferation and hepatomegaly induced by phenobarbital and 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene is suppressed in hepatocyte-targeted glypican 3 transgenic mice. Hepatology (Baltimore, Md.). 2011 Aug; 54 (2):620-30. PMID: 21574168.
- Bhave VS, Paranjpe S, Bowen WC, Donthamsetty S, Bell AW, Khillan JS, Michalopoulos GK. Genes inducing iPS phenotype play a role in hepatocyte survival and proliferation in vitro and liver regeneration in vivo. Hepatology. 2011 Oct;54(4):1360-70. doi: 110.1002/hep.24507. Epub 2011 Aug 24.