Leading article Hepatic stem cells
For veral decades investigators have been addressing the tantalising question,is there a hepatic stem cell?1Despite widespread attempts to identify and characteri such cells in the liver and a plethora of papers,reviews,and monographs on the subject,2–4doubts as to their very exist-ence have remained.It is only relatively recently that the doubts have been removed,at least in the eyes of most investigators,with convincing evidence from rodent studies and novel developments in the cell biology of the pathogenesis of human liver dia.Moreover,new excit-ingfindings indicate that in tissues,including bone marrow and the brain,there reside cells with an innate ability to di V erentiate into divergent cell types.The stem cellfield is currently a“hot”topic.
Although esntially a quiescent organ,the normal adult liver can fully regenerate following surgical rection or injury.Much of what we have learned about liver growth control derives from the classical two thirds partial hepatec-tomy model in the rat.The process begins with growth activation of mature hepatocytes;other cell types,includ-ing biliary epithelial cells(BEC)and sinusoidal cells,pro-liferate with a delayed respon.5However,if liver damage is so vere that hepatocytes are largely obliterated or for some reason are prevented from entering the growth cycle by exposure to hepatotoxins or carcinogens,then activation of a liver stem(progenitor)cell population is postulated,23 giving ri to so-c
alled“oval”cells.The cells are thought to have both clonogenic and bipotential capacity—that is, the ability to proliferate and di V erentiate into cells of either hepatocyte or BEC lineage.67There is also evidence that under certain conditions oval cells can be induced to di V erentiate into non-hepatic lineages including intestinal and pancreatic epithelium.3The origin of oval cells and their preci location within the liver has remained enigmatic.However,recent evidence from a variety of ani-mal models and indeed now human studies has begun to provide answers.猴冲什么属相
Experimental studies
Oval cells are activated following dosing of animals with a variety of toxins and carcinogens,alone or combined with other surgical or dietary regimens.2389In one of the most studied models,acetylaminofluorene treatment followed by partial hepatectomy,an array of cytokines and growth factors have been shown to be up regulated during the respon.2Notably,some of the regulatory mechanisms are beginning to be delineated,for example the recent interesting obrvation that interferon is implicated in orchestrating the process.10Oval cells themlves however probably reprent the activated progeny of a dormant stem cell compartment and while oval cells are readily identified in injured liver,one area of great controversy is the question of where the putative stem cells reside in the normal liver.
Becau of the lack of specific markers of liver stem cells (even the so-called oval cell specific marker OV6recognis bile duct epithelium in normal rat liver)11they have been notoriously di Y cult to locali other than in the injury models described above.That they are prent is supported by the relative ea with which liver epithelial cell lines have been established from normal liver.9Where however,do the putative stem cells reside?One suggestion is that they are prent in the canals of Hering,that is the region where cells are transitional between the periportal hepatocytes and the biliary cells lining the smallest terminal bile ducts.8 Others suggest that there are cells which are found located in the portal tracts,in the periductular region,or even that periportal hepatocytes have stem cell or metaplastic properties.3
Further confusing terminology aris with the descrip-tion of a population of cells isolated from rat liver called “small hepatocytes”12and recently extended to include clonal expansion of“small”human hepatocytes.13The cells appear to have the capacity to clonally expand and yet retain hepatocyte phenotype in vitro.Again,the preci origin or location within the liver of the cells has not been defined.Independently,in a ries of hepatocyte transplan-tation studies using a mou model of hereditary tyrosinaemia,a population of adult mou hepatocytes with apparent stem cell capacity—that is,multiple rounds of proliferation—demonstrated the ability to largely regen-erate and repopulat
e the liver.14In neither approach was there evidence to suggest that the proliferative cells in question gave ri to epithelium of ductal biliary phenotype.While not proved,it ems likely that the cell populations of Mitaka et al,Hino et al,and Overturf et al are the same or similar.Thus the small hepatocytes dif-fer from oval cells and the term unipotential ems more applicable to this population.
Human liver stem cells
Identifying stem cells or their progeny in human liver has of cour been even more of a challenge.In the developing human fetal liver,di V erentiation of hepatoblasts into biliary epithelium is regulated by signals from the portal menchyme15;hepatoblasts not in contact with portal menchyme mature into di V erentiated hepatocytes.Al-though much is known about the bipotential nature of
Abbreviations ud in this paper:BEC,biliary epithelial cells.
Leading articles express the views of the author and not tho of the editor and editorial board.
Gut2000;46:743–745743
hepatoblasts,prent in fetal liver in large numbers,previ-
ous work has shown that while the cells can proliferate in
vitro16they are thought not to demonstrate clonogenic
potential.Thus although hepatoblasts are considered by
some as liver stem cells,to describe them as equivalent to
oval cells or their progenitors is misleading.
The identity of stem cells in the adult human liver and
their role in respon to liver damage/injury has also been
contentious.Numerous morphological studies have high-
lighted the prence of small cells prent in diad
human liver that are suggested to be putative progenitor
cell derivatives,17located in or clo to bile ducts or in peri-
portal regions adjacent to hepatocyte margins.18More
convincingly,using markers originally shown to be
expresd or up regulated by rat oval cells(including OV-6,
c-kit,and CD34),veral groups have identified oval cells
in hepatoblastoma,19hepatocellular carcinoma,20and
cirrhotic liver.21–23Using double immunolabelling tech-
niques,some of the cells co-express hepatocytic or biliary
phenotypic markers implying lineage progression.2123
However,morphological immunocytochemical studies on
tissue ctions convey only a limited picture since they
prent a static single“snap shot”of what is undoubtedly a
dynamic process and interpretation is di Y cult.Addition-
ally,it is likely that some(or all)of the markers in question
are expresd on cells transiently.西兰花泥
One means of solving this problem is to develop a
defined cell culture bad model where the cell fractions in
question can be isolated,the regulatory events carefully
investigated,and agents responsible for induction of
growth and di V erentiation determined.T o this end,using
antibodies against c-kit and CD34which recogni surface
determinants,cells have been specifically immuno isolated
and cultured from fetal,paediatric,and adult human
liver2425and lineage progression followed using well
characterid phenotypic markers of hepatocyte or biliary
specificity.This work is ongoing and it is hoped will help
resolve the questions which remain concerning the identity
and potential u of liver derived stem cells. Haematopoiesis and liver stem cells
While the debate on the source and location of hepatic
stem cells is ongoing,two recent papers add a new dimen-
sion and o V er a challenging alternative hypothesis to
explain the origin of oval cells.As already discusd,we十二生肖的歇后语
know that a number of surface determinants are shared
between haematopoietic derived progenitor cells and oval
cells,including c-kit,26CD34,27and Thy-128in rodents,and
c-kit23and CD3424in humans.The obrvations have
been brought sharply into focus with the demonstration
that a population of haematopoietic stem cells originating
in the bone marrow may give ri to oval cells in the liver
and have the potential to further di V erentiate into hepato-
cytes and/or ductal cells.29By transplanting rat bone mar-
row into lethally irradiated recipients and following the fate
of syngeneic cells using various markers,they clearly
showed striking changes in the livers of animals induced to
regenerate following2-acetylaminofluorene and CCl
4 treatment.Male donor marrow cells were visualid in
female recipients and in a cond model,marrow from
dipeptidyl peptida IV positive animals was transplanted
into dipeptidyl peptida IV deficient recipients.In both
cas evidence was prented to suggest that the donor cells
migrated into the livers of recipient animals and sub-
quently underwent di V erentiation to become hepatocytes
although it was less clear whether ductular cells of biliary
phenotype developed.29
A cond recently published study describes a similar
approach comprising a mou marrow transplant model
爱心捐赠活动华中科技大
but which interestingly did not include a liver injury step.30This new report provides important confirmatory evidence that bone marrow derived haematopoietic stem cells can indeed give ri to hepatocytes.In both studies,the number of cells which undergo the transition appears to be relatively small.Therefore,one is left unsure as to whether the respon reprents a true physiological or pathophysi-ological phenomenon or simply a quirk of nature uncovered by chance experimental obrvations.Following bone marrow transplantation,the immune cell chimaerism which ensues will result in cells in the liver with the donor genotype.Therefore,to prove the hypothesis unequivo-cally,it is vital that convincing marker co-expression work be ud to confirm the phenotype of the cells purported to di V erentiate from haematopoietic derived cells into cells of hepatic epithelial(hepatocyte)lineage.Such studies are prently underway in a number of centres.
Parallels between liver and brain
Fascinating recentfindings in neural cell biology studies add a further dimension to this emerging stem cellfield. Neural cells found in a post-mitotic epithelial cell layer,the ependyma,overlying the ventricular layer in the brain appear to have stem cell properties.31Rather like the puta-tive hepatic stem cells discusd above,they appear to remain dormant in normal adult tissue but when activated, they proliferate,migrate,and then di V erentiate.They divide asymmmetrically,one daughter
cell staying as an undi V erentiated stem cell while the other migrates and gives ri to neuronal or glial cells.31It is not known whether hepatic stem cells demonstrate this property.Thus two organs,the liver and brain,where normally little cell turnover occurs,harbour cells with surprising di V erentia-tion potential.In other studies,32putative neural stem cells transplanted into bone marrow have been shown to di V er-entiate into blood cells.As an interesting caveat,this transdi V erentiation respon occurred only in vivo,32 raising the problem of designing culture models with which to investigate the regulatory features of the(neural or hepatic)stem cell di V erentiation process.
Clinical implications
The ability to identify and exploit a human hepatic clonal stem cell could have important clinical implications,as generating large numbers of di V erentiated and therefore fully functional human hepatocytes has enormous poten-tial.Primary hepatocytes remain the ultimate choice for u in bioartificial liver support devices.33Reliance on pri-mary hepatocytes from pigs or other species remains prob-lematical due to the nsitive issue,now under the wider public debate,of xenotransplantation and the perceived inherent risks(possible cross over retroviral infection)of approaches which involve the u of cells or tissue from foreign species.Other important areas where progress has been limited due to lack of su Y cient numbers of good quality primary human h
epatocytes include hepatocyte transplantation for the treatment of metabolic disorders or fulminant liver failure,34and evaluation of drug toxicology and pharmacokinetics so vital today for the development of safe new therapeutic drugs.35Despite widespread e V orts, no one has yet achieved the goal of generating a safe,fully functional yet clonal,immortalid,or genetically engi-neered human cell model that can be substituted for primary hepatocytes in the various applications.This clearly adds further impetus to the arch for the definitive human hepatic stem cell.
Conclusions
In summary,the connsus that there are cells in the liver with stem cell potential has achieved acceptance.T ogether with thefindings from otherfields of cell biology,the plas-
744Strain,Crosby
ticity of certain cell types is clearly more extensive than previously realid,at least when dealing with organs or tissues traditionally regarded as cell quiescent.The poten-tial exploitability of the recent developments in hepatic stem cell biology awaits further investigation.
A J STRAIN
H A CROSBY School of Biosciences,
University of Birmingham and Liver and Hepatobiliary Unit, University Hospital,Birmingham,
Edgbaston,Birmingham B152TH,UK
Email:A.J.Strain@bham.ac.uk/H.A.Crosby.bcm@bham.ac.uk
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Hepatic stem cells745
doi: 10.1136/gut.46.6.743
2000 46: 743-745
Gut
A J STRAIN and H A CROSBY
Hepatic stem cells
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