Group Leader, Stem Cells and Tissue Regeneration Laboratory, The Gurdon Institute
Sir Henry Dale Wellcome Trust Fellow
In adult mammals, self-renewal is required for the maintenance of tissue homeostasis and tissue repair. In organs with extensive self-renewal, such as the intestine and stomach, adult stem cell populations are constantly cycling to maintain cellular turnover. In organs with limited proliferative capacity, though, such as the liver or pancreas, we have recently described a population of stem/progenitor cells that become activated exclusively upon damage to repair the lost tissue and reinstall homeostasis. However, the mechanism that regulates the activation of the cells during regeneration, from the implication of the niche to the epigenetic mechanisms regulating this activation remains unsolved. One of our main goals is to understand the mechanism of adult tissue regeneration, using the liver and pancreas as model organs. Chronic liver disease and liver and pancreas cancer are highly associated to inflammation and tissue damage. Understanding the mechanism regulating these processes holds promise to extend our knowledge on tissue regeneration, disease and cancer.
We are also interested in tissue engineering and disease modelling. Despite the enormous regenerative capacity of the liver in vivo, liver cells have resisted expansion in culture. We have recently described a culture system (liver organoid culture) that allows, for the first time, the long-term (>1year) expansion of mouse liver stem/progenitor cells into 3D structures that we have termed 'liver organoids'. In this novel culture system adult liver stem/progenitor cells maintain their ability of self-renewal and differentiation towards functional liver cells. When transplanted into a mouse model of liver disease (FAH-/- mice), the cultured cells partially rescued the liver phenotype, showing their therapeutic potential. We have observed similar results using adult pancreas tissue. Following on that discovery, we would now like to transfer this technology to the study of liver diseases with the aim of better understanding these and potentially finding better therapeutic strategies.
Huch M, Koo BK, (2015), Modeling mouse and human development using organoid cultures, Development, (in press)
Huch M, (2015), Building stomach in a dish, Nat Cell Biol, 17(8): 966-967.
Huch M, (2015), Regenerative biology: The versatile and plastic liver, Nature, 517(7533): 155-156
Huch M, Gehart H, van Boxtel R, Hamer K, Blokzijl F, Verstegen MM, Ellis E, van Wenum M, Fuchs SA, de Ligt J, van de Wetering M, Sasaki N, Boers SJ, Kemperman H, de Jonge J, Ijzermans JN, Nieuwenhuis EE, Hoekstra R, Strom S, Vries RR, van der Laan LJ, Cuppen E, Clevers H, (2015), Long-term culture of genome-stable bipotent stem cells from adult human liver, Cell, 160(1-2): 299-312
Boj SF, Hwang CI, Baker LA, Chio, II, Engle DD, Corbo V, Jager M, Ponz-Sarvise M, Tiriac H, Spector MS, Gracanin A, Oni T, Yu KH, van Boxtel R, Huch M, Rivera KD, Wilson JP, Feigin ME, Ohlund D, Handly-Santana A, Ardito-Abraham CM, Ludwig M, Elyada E, Alagesan B, Biffi G, Yordanov GN, Delcuze B, Creighton B, Wright K, Park Y, Morsink FH, Molenaar IQ, Borel Rinkes IH, Cuppen E, Hao Y, Jin Y, Nijman IJ, Iacobuzio-Donahue C, Leach SD, Pappin DJ, Hammell M, Klimstra DS, Basturk O, Hruban RH, Offerhaus GJ, Vries RG, Clevers H, Tuveson DA, (2015), Organoid models of human and mouse ductal pancreatic cancer, Cell, 160(1-2): 324-338
Bartfeld S, BayramT, van de Wetering M, Huch M, Begthel H, Kujala P, Vries R, Peters PJ, Clevers H, (2015), In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection, Gastroenterology, 148(1): 126-136 e126
Simmini S, Bialecka M, Huch M, Kester L, van de Wetering M, Sato T, Beck F, van Oudenaarden A, Clevers H, Deschamps J, (2014), Transformation of intestinal stem cells into gastric stem cells on loss of transcription factor Cdx2, Nat Commun, 5: 5728
Hindley CJ, Mastrogiovanni G, Huch M, (2014), The plastic liver: differentiated cells, stem cells, every cell?, J Clin Invest, 124(12): 5099-5102
Behjat S, Huch M, van Boxtel R, Karthaus W, Wedge DC, Tamuri AU, Martincorena I, Petljak M, Alexandrov LB, Gundem G, Tarpey PS, Roerink S, Blokker J, Maddison M, Mudie L, Robinson B, Nik-Zainal S, Campbell P, Goldman N, van de Wetering M, Cuppen E, Clevers H, Stratton MR, (2014), Genome sequencing of normal cells reveals developmental lineages and mutational processes, Nature, 513(7518): 422-425
Stange DE, Koo BK, Huch M, Sibbel G, Basak O, Lyubimova A, Kujala P, Bartfeld S, Koster J, Geahlen JH, Peters PJ, van Es JH, van de Wetering M, Mills JC, Clevers H, (2013), Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium, Cell, 155(2): 357-368
Peng WC, de Lau W, Forneris F, Granneman JC, Huch M, Clevers H, Gros P, (2013), Structure of stem cell growth factor R-spondin 1 in complex with the ectodomain of its receptor LGR5, Cell Rep, 3(6): 1885-1892
Jose A, Sobrevals L, Miguel Camacho-Sanchez J, Huch M, Andreu N, Ayuso E, Navarro P, Alemany R, Fillat C, (2013), Intraductal delivery of adenoviruses targets pancreatic tumors in transgenic Ela-myc mice and orthotopic xenografts, Oncotarget, 4(1): 94-105
Huch M, Dorrell C, Boj SF, van Es JH, Li VS, van de Wetering M, Sato T, Hamer K, Sasaki N, Finegold MJ, Haft A, Vries RG, Grompe M, Clevers H, (2013), In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration, Nature, 494(7436): 247-250