Medical College of Wisconsin
Department of Cell Biology, Neurobiology & Anatomy
8701 Watertown Plank Road
Milwaukee, WI 53226-3548
(414) 955-6517 (fax)
PhD, Peking University, China
Faculty Advisor: Stephen Duncan, DPhil
Hepatic differentiation of human pluripotent stem cells
Liver develops from ventral foregut through sequential steps. In addition to the inductive signals from the cardiac mesoderm and the septum transversum mesenchyme that together induce the endoderm to adopt a hepatic fate, little is known about the transcriptional circuit regulating early liver development.
The model based on the differentiation of human pluripotent stem cells into hepatocytes is able to recapitulate the known molecular events occurring during mammalian hepatic development and since this system can be genetically modified it can be used to further characterize the molecular processes underlying the specification of human hepatocytes. This is important, under the therapeutic point of view, for the in vitro generation of hepatic cells from embryonic stem or somatic stem cells, for regenerative medicine.
My research interest is to investigate the role of the transcription factor HNF1beta in the hepatic development.
The homozygous mutation of this gene in mouse embryos results in lethality by day 7.5 of development and embryos display a disorganized visceral endoderm and a signiﬁcantly reduced size suggesting that vHNF1 expression is necessary for visceral endoderm differentiation. The complementation with wild-type visceral endoderm rescues the lethality but reveals an additional phenotype linked to vHNF1 later expression: the embryos show abnormalities in the morphogenesis of different organs.
Among others, rescued embryos exhibit a severe defect in liver development including hypoplasia and reduced dimension of the organ together with a severely disorganized architecture. In particular HNF1beta seems to be required in two different steps of the early hepatic organogenesis in mouse: the thickening of the hepatic bud and the expression of essential hepatic genes. Interestingly, studies in Zebrafish suggest a conserved role of this factor in vertebrates.
The hypothesis of my work is that HNF1beta performs a similar and critical role also in the early human liver development. I am currently investigating this hypothesis using hiPSC lines expressing shRNAs that specifically silence HNF1beta. This approach in combination with the use of molecular assays will make it possible to characterize the role of this factor in the early stages of hepatic specification and to unravel the underlying molecular mechanism, which is mainly unknown so far. In this context I will also inquire about the reciprocal interaction between HNF1beta and HNF4alpha, a transcription factor known to be essential for the establishment and maintenance of liver-specific gene expression.