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Meritxell Huch

huchMeri Huch PhD, Wellcome Trust Research Fellow.

Europe PMC | Pubmed

Winner of the 2013 NC3Rs Award 2013
 

 

 

Stem cells and tissue regeneration - implications in disease and cancer.

huch 2013

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.

 

Selected publications:

• Huch M*, Bonfanti P*, Boj SF*, Sato T*, Loomans CJ, van de Wetering M, Sojoodi M, Li VS, Schuijers J, Gracanin A, Ringnalda F, Begthel H, Hamer K, Mulder J, van Es JH, de Koning E, Vries RG, Heimberg H and Clevers H (2013) Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J 32(20):2708-21

• Huch M*, Dorrell C*, Boj SF, van Es JH, Li VSW, van de Wetering M, Sato T, Hamer K, Sasaki N, Finegold MJ, Haft A, Vries R, Grompe M and Clevers H (2013) In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494: 247-50

• Barker N*, Huch M*, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, Danenberg E, van den Brink S, Korving J, Abo A, Peters PJ, Wright N, Poulsom R and Clevers H (2010) Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6(1):25-36

* Denotes joint first authors.

Plain English

The liver is a very slowly dividing organ but, when damaged by toxins present on the food or other environmental agents, it starts the machinery to regenerate itself and bring the organ back to its original resting state. Our aim is to understand the molecular mechanism by which liver or other adult cells sense the damage infringed to the tissue and start the repairing process. Understanding these mechanisms is crucial to improve our knowledge on the basics of cancer initiation, as during tumorigenesis, similar mechanisms have to be put in place to activate the resting cells to start proliferating. 

We are also interested in developing tools to study human physiology and disease in vitro in a petri dish. Because of their numerous biomedical implications in studies of hepatitis, drug testing, as well as transplantation for chronic liver diseases, scientists around the world have unsuccessfully attempted for decades to regenerate primary liver cells. 

We have recently achieved that challenge by establishing a novel liver culture system named 'liver organoid culture' that allows the massive and infinite expansion of mouse liver cells into 3D structures that resemble functional liver tissue in a dish. Of note, when these cells are grown in vitro and transplanted into a mouse model of an inherited liver disease, which resembles the Tyrosinemia type I human liver disease, the cultured and transplanted liver cells continued to grow in the recipient livers and alleviated the pathology of the disease by prolonging the survival of the transplanted mice, thus proving their therapeutic potential.

Co-workers

John Crang