Current models employed by the pharmaceutical industry and academia to investigate disease, drug discovery/ safety/ efficacy, and toxicity are inadequate, as they do not faithfully recapitulate the human physiology, metabolism or cellular behavior. Consequently, there is a pressing need to improve this. The development of human induced pluripotent stem cell (hiPSC) technology, provides a novel way to model human disease and offers an alternative to current cell-based systems, most importantly as a potentially limitless supply of genetically defined stem cells that can be differentiated into virtually any cell type under defined conditions. This approach decreases dependency, usage and the overall numbers of animal models, in compliance with the 3R's (Reduction, Refinement and Replacement). Current hiPSC technology itself has its own limitations, which include lack of differentiation procedures to many cell types required combined with an immature phenotype of derived somatic progeny. We are addressing these shortcomings by investigating a number of key areas listed below. This will allow the potential use of the derived hiPSCs and their progeny in disease modeling, toxicity studies, drug discovery/ safety/ efficacy and in the long term, potential therapeutic application.
The long-term goal of our work is to improve current methods of reprogramming and transdifferentiation while gaining insight into the mechanistic processes involved. In addition we will utilize these technologies to derive disease specific models to investigate disease processes in the dish. To reach these goals, we are (ii) establishing methods of transdifferentiation, (ii) improving current methodologies of differentiation towards endoderm and other lineages, and (iii) applying these to disease models.
I. Nuclear reprogramming and changing cell fate – Transdifferentiation.
II. Understanding differentiation.
III. The use of small molecules for the derivation of hepatic cell types from human pluripotent stem cells.
IV. 3D culture systems to develop physiologically relevent tissue models
V. Disease modelling
VI. Conservation of critically endangered species
Selected publications (2010-2017):
Siller R, Dufour E, Wilmut I, Jung Y-W, Park IH and Sullivan GJ*. Development of an inducible platform for intercellular protein delivery.International Journal of Pharmaceutics.2017: http://dx.doi.org/10.1016/j.ijpharm.2017.02.067. (*corresponding).
Gamal W, Treskes P, Chesne CG, Samuel K, Sullivan GJ, Siller R, Srsen V, Underwood I, Smith S, Hayes PC, Plevris JN, Bagnaninchi PO and Nelson LJ. Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver. Scientific Reports.2017:DOI: 10.1038/srep37541.
Siller R, Naumovska E, Mathapati S, Lycke M and Sullivan GJ*. Development of a rapid screen for the endodermal differentiation potential of human pluripotent stem cell lines. Scientific Reports.2016:DOI: 10.1038/srep37178. (*corresponding).
Mathapati S, Siller R, Impellizzeri AR, Lycke M, Vegheim K, Almass R and Sullivan GJ*. Small molecule directed hepatocytes like cells differentiation of human pluripotent stem cells. Curr. Protoc. Stem Cell Biol.2016:38:1G.6.1-1G.6.18.doi: 10.1002/cpsc.13. (*corresponding).
Xu M, Stattin E-L, Shaw G, Heinegård D, Sullivan G, Wilmut I, Colman A, Önnerfjord P, Khabut A, Aspberg A, Dockery P, Hardingham T, Murphy M, Barry F. Chondrocytes derived from mesenchymal stromal cells and induced pluripotent cells of patients with familial osteochondritis dissecans exhibit an ER stress response and defective matrix assembly. Stem Cells Transl. Med. 2016: 5:1171-1181.
Siller R, Greenhough S, Naumovska E and Sullivan GJ*.Small molecule driven hepatocyte differentiation of human pluripotent stem cells. Stem Cell Reports. 2015: 4:939-952. (*corresponding).
Siller R, Greenhough S, Park IH and Sullivan GJ*. Modelling human disease with pluripotent stem cells. Current Gene Therapy. 2013: 13:99-110. (*corresponding).
Dajani R, Koo SE, Sullivan GJ*, Park IH*. Investigation of Rett syndrome using pluripotent stem cells. J Cell Biochem. 2013: 114:2446-2453 (*co-corresponding).
Bilican B, Serio A, Barmada SJ, Nishimura AL, Sullivan GJ,Carrasco M, Phatnani HP, Puddifoot CA, Story D, Fletcher J, Park IH, Friedman BA, Daley GQ, Wyllie DJ, Hardingham GE, Wilmut I, Finkbeiner S, Maniatis T, Shaw CE, Chandran S. (2013) Comment on "Drug screening for ALS using patient-specific induced pluripotent stem cells". Sci Transl Med. 5(188):188le2.
Kim KY, Jung YW, Sullivan GJ, Chung L and Park IH. Cellular Reprogramming: a novel tool in investigating ASDs. Trends Mol Med 2012: 18:463-71.
Yamazaki T, Chen S, Yu Y, Yan B, Carrasco MA, Tapia JC, Zhai B, Das R, Lalancette-Hebert M, Sharma A, Chandran S, Sullivan G,Nishimura AL, Shaw CE, Gygi SP, Shneider NA, Maniatis T, and Reed R.FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep. 2012: 25;2:799-806. F1000 recommended.
Bilican B, Serio A, Barmada SJ, Nishimura AL, Sullivan GJ,Carrasco M, Phatnani HP, Puddifoot CA, Story D, Fletcher J, Park IH, Friedman BA, Daley GQ, Wyllie DJ, Hardingham GE, Wilmut I, Finkbeiner S, Maniatis T, Shaw CE, Chandran S. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci USA.2012: 109:5803-8. F1000 recommended.
Zhou XL, Sullivan GJ,Sun P, and Park IH. Humanized murine model for HBV and HCV using human induced pluripotent stem cells. Archives of Pharmacal Research. 2012: 35:261-269.
Hysolli E, Zhou XL, Liu R, Kim JH, Adams B, Sullivan GJ, and Park IH. Role of Pluripotent Stem Cells in Regenerative Medicine. Regenerative Medicine, Stem Cells and the Liver. Book Chapter, March 15, (2012) by Science Publishers.
Wilmut I, Sullivan G and Chambers I. The evolving biology of cell reprogramming. Philosophical Transactions of the Royal Society B. Philosophical Transactions of the Royal Society B. 2011: 366:2183-2197.
Wilmut I, Wongtawan T, Quigley M and Sullivan GJ. Biomedical and social contributions to sustainability. Philosophical Transactions of the Royal Society A.2011: 369:1730-1747.
Ruzov A, Tsenkina Y, Serio A, Dudnakova T, Fletcher J, Bai Y, Chebotareva T, Pells S, Hannoun Z, Sullivan GJ,Chandran S, Hay D, Bradley M, Wilmut I and De Sousa P. Lineage specific distribution of high levels of genomic 5-hydroxymethylcytosine in mammalian development. Cell Research. 2011: 21:1332-42.
Sullivan GJ,Bai YM, Fletcher J and Wilmut I.Induced pluripotent stem cells: epigenetic memories and practical implications. Molecular Human Reproduction. 2010: 16:880–885.
Hannoun Z, Filippi C, Sullivan GJ,Hay DC and Iredale JP. Hepatic Endoderm Differentiation from Human Embryonic Stem Cells. Current Stem Cell Research &Therapy. 2010: 5:233-244.
SullivanGJ*,Hay DC, Park IH, Fletcher J, Hannoun Z, Payne CM, Dalgetty D, Black JR, Ross JA, Samuel K, Wang G, Daley GQ, Lee JH, Church GM, Forbes SJ, Iredale JP and Wilmut I.Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology.2010: 51:329-335. (*corresponding). F1000 recommended. Editiorial Hepatology and Press coverage BBC.
Taylor J, Wilmut I, Sullivan GJ. What are the limits to cell plasticity? [Research Highlight] Cell Research.2010: 20:502-503.