Stephen A. Duncan, DPhil
Smartstate Chair in Regenerative Medicine
Professor and Chair
Room 657A, Basic Science Building
Office: (843) 792-9104
Lab: BSB653; (843) 792-5483
Education:D Phil, Oxford University, 1992
Postdoctoral, Rockefeller University, New York
Research in the Duncan laboratory focuses on liver development and disease using mice and induced pluripotent stem cells (iPSCs) as model systems.
Molecular mechanisms underlying liver development
Development of a simple two-cell embryo to a complex multicellular organism is a highly dynamic procedure requiring orchestrated cell movements and multiple interactions between cells and their surroundings. As cells differentiate, not only do they receive extra-cellular signals they secrete and display signals of their own, thereby defining the makeup of their local environments. The result of these intercellular communications is the controlled differentiation of populations of progenitor cells to produce novel cell types. The repertoire of genes expressed by the cell defines the phenotype. Gene transcription therefore plays a critical role in regulating cell fate. To comprehend the molecular mechanisms controlling embryonic development my laboratory is, therefore, attempting to understand how transcription factors interact with extracellular signaling mechanisms to drive cell differentiation.
Most organs are a complex array of different cell types and tissues, all of which dynamically interact to regulate organogenesis. Tissue complexity can make it challenging to measure the contribution of a specific transcription factor to overall organ or tissue development. However, the liver, in which 80% of the cells are hepatocytes, offers an attractive and relatively simple system in which to study the role of transcription factors during morphogenesis and development. In the laboratory, we use transgenic and knockout mice and genetically modified iPSCs to uncover the mechanisms through which transcription factors and cell signaling molecules are required to drive liver development.
Using pluripotent stem cells to study inborn errors of hepatic metabolism
The liver has vital endocrine and exocrine functions that regulate a diverse array of metabolic activities. Although specific forms of inborn errors of hepatic metabolism are relatively rare, cumulatively they are common and without treatment are often fatal. To date, a liver transplant can treat the most severe hepatic metabolic deficiencies. Unfortunately, the number of available donor livers is limited, and demand for transplant-quality livers continues to increase. With donor livers being scarce, it has been proposed that cell transplant therapy may offer an alternative to an organ transplant. One source of hepatocytes for transplant could be human iPSCs. Several projects in the laboratory, therefore, focus on generating functional hepatocytes from iPSCs.
Metabolic liver disease can also often be treated using small molecules or biologics that, in general, have an established track record of success. With this in mind, we are developing a platform that will facilitate the efficient identification of treatments for rare inborn errors of hepatic metabolism. We propose to 1) establish human pluripotent stem cells harboring genetic variants associated with disease in patients, 2) differentiate the stem cells to hepatocytes and examine whether genetic variations recapitulate the disease in culture, 3) establish assays that are compatible with moderate to high throughput screening to identify existing drugs that could be repurposed to correct the pathophysiology of the disease, and 4) establish the efficacy and safety of lead drugs using humanized animal models and human trials.
- Pashos EE, Park Y, Wang X, Raghavan A, Yang W, Abbey D, Peters DT, Arbelaez J, Hernandez M, Kuperwasser N, Li W, Lian Z, Liu Y, Lv W, Lytle-Gabbin SL, Marchadier DH, Rogov P, Shi J, Slovik KJ, Stylianou IM, Wang L, Yan R, Zhang X, Kathiresan S, Duncan SA, Mikkelsen TS, Morrisey EE, Rader DJ, Brown CD, Musunuru K. Large, Diverse Population Cohorts of hiPSCs and Derived Hepatocyte-like Cells Reveal Functional Genetic Variation at Blood Lipid-Associated Loci.
Cell Stem Cell. 2017 Apr 6;20(4):558-570.e10. doi: 10.1016/j.stem.2017.03.017. PMID: 28388432
- Cayo MA, Mallanna SK, Di Furio F, Jing R, Tolliver LB, Bures M, Urick A, Noto FK, Pashos EE, Greseth MD, Czarnecki M, Traktman P, Yang W, Morrisey EE, Grompe M, Rader DJ, Duncan SA. A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia. Cell Stem Cell. 2017 Apr 6;20(4):478-489.e5. doi: 10.1016/j.stem.2017.01.011. PMID: 28388428
- Jing R, Duncan CB, Duncan SA. A small molecule screen reveals that HSP90β promotes the conversion of iPSC-derived endoderm to a hepatic fate and regulates HNF4A turnover. Development. 2017 Mar 30. pii: dev.146845. doi: 10.1242/dev.146845. PMID: 28360131
- Bi X, Pashos EE, Cuchel M, Lyssenko NN, Hernandez M, Picataggi A, McParland J, Yang W, Liu Y, Yan R, Yu C, DerOhannessian SL, Phillips MC, Morrisey EE, Duncan SA, Rader DJ. ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion. EBioMedicine. 2017 Apr;18:139-145. doi: 10.1016/j.ebiom.2017.03.018. PMID: 28330813
- Mallanna SK, Waas M, Duncan SA, Gundry RL. N-glycoprotein surfaceome of human induced pluripotent stem cell derived hepatic endoderm. Proteomics. 2016, Dec 14 PMID: 27966262
- Mallanna SK, Cayo MA, Twaroski K, Gundry RL, Duncan SA. Mapping the Cell-Surface N-Glycoproteome of Human Hepatocytes Reveals Markers for Selecting a Homogeneous Population of iPSC-Derived Hepatocytes. Stem Cell Reports. 2016, Sep 13;7(3):543-56 PMID: 27569060 PMCID: PMC5032032
- Duncan SA. Multipotent stem cells and their lineage restriction to hepatocytes. Hepatology. 2016, Oct;64(4):1330. doi: 10.1002/hep.28727 PMID: 27405444
- Twaroski K, Mallanna SK, Jing R, DiFurio F, Urick A, Duncan SA. FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1. Genes Dev. 2015 Dec 1;29(23):2463-74. doi: 10.1101/gad.268961.115. PMID: 26637527
- Nagaoka M, Kobayashi M, Kawai C, Mallanna SK, Duncan SA. Design of a Vitronectin-Based Recombinant Protein as a Defined Substrate for Differentiation of Human Pluripotent Stem Cells into Hepatocyte-Like Cells. PLoS One. 2015, Aug 26;10(8):e0136350 PMID: 26308339
- Yang W, Liu Y, Slovik KJ, Wu JC, Duncan SA, Rader DJ, Morrisey EE. Generation of iPSCs as a Pooled Culture Using Magnetic Activated Cell Sorting of Newly Reprogrammed Cells. PLoS One. 2015, Aug 17;10(8):e0134995 PMID: 26281015
- Milanovich S, Peterson J, Allred J, Stelloh C, Rajasekaran K, Fisher J, Duncan SA, Malarkannan S, Rao S Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner. Exp Hematol. 2015 Jan;43(1):53-64 PMID: 25246269
- Noto FK, Determan MR, Cai J, Cayo MA, Mallanna SK, Duncan SA Aneuploidy is permissive for hepatocyte-like cell differentiation from human induced pluripotent stem cells. BMC Res Notes. 2014 Jul 8;7:437 PMID: 25002137
- Mallanna SK, Duncan SA. Differentiation of hepatocytes from pluripotent stem cells. Curr Protoc Stem Cell Biol. 2013;26:Unit 1G.4.PMID: 24510789
- Kolander KD, Holtz ML, Cossette SM, Duncan SA, Misra RP. Epicardial GATA factors regulate early coronary vascular plexus formation. Dev Biol. 2014 Feb 1;386(1):204-15.PMID: 24380800
- Fox IJ, Duncan SA. Engineering liver tissue from induced pluripotent stem cells: a first step in generating new organs for transplantation? Hepatology. 2013 Dec;58(6):2198-201.PMID: 24114924
- Shan J, Schwartz RE, Ross NT, Logan DJ, Thomas D, Duncan SA, North TE, Goessling W, Carpenter AE, Bhatia SN. Identification of small molecules for human hepatocyte expansion and iPS differentiation. Nat Chem Biol. 2013 Aug;9(8):514-20.PMID: 23728495
- Xuan S, Borok MJ, Decker KJ, Battle MA, Duncan SA, Hale MA, Macdonald RJ, Sussel L. Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis. J Clin Invest. 2012 Oct;122(10):3516-28.PMID: 23006325
- Yu Y, Liu H, Ikeda Y, Amiot BP, Rinaldo P, Duncan SA, Nyberg SL. Hepatocyte-like cells differentiated from human induced pluripotent stem cells: relevance to cellular therapies. Stem Cell Res. 2012 Nov;9(3):196-207.PMID: 22885101
- Sepac A, Si-Tayeb K, Sedlic F, Barrett S, Canfield S, Duncan SA, Bosnjak ZJ, Lough JW. Comparison of cardiomyogenic potential among human ESC and iPSC lines. Cell Transplant. 2012;21(11):2523-30.PMID: 22863088
- Cayo MA, Cai J, DeLaForest A, Noto FK, Nagaoka M, Clark BS, Collery RF, Si-Tayeb K, Duncan SA. JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia. Hepatology. 2012 Dec;56(6):2163-71. PMID: 22653811
- Gundry RL, Riordon DR, Tarasova Y, Chuppa S, Bhattacharya S, Juhasz O, Wiedemeier O, Milanovich S, Noto FK, Tchernyshyov I, Raginski K, Bausch-Fluck D, Tae HJ, Marshall S, Duncan SA, Wollscheid B, Wersto RP, Rao S, Van Eyk JE, Boheler KR. A cell surfaceome map for immunophenotyping and sorting pluripotent stem cells. Mol Cell Proteomics. 2012 Aug;11(8):303-16.PMID: 22493178
- Schwartz RE, Trehan K, Andrus L, Sheahan TP, Ploss A, Duncan SA, Rice CM, Bhatia SN. Modeling hepatitis C virus infection using human induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2544-8.PMID: 22308485
- Zhang C, Wang G, Zheng Z, Maddipati KR, Zhang X, Dyson G, Williams P, Duncan SA, Kaufman RJ, Zhang K. Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice. Hepatology. 2012 Apr;55(4):1070-82. PMID: 22095841
- DeLaForest A, Nagaoka M, Si-Tayeb K, Noto FK, Konopka G, Battle MA, Duncan SA. HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development. 2011 Oct;138(19):4143-53. PMID: 21852396