Cell News 04/2019
16
PRIZE WINNERS 2019
1)
The Wellcome Trust/ Cancer Research UK Gurdon Institute,
University of Cambridge, Tennis Court Road, Cambridge,
CB2 1QN, UK
2)
The Max Planck Institute of Molecular Cell Biology and
Genetics, Dresden, Germany
correspondence:
Summary
Organoid cultures have risen as a promising in vitro culture
model that recapitulates tissues in a dish, in particular the com-
plex architecture and metabolic functions. Recently, liver organ-
oid models have been developed to further our understanding of
liver biology and associated diseases, in particular where mouse
models and cell lines cannot replicate key aspects of human liver
tissue. Liver organoids have now been established for multiple
species from iPSC, ESCs, hepatoblasts and adult tissue derived
cells. These represent a promising tool to gain a deeper under-
standing of this complex organ. In our lab we have developed
organoid cultures from mouse and human adult and embryonic
liver tissue and demonstrated their utility for recapitulating
some aspects of liver development, liver regeneration and liver
disease, in a dish. Here, I will aim at summarizing some of our
contributions and their potential future directions.
Organoid definition and historical context
The term ‘organoid’ is being utilized to refer to a range of 3D
culture systems that recapitulate key features of an organ. In-
deed, here we define “organoid culture” as an
in vitro
3D culture
system formed by cells derived from either tissue resident stem/
progenitor cells or pluripotent stem cells [either embryonic stem
cells (ESC), or induced pluripotent stem cells (iPSC)], capable of
self-organization and self-renewal and that recapitulates the
function of the tissue they derive from, as described by Lancast-
er and Knoblich(1) and Koo and Huch(2). The term “organoid”,
though, is not new, in fact it was first used in 1946 to describe
certain histological features of tumors, such as glandular orga-
nization (3). Recently, the development of intestinal organoids
in 2009 (4), resulted in the re-birth of the term and was used
for the first time to more specifically describe intestinal cultures
that would retain the ability to self-organize into epithelial
structures
in vitro
. Since then, organoids have been developed to
recapitulate many organs and tissues and have been are being
increasingly adopted for a wide range of studies. For instance,
their ability to recapitulate the intrinsic patterning events of
the developing organ makes them very useful for investigating
developmental organogenesis as well as processes of adult repair
and homeostasis. Furthermore, their more accurate organ-like
organization makes them a valuable tool for disease modelling.
We have extensively worked in developing organoid models from
adult and embryonic tissues for a range of different organs in-
cluding the stomach (5), pancreas (6-7) and liver (8-10) (Figure
1). Here we focus this manuscript on the development of liver
organoids from mouse and human adult and embryonic liver
tissue.
Liver development, homeostasis and regeneration
The liver is the largest internal organ in the human body. It
is mainly composed of hepatocytes and cholangiocytes (also
known as ductal cells), which work in conjunction with endo-
thelial and mesenchymal cells. Its function is mainly to produce
serum proteins, detoxify the body of a wide variety of endoge-
nous and exogenous molecules and regulate glucose and lipid
metabolism. In addition, the liver secretes bile, essential for the
digestion of fats. The architecture of the tissue is quite complex.
The primary functional unit of the liver is the hepatic lobule,
a perfectly organized structure resulting from the interaction
BINDER Innovation Prize
Liver organoids for the understanding of liver regeneration and
human liver disease
Meritxell Huch
1,2
Figure 1: Organoids derived from gastrointestinal tissues. Adapted from
Lancaster and Huch DMM 2019
Gut
tomach
r
Pancrea
s
e
Liv
S
biopsy
Rspo, Egf, Noggin
Tgfbi, Wnt, p38i
Rspo, Egf, Noggin
Fgf,Tgfbi
Rspo, Egf, Hgf,Fgf,
Tgfbi,Nic,FSK
Rspo, Egf, Noggin,
Fgf,Tgfbi
Gut organoids are composed of
stem cells, paneth, goblet and
enterocyte cells arranged into
crypt- and- villus structures that
resemble the intestinal epithelium.
Expand long-term.
Pancreas organoids are composed
exclusively of ductal cells. Acinar
cells are not found and some endo-
crine differentiation is observed
upon transplantation. Can only be
expanded short term.
Stomach organoids expand
long-term. These are composed
of stem cells, mucin producing
cells and pit cells arranged into
gland-and-pit
structures that
resemble the gastric epithelium.
Liver organoids expand long-term from
both ductal and hepatocyte cells.
Ductal derived organoids are formed
by ductal epithelium that self-renews
and differentiates towards hepato-
cyte-like cells in vitro. Hepatocyte
organoids are formed exclusively by
hepatocytes. Ductal derived organoids
retain their genetic stability over time.
