Research focus

The liver sustains reserves of iron, vitamins and minerals and detoxifies alcohol, drugs and other chemicals. The liver has also a function in synthesis by producing albumin which represents the most abundant protein in the plasma, and blood clotting factors. Finally, the liver has an essential metabolic function by storing glycogen and lipids.

Diseases targeting these functions are life threatening, with chronic liver disorders resulting in life-long treatment, a significant reduction in the quality of life, and progression to hepatocellular carcinoma, a form of cancer with very prognosis. Although the therapeutic arsenal has increased in the past decades, treatments for acute liver failure and end-stage chronic liver disease remain limited.

The overarching objective of our research is to understand the basic mechanisms controlling human development and liver biology to develop new therapies against liver diseases. For that we combine in vitro platforms based human Induced pluripotent stem cells (hIPSCs) and organoids with patient’s data and animal models.

hIPSCs and organoids can be derived from almost any patients and then grown indefinitely in large quantity allowing investigations impossible otherwise. Of particular interest, we perform gain and loss of functions experiments using CRISPR/Cas9 genome editing followed by phenotyping analyses taking advantage of state-of-the-art technologies for single cell transcriptomics and epigenomics. We then validate data generated in vitro using patients’ samples and animal model for disease.

This approach allows us to study detailed molecular mechanisms and then validate the interest of these result for clinical applications including drug discovery and regenerative medicine.

Details: https://www.bihealth.org/en/research/research-group/regenerative-hepatology

Selected publications

Brevini T, Maes M, Webb GJ, Fuchs CD, Buescher G, Wang L, Griffiths C, Brown M, Scott W, Pereyra-Gerber P, Gelson WTH, Brown S, Dillon S, Muraro D, Sharp J, Neary M, Box H, Tatham L, Stewart J, Curley P, Pertinez H, Forrest S, Mlcochova P, Varankar SS, Darvish-Damavandi M, Mulcahy VL, Kuc RE, Williams TL, Heslop JA, Rossetti D, Galanakis V,  Vila-Gonzalez M, Tysoe OC, Crozier TWM, Bargehr J, Sinha S, Upponi SS,  Fear C, Swift L, Saeb-Parsy K, Davies SE, Clements D, Humphreys P, Herriott J, Kijak E, Cox H, Bramwell C, Valentijn A, Illingworth CJR, UK-PBC research consortium, Marjot T, Barnes E, Moon AM, Barritt AS, Gupta RK, Baker S, Davenport AP, Corbett G, Buczacki SJA, Lee JH, Matheson NJ, Trauner M, Fisher AJ, Gibbs P, Butler AJ, Watson CJE, Mells GF, Dougan G, Owen A, Lohse AW, Vallier L* and Sampaziotis F*. FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome. Nature in press. *joint authorship.

Wesley B, Ross A, Muraro D, Miao Z, Saxton S, Tomaz R, Morell C, Ridley K, Zacharis E, Petrus-Reurer S, Kraiczy J, Mahbubani K, Brown S, Garcia-Bernardo J, Alsinet C, Gaffney D, Tysoe O, Botting RA, Stephenson E, Popescu DM, MacParland S, Bader GA, Ortmann D, Sampaziotis F, Saeb-Parsy K, Haniffa M, Stevens K, Zilbauer M, Teichmann S, Vallier L (2022). Single-cell atlas of human liver development reveals pathways directing hepatic cell fates. Nature Cell Biology. 2022 Oct;24(10):1487-1498. doi: 10.1038/s41556-022-00989-7. PMID: 36109670

Bertero A, Brown S, Madrigal P, Osnato A, Ortmann D, Yiangou L, Kadiwala J, Hubner NC, de Los Mozos IR, Sadée C, Lenaerts AS, Nakanoh S, Grandy R, Farnell E, Ule J, Stunnenberg HG, Mendjan S, Vallier L (2018). The SMAD2/3 interactome reveals that TGFβ controls m6A mRNA methylation in pluripotency. Nature. 2018 Mar 8;555(7695):256-259. doi: 10.1038/nature25784.

Sampaziotis F, Justin AW, Tysoe OC, Sawiak S, Godfrey EM, Upponi SS, Gieseck RL 3rd, de Brito MC, Berntsen NL, Gómez-Vázquez MJ, Ortmann D, Yiangou L, Ross A, Bargehr J, Bertero A, Zonneveld MCF, Pedersen MT, Pawlowski M, Valestrand L, Madrigal P, Georgakopoulos N, Pirmadjid N, Skeldon GM, Casey J, Shu W, Materek PM, Snijders KE, Brown SE, Rimland CA, Simonic I, Davies SE, Jensen KB, Zilbauer M, Gelson WTH, Alexander GJ, Sinha S, Hannan NRF, Wynn TA, Karlsen TH, Melum E, Markaki AE, Saeb-Parsy K*, Vallier L*. (2017). Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids. Nature Medicine. 2017 Jul 3. doi: 10.1038/nm.4360. PMID: 28671689. *joint authorship

Sampaziotis F, Cardoso de Brito M, Madrigal P, Bertero A, Saeb-Parsy K, Soares FAC, Schrumpf E, Melum E, Karlsen TH, Bradley JA, Gelson WTH, Davies S, Baker A, Kaser A, Alexander GJ, Hannan NRF* and Vallier L* (2015). Human Induced Pluripotent Stem Cell derived cholangiocytes for disease modeling and drug validation. Nature Biotechnology. Aug;33(8):845-52. doi: 10.1038/nbt.3275. *joint authorship

Yusa K*, Rashid ST*, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, Miranda E, Ordóñez A, Hannan N, Rouhani FJ, Darche S, Alexander G, Marciniak SJ, Fusaki N, Hasegawa M, Holmes MC, Di Santo JP, Lomas DA*, Bradley A* and Vallier L* (2011). Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature. 2011 Oct 12;478(7369):391-4. doi: 10.1038/nature10424. *joint authorship.