Hepatic Stellate Cells and Liver Fibrosis

Juan E. Puche,1,2 Yedidya Saiman,1 and Scott L. Friedman*1

ABSTRACT
Hepatic stellate cells are resident perisinusoidal cells distributed throughout the liver, with a
remarkable range of functions in normal and injured liver. Derived embryologically from sep-
tum transversum mesenchyme, their precursors include submesothelial cells that invade the liver
parenchyma from the hepatic capsule. In normal adult liver, their most characteristic feature is
the presence of cytoplasmic perinuclear droplets that are laden with retinyl (vitamin A) esters.
Normal stellate cells display several patterns of intermediate filaments expression (e.g., desmin,
vimentin, and/or glial fibrillary acidic protein) suggesting that there are subpopulations within
this parental cell type. In the normal liver, stellate cells participate in retinoid storage, vasoregu-
lation through endothelial cell interactions, extracellular matrix homeostasis, drug detoxification,
immunotolerance, and possibly the preservation of hepatocyte mass through secretion of mi-
togens including hepatocyte growth factor. During liver injury, stellate cells activate into alpha
smooth muscle actin-expressing contractile myofibroblasts, which contribute to vascular distor-
tion and increased vascular resistance, thereby promoting portal hypertension. Other features of
stellate cell activation include mitogen-mediated proliferation, increased fibrogenesis driven by
connective tissue growth factor, and transforming growth factor beta 1, amplified inflammation
and immunoregulation, and altered matrix degradation. Evolving areas of interest in stellate cell
biology seek to understand mechanisms of their clearance during fibrosis resolution by either
apoptosis, senescence, or reversion, and their contribution to hepatic stem cell amplification, re-
generation, and hepatocellular cancer.  C 2013 American Physiological Society. Compr Physiol

3:1473-1492, 2013.

Introduction to one that is proliferative fibrogenic and contractile (62, 82,

Liver fibrosis is a common outcome of virtually all chronic
hepatic insults including viral hepatitis (i.e., hepatitis B
and C), alcoholic or obesity-associated steatohepatitis (i.e.,
nonalcoholic steatohepatitis (NASH)), parasitic disease
(i.e., schistosomiasis), metabolic disorders (i.e., Wilson’s),
hemochromatosis and other storage diseases, congenital
abnormalities, autoimmune and chronic inflammatory condi-
tions (i.e., sarcoidosis), and drug toxicity, among others (102).
Fibrosis was described in 1951 as a passive process with
“no direct evidence of fibrous tissue proliferation but the sug-
gestion of connective tissue appearance just by stromal con-
densation due to hepatocyte cell collapse.” However, in 1978,
a growing body of evidence prompted the World Health Orga-
nization to update its definition of fibrosis as “the presence of
excess collagen due to new fiber formation (3).” It is virtually
axiomatic now that liver fibrosis results from enhanced pro-
duction of extracellular matrix (ECM) due to accumulation
and activation of myofibroblasts in the context of ongoing
or repetitive liver damage. Early studies focused on meth-
ods to isolate and grow primary hepatic stellate cells (HSCs)
in culture establishing them as one of the main sources of
myofibroblasts in liver parenchymal disease resulting from
hepatocyte as oppsed to biliary injury (49, 71). Immediately
thereafter, the concept of stelllate cell “activation” emerged,
which represents a transdifferentiation of the cell during liver
injury from a quiescent state that is rich in vitamin A droplets,
83, 234, 241, 289). While HSCs are a major source of myofi-
broblasts, mounting evidence also implicates portal fibrob-
lasts as a source when the injury is to bile ducts rather than
hepatocytes (53, 162).
From early studies focusing on the role of the stellate
cells solely as a source of ECM during liver injury, a sus-
tained effort has subsequently uncovered broadening roles
of the cell type as a source of regenerative cytokines, an
immunomodulatory cell with a range of activities and one
that serves roles far beyond those envisioned at the time of its
isolation 35 years ago (65). From these studies realistic hopes
have emerged for exploiting features of stellate cell activation
and hepatic inflammation in devising effective antifibrotic and
regenerative therapies for patients with chronic liver disease
and fibrosis.
This article builds upon a comprehensive review of stel-
late cell biology in 2008 by one of the authors (S.L.F.) (65),
* Correspondence to scott.friedman@mssm.edu
1 Division of Liver Diseases, Icahn School of Medicine at Mount Sinai
Hospital, New York, New York
2 University CEU-San Pablo, School of Medicine, Institute of Applied
Molecular Medicine (IMMA), Madrid, Spain
Published online, October 2013 (comprehensivephysiology.com)
DOI: 10.1002/cphy.c120035
Copyright  C American Physiological Society.

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Hepatic Stellate Cells and Liver Fibrosis Comprehensive Physiology

Figure 1 Appearance of hepatic stellate cells and the sinusoidal microenvironment in normal and injured
liver. In normal liver, stellate cells (shown in blue) are laden with perinuclear retinoid droplets and preserve
the differentiated function of surrounding cells, including hepatocytes and sinusoidal endothelial cells. In liver
injury, the cells multiply, lose vitamin A and become embedded within dense extracellular matrix. This leads
to deterioration of hepatocyte function manifested as loss of microvilli, and decreased size and number of
endothelial fenestrations. Reprinted, with permission, from (68).

by highlighting the accelerating pace of progress and increas-
ingly nuanced understanding of a cell type that is unique not
only in liver, but throughout mammalian biology. The fas-
cination with stellate cells may explain why the published
literature contains more than 2800 articles about this cell type
only in the last ten years (Pubmed search using the keyword
“hepatic stellate cell” from 2002-2012).
Hepatic Stellate Cell Biology, Origin
and Ultrastructure
HSCs are resident nonparenchymal cells located in the suben-
dothelial space of Disse, between the basolateral surface of
hepatocytes and the antiluminal side of sinusoidal endothe-
lial cells (Fig. 1). This privileged location, together with their
dendritic cytoplasmic processes, facilitates their direct con-
tact with hepatocytes, endothelial cells, other stellate cells,
and Kupffer cells up to 140 μm away (86, 126). This intimate
contact between stellate cells and their neighboring cell types
may facilitate intercellular transport of soluble mediators and
cytokines. In addition, stellate cells are directly adjacent to
nerve endings (19, 299), which is consistent with reports
identifying neurotrophin receptors (36, 137, 284, 333), and
with functional studies confirming neurohumoral responsive-
ness of stellate cells (158, 203, 249). Interestingly, apart from
the different patterns of distribution (pericentral vs. periportal
predominances) among species (28, 65, 305), stellate cells
only represent ∼10% of the total number of resident cells in
normal liver (86) and ∼1.5% of total liver volume, a low pro-
portion of the total cell number in contrast to their remarkably
divergent functions in normal and diseased liver.
Prominent dendritic cytoplasmic processes from stellate
cells contact hepatocytes and endothelial cells (65, 266,
302, 304). These subendothelial processes have three cell
surfaces: inner, outer, and lateral. The inner one is smooth and
adheres to the adluminal (basal) surface of the liver sinusoidal
endothelial cells (LSECs) while the outer surface, facing
the space of Disse, has numerous micro-projections which
contact with hepatocytes and may function in detecting
chemotactic signals, and transmitting them to the cell’s
mechanical apparatus to generate a contractile force that
regulates blood flow (180). Actin filaments and microtubules
are distributed in both the periphery and the core of the cell’s
processes, respectively, and could be responsible for their
extension and retraction (115, 148, 204, 246, 252). While no
electron dense basement membrane can be identified within
the perisinusoidal space of Disse, basement membrane
proteins, including type IV collagen, nidogen, and laminin,
have been identified, which are thought be functionally
important in preserving differentiated hepatocellular function
and stellate cell quiescence (20, 29, 70).
HSCs were first described by Kupffer in 1876 (303), using
a gold chloride method for detection of neuronal components
in the liver. Their star-shaped characteristics led Kupffer to
call them “sternzellen” (“star cell,” in German). However, in
1898, a misinterpretation based on India ink staining led him
to conclude that they were actually “special endothelial cells
of the sinusoids with phagocytic capacity,” thereby confusing
them with macrophages (now often called “Kupffer cells”
(304)). Ironically, recent studies have indeed established that
stellate cells have phagocytic properties (35, 129, 190, 301).
Since Kupffer first identified stellate cells nearly 150
years ago (303), a number of new techniques for their detec-
tion and isolation have been developed based on their lipid
droplet content, cytoskeletal features, and cell surface mark-
ers (288). These approaches have aided in further defining
their ultrastructure and enhancing their purity during isola-
tion, for example, by using vitamin A fluorescence to isolate
the cells using flow cytometry (45). In normal liver, stel-
late cells have spindle-shaped cell bodies with perikaryons
within recesses between neighboring parenchymal cells, with
oval or elongated nuclei. Vitamin A lipid droplets are con-
spicuous features of the cytoplasm. Stellate cells also have

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Comprehensive Physiology
well-developed juxtanuclear small Golgi complex and rough
endoplasmic reticulum spaces indicating active biosynthe-
sis of secreted polypeptides or proteins (56). The presence
of active lysosomes in stellate cell cytoplasm described for
decades (33, 129) is now recognized to indicate a high capac-
ity for the cells to undergo autophagy during cellular acti-
vation (104, 105). Endosomes and multivesicular bodies are
also present in HSCs (267) and contribute to the generation
of vitamin A-containing lipid droplets.
In contrast to the well-established origins of other liver
populations (endoderm-derived hepatocytes and cholangio-
cytes, mesoderm-derived endothelial cells and fibroblasts,
and ectoderm-derived neurons), the ontogeny of this enig-
matic cell has been controversial for decades, because the
cells express a pattern of cytoskeletal markers reflecting a
range of origins including ectoderm (e.g., glial fibrillary acidic
protein (GFAP), nestin, neurotrophins and their receptors,
nerve growth factor (NGF), brain-derived neurotrophic factor,
synaptophysin, and N-CAM) and mesoderm (e.g., vimentin,
desmin, alpha smooth muscle actin, hematopoietic markers)
(80, 186).
More recently, elegant developmental studies have estab-
lished that stellate cells are traced to mesothelial cells
(likely derived from septum transversum mesenchyme),
which appear to give rise to cells that invade the hepatic
bud (8, 11, 165). However, due to the limited labeling effi-
ciency of the mesothelium, the proportion of stellate cells
derived from the mesothelium is not known and other cel-
lular sources may also be possible. There is ample evidence
that HSCs are remarkably heterogeneous in their content of
retinoid, cytoskeletal phenotype, potential for activation, and
even their capacity to revert to a quiescent state after liver
injury resolves (45, 80, 143, 170). For example, there is a
subpopulation of stellate cells that may lack typical cytoskele-
tal markers (16, 235, 257) depending on the lobular location.
Pericentral areas are rich in stellate cells with longer cytoplas-
mic processes (i.e., more astrocytic morphology), predomi-
nant GFAP expression (instead of desmin), decreased number
and size of lipid droplets, and more differentiated. Peripor-
tal stellate cells are typically desmin positive with shorter
cytoplasmic processes (with a more contractile phenotype),
contain more and larger lipid droplets and may be less differ-
entiated (82, 195, 304, 305).
While the origin of stellate cells is becoming less con-
troversial, still uncertain is the possibility that stellate cells
are pluripotent and can give rise to multiple cell lineages.
This phenomenon has been reported in at least two studies
(154, 324), but based only on cell culture findings, where
modulation of cellular phenotype is notoriously promiscuous
and may not reflect events in vivo. On the other hand, it is
increasingly clear that HSCs are intimately associated with
the progenitor cell niche and typically surround cells that
have stem cell-like properties (39, 40, 89, 219, 311). These
findings indicate a strong likelihood that stellate cells support
stem cell expansion, although underlying mechanisms and
mediators that drive this interaction are not known.
Volume 3, October 2013
Hepatic Stellate Cells and Liver Fibrosis
Extrahepatic stellate cells have also been described
throughout many organs in particular pancreas, where they
retain their characteristic shape and markers (267). Stellate
cells in other tissues typically store vitamin A and synthe-
size and secrete ECM components. Best characterized among
these are pancreatic stellate cells, which clearly contribute
to pancreatic fibrosis and tumor stroma (4, 5, 57). Pancre-
atic stellate cells reportedly generate stem cells that may also
directly contribute to liver regeneration through differentia-
tion into hepatocytes and duct-forming cholangiocytes across
tissue boundaries, but this observation requires confirmation
(153).
Role of Hepatic Stellate Cells in
Normal Liver
Because of their recognized role in hepatic fibrosis, most
studies of HSCs have focused primarily on their behavior
during liver injury, but have neglected their contribution to
normal liver homeostasis. With an increased availability of
tools to selectively express transgenes in stellate cells, their
role in normal liver development and function is now being
illuminated (Fig. 2).
Contribution of stellate cells to
liver development
As noted above, stellate cells can be identified within the
progenitor cell niche (near the canals of Hering) in normal,
developing, and regenerating liver (248, 326). Additionally,
murine fetal liver-derived Thy1+ cells, which express classi-
cal markers of HSCs (α-SMA, desmin, and vimentin), pro-
mote maturation of hepatic progenitors through cell-cell con-
tact in culture (12). Pleiotrophin, a morphogen secreted by
stellate cell precursors (ALCAM+ submesothelial cells) dur-
ing liver development, may contribute to liver organogenesis
and regeneration (9, 10). Quiescent stellate cells also express
epimorphin, a mesenchymal morphogenic protein involved
Extracellular matrix
homeostasis
Vasoregulation Normal liver
development
Quiescent
Preservation of stellate cell
hepatocyte mass Retinoid metabolism
Drug metabolism
and detoxification
Figure 2 Roles of hepatic stellate cells in normal liver.
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Hepatic Stellate Cells and Liver Fibrosis
in differentiation of rat hepatic stem-like cells by a puta-
tive epithelial-mesenchymal contact that promotes bile duct
epithelial morphogenesis (184), which involves the RhoA and
C/EBPβ pathways. These findings complement evidence of
paracrine interactions between bile duct epithelium and either
stellate cells or portal fibroblasts both in culture (156, 166)
and in vivo (141, 156, 285). While not limited to stellate cell-
bile duct crosstalk, components of the Notch (254) and Wnt
pathways (178, 330), purinergic signaling (52), chemokines
(156) and the Dlk1 protein (298, 330) are also important in
hepatic development. Stellate cell precursors, isolated from
fetal liver based on UV fluorescence in flow cytometry (157),
display extensive proliferative activity, and a high capacity
to express hepatocyte growth factor (HGF), CXCL12, and
homeobox transcription factors, supporting their potential
contributions to both hepatic development and hematopoiesis
(157). A recent study has identified stellate cells in zebrafish
using a reporter gene driven by the Hand2 promoter (325).
Use of this model will further clarify the stellate cell’s contri-
butions to hepatic development and homeostasis.
Retinoid metabolism (see section on
Perpetuation, Section V, below)
Vitamin A (retinoid) is primarily stored in the liver in
mammals, and among liver cell types stellate cells are the
primary cellular depot (303). Normally, dietary retinoids are
absorbed by the gut and transported in chylomicron remnants
as retinyl esters to hepatocytes, where they are hydrolyzed
into free retinol. Retinol is then transferred to stellate
cells, where they are reesterified (101). Importantly, these
droplets contain not only retinoids, but also triglycerides,
phospholipids, cholesterol, and free fatty acids, among others
(188, 320). Recent studies have identified a family of proteins
that coat lipid droplets known as perilipins (27, 28, 253). One
perilipin, adipose-differentiation-related protein, is expressed
by stellate cells and its levels are reduced as the cells activate
and lose retinoid droplets (161). The contributions of these
lipid droplets go beyond the simple storage of Vitamin A, and
extend to the regulation of stellate cell activation (206, 207),
possibly through the impact of lipids in fueling autophagy
(103, 104). The importance of these retinoid mechanisms
in fibrosis however has been challenged, however, as mice
deficient in lecithin retinol acetyl transferase (LRAT), the
enzyme that catalyzes the esterification of retinol into retinyl
esters nonetheless undergo fibrosis (144) following toxic
liver injury, perhaps indicating an alternate or more complex
role for retinoid metabolism in hepatic and stellate cell
homeostasis.
Extracellular matrix homeostasis
In normal liver, the ECM comprises ∼0.5% of the total liver
weight (245) and is distributed between portal triads, central
veins and Glisson’s capsule, with only a small portion present
in the space of Disse (81). Normal ECM components include
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Comprehensive Physiology
collagens (type I, III, IV, V, VI, XIV, and XVIII), elastin,
structural glycoproteins (laminin, fibronectin, nidogen/
entactin, tenascin, osteopontin, and secreted acidic proteins
rich in cysteine), proteoglycans (heparan sulfate, chondroitin
4-sulfate, chondroitin 6-sulfate, and dermatan sulfate, synde-
can, biglycan, and decorin), and the free glycosaminoglycan
hyaluronan (74, 136, 259). While quantitatively modest in the
latter location, ECM in the space of Disse has an important
role in preserving liver homeostasis and has a unique spa-
tial expression pattern. Type IV collagen is primarily located
between LSECs and stellate cells while type I and III fibrillar
collagens are located between HCSs and hepatocytes in nor-
mal liver (20, 70). Primarily, the ECM composition can affect
the behavior of surrounding liver cells through cell surface
receptors, especially integrins, of which stellate cells express
α1β1, α1β2 (227), αvβ6 (222), α5 β1 (110), αvβ6 (216,
222), as well as integrin linked kinase (269).
The three cell types surrounding the space of Disse (hep-
atocytes, endothelial cells, and stellate cells) each produce
ECM components in normal liver. While all of them express
collagen type I, hepatocytes mainly produce fibronectin (233),
endothelial cells express collagen IV, and quiescent stellate
cells secrete laminin and collagen types III and IV (83, 171),
among several other ECM proteins.
The maintenance of ECM homeostasis requires turnover
in which production of new components is offset by parallel
rates of degradation. Matrix metalloproteinases (MMPs) are
the primary effectors of ECM degradation, whose activity is
regulated in turn by tissue inhibitors of metalloproteinases
(TIMPs) (6, 145). Several liver cell populations (i.e., Kupf-
fer cells, myofibroblast, and hepatocytes) can produce both
MMPs and TIMPs (6, 145), however a subgroup of this fam-
ily, the A Disintegrin and Metalloproteinase-domain proteins
(ADAMs) may elude TIMP action and contribute to trans-
forming growth factor beta (TGF-β) activation (26), the most
potent stimulus for collagen I production by stellate cells (91,
116, 296). While most ADAMs are expressed by more than
one liver cell type, at least two (ADAM 13 and 28) are pro-
duced solely by stellate cells (194, 261, 273, 314).
Secretion of mediators
While stellate cell-derived molecules are a major driving
force in hepatic fibrosis they may also play an important
role in preserving liver homeostasis and promoting regener-
ation, although the data do not fully support such a role yet.
The specific spatial and temporal expression patterns of these
molecules may therefore be important to promoting proper
hepatic development and regeneration after injury. In steady
state conditions, stellate cells are reported to secrete a range
of molecules detailed in the following sections.
Growth factors
HGF is the most potent mitogen for hepatocytes (256). Quies-
cent stellate cells can produce HGF, but interestingly, during
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Comprehensive Physiology
liver damage the expression of this growth factor is downreg-
ulated in stellate cells by the action of transforming growth
factor β (TGF-β) (232). This temporal expression of HGF
may, therefore, explain the decreased rate of hepatic regener-
ation in a fibrotic/injured liver.
TGF-β is among most potent cytokines that regulate stel-
late cell phenotype (21, 51). In normal liver TGF-β iso-
form expression (TGF-β1,2,3 ) is shared between hepatocytes,
Kupffer cells and stellate cells (21). While TGF-β1 is more
highly expressed by Kupffer cells than HSCs, TGF-β3 is only
expressed by stellate cells (48). Regardless, TGF-β is secreted
in its latent form, and requires a further activation of the latent
molecule to exert its action. The predominant pathways of
TGF-β activation diverge among different tissues. In liver,
integrins, fibrinogen, and urokinase-type plasminogen acti-
vator, among others, can activate latent TGF-β during liver
injury, which eventually induces stellate cell activation (25,
227, 278). On the other hand, it can be inactivated by binding
to the proteoglycan decorin (15). The recent elucidation of
the latent TGF-β structure (271) could yield important new
approaches to selectively blocking its activation in vivo.
Vascular endothelial growth factor (VEGF) is also
expressed by quiescent stellate cells (316). Its potent mito-
genic effect toward sinusoidal and endothelial cells under-
scores the key role that stellate cells play in communication
and control of liver homeostasis. This important paracrine sig-
naling pathway between stellate cells and sinusoidal endothe-
lium, mediated by VEGF and soluble guanylate cyclase, may
be critical for sinusoidal homeostasis in normal liver and
regeneration (309, 310, 319).
Other growth factors synthesized by stellate cells are
insulin-like growth factors (IGF-I and IGF-II), transforming
growth factor α (TGF-α), EGF, stem cell factor, and fibrob-
last growth factors (both acidic and basic FGF), although their
contributions may be more critical during liver development
and regeneration (39, 40, 75, 177, 182, 191, 247, 298, 332).
Neurotrophins and their receptors
NGF, brain-derived neurotrophin, neurotrophin 3, neu-
rotrophin 4/5, the low-affinity NGF receptor p75 and the high-
affinity tyrosine kinase receptors B and C are all expressed
by HSCs (36), and/or their precursors (284). A number of
potential functions of these pathways are suggested by their
activities in other tissues; however, to date, their best known
function in liver is in contributing to stellate cell activation
and tissue repair (36, 137, 215).
Other mediators
Endothelin-1 (ET-1) is a potent vasoconstrictor produced pri-
marily by endothelial cells in normal liver (322), but also
by stellate cells. Interestingly, during liver injury, endothe-
lial cells decrease their production and stellate cells become
the dominant source of ET-1, which correlates with stel-
late cell activation (138, 221, 242, 270) highlighting the
complex interplay of ET-1 between stellate and endothelial
Volume 3, October 2013
Hepatic Stellate Cells and Liver Fibrosis
cells. A carefully regulated pathway exists for activation of
latent endothelin in stellate cells (138, 164).
Human stellate cells have also functional receptors for
adrenomedullin (ADM), a peptide produced by most contrac-
tile cells, which modulates the contractile effect of ET-1 (88).
Moreover, cultured human stellate cells secrete ADM in base-
line conditions, and its production is markedly increased by
cytokines (88), a surprising finding given that stellate cell acti-
vation promotes cellular contraction. ADM can also attenuate
activation of stellate cells by inhibiting TGF-β1 production
and TGF-β-induced MMP-2 expression partially through the
ERK pathway (312). These results suggest that ADM regu-
lates stellate cell activation and contractility in an autocrine
manner.
A more comprehensive assessment of protein production
by stellate cells was generated by an unbiased proteomic anal-
ysis of the cells and their surrounding ECM (13, 127, 236).
In initial work by Kristensen, the patterns of protein expres-
sion were compared between quiescent, in vivo activated and
in vitro activated stellate cells, by two-dimensional-gel elec-
trophoresis. From the 300 identified proteins, 83 were found to
be secreted, including collagen α1 (I), α1 (III), and α2 (I); α1-
antitrypsin; calcyclin, calgizzarin, and galectin-1; proteases
including plasminogen activator inhibitor-1 and cathepsin A,
B, and D; ganglioside GM2; among others. A more recent
analysis by Ji et al. has emphasized the importance of stellate
cells in also generating immunoregulatory molecules, con-
sistent with their function in conferring immune tolerance in
liver (130, 290, 318).
Drug metabolism and detoxification
HSCs express both alcohol- and acetaldehyde-
dehydrogenases, but not cytochrome P450-2E1 (34)
and it is likely that their contribution to ethanol detoxification
is minimal compared to hepatocytes. Apart from P450-2E1,
other isoforms of cytochrome p450 are expressed by stellate
cells, and are downregulated during cellular activation (321);
however, their roles in cellular quiescence and activation are
unknown. Some cytochrome p450 isoforms have been iden-
tified in stellate cells (160), implicating their participation in
xenobiotic detoxification and oxidant stress response.
Role of Hepatic Stellate Cells in Liver
Injury and Fibrosis
The framework for understanding stellate cell activation was
established several years ago (63), and remains a practical
and relevant template for characterizing the cell’s response to
injury. A common consequence of liver injury is parenchy-
mal damage with an increase in apoptotic bodies, Kupffer
cell activation, production of oxidative species, and ECM
remodeling (65), which all function as triggers for cellu-
lar activation. Activation of stellate cells comprises two
well-established phases: initiation (also called “preinflamma-
tory stage”) and perpetuation, which can be followed by a
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Hepatic Stellate Cells and Liver Fibrosis
potential third phase, resolution, if the liver injury resolves
(58, 64, 69). During resolution of fibrosis, loss of activated
stellate cells occurs through numerous pathways and there is
now evidence that stellate cells can not only undergo apopto-
sis, but are also able to either become senescent or revert to a
quiescent phenotype (67, 143, 294). The elucidation of molec-
ular mechanisms underlying these events may accelerate the
discovery of potential antifibrotic drug targets.
Initiation of stellate cell activation
Stellate cell initiation promotes changes in gene expression
and phenotype that render the cells susceptible to the changing
environment and stimuli in the injured liver, thereby promot-
ing the transition to the perpetuation phase. The earliest sig-
nals triggering the initiation of stellate cell activation result
from paracrine stimulation by neighboring cell populations
(endothelial cells, platelets, immune cells, and hepatocytes)
and changes in its surrounding ECM (Fig. 3).
As endothelial cells comprise the vascular lining of the
liver’s sinusoids, they play a vital role in these early stages.
They induce the activation of stellate cells by secreting
fibronectin (125) and by activating latent transforming TGF-β
(149), as well as through secretion of a range of mediators that
modulate inflammation and participate in cellular crosstalk
(275, 319). Fibronectin’s effects are largely promigratory and
not fibrogenic, suggesting that stellate cell migration is an
important first step in responding to injury (210). Platelets also
contribute by secreting TGF-β, as well as EGF and platelet-
derived growth factor (PDGF), the most potent stellate cell
mitogen identified (14, 24). Overall however, the resident
hepatic macrophage population may be the main source of
PDGF, as well as other paracrine mediators that drive stellate
cell activation (106, 287, 308).
There is an increasingly nuanced understanding of
how inflammatory and immune cells regulate stellate cell
responses and activation. In particular, T cells, dendritic cells
(DC), and macrophage subsets all have well defined inter-
actions with stellate cells [see (76, 131, 152, 179, 313) for
reviews]. Among these, recent studies have characterized a
specific macrophage subset in rodents, Ly-6Clo , that are vital
for regression of hepatic fibrosis (231). On the other hand,
different macrophages can drive stellate cell function includ-
ing stimulation of matrix synthesis, cell proliferation, and
retinoid release by secreting TGF-β, TNF-α, and MMP-9, and
production of reactive oxygen species (ROS) and lipid perox-
ides (230). Moreover, ROS produced by hepatic macrophages
can initiate downstream signals that include osteopontin, an
ECM protein that can induce collagen (300) and perpetuate
the activated stellate cell phenotype. Recent studies further
implicate an inhibitory role of platelets in blocking stellate
cell activation based on the following: (i) transgenic throm-
bocytopenic mice develop exacerbated liver fibrosis, with
increased expression of type I collagen α1 and α2, during
cholestasis (147); (ii) in vitro experiments reveal that, upon
exposure to stellate cells, platelets became activated, released
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Comprehensive Physiology
HGF, and then inhibited stellate cell expression of the type I
collagen gene in a Met signal-dependent manner (147); and,
(iii) activation of human stellate cells in culture is suppressed
by human platelets or platelet-derived ATP via the adenosine-
cAMP signaling pathway (114).
Hepatocytes are the main target for most forms of liver
injury including viral infection, alcohol, and obesity, among
others (198). Following injury, damaged hepatocytes become
a major source of lipid peroxides and apoptotic bodies
that initiate stellate activation through a process mediated
by Fas and TRAIL (32). The contribution of hepatocyte-
derived apoptotic bodies to stellate cell activation is indepen-
dent of the inflammatory response, since in cultured stellate
cells, addition of hepatocyte apoptotic fragments are directly
fibrogenic (33), and can also activate Kupffer cells (31).
Hepatocytes also express P450-2E1, an important enzyme
involved in the metabolism of xenobiotics as ethanol, and a
potent source of ROS (193) that can stimulate stellate cell
fibrogenesis (193).
Changes in the composition and stiffness of ECM also
impact on stellate cell responses (84, 121, 315) suggesting
a feed-forward loop where stellate cell mediated changes in
ECM further drive stellate cell activation. Early changes in
transcription factor activity in response to ECM, as well as
soluble signals set the stage for a broad phenotypic transi-
tion of the cells, and a large number of nuclear factors have
been implicated [see (173) for review]. Additionally, path-
ways of translational, transcriptional and posttranscriptional
regulatory control (including epigenetic pathways and miR-
NAs) contribute to this process (18, 41, 99, 163, 172, 174,
218, 243, 297).
While the initial presumption that transcription factors
largely stimulate stellate cell activation, it appears equally
true that other factors repress activation, and their activity is
downregulated during cellular activation. Three key examples
include Lhx2 (306), KLF6 (85), and Foxf1 (133), in which
each contribute to preservation of a quiescent phenotype, such
that their loss or downregulation derepresses the activation
program.
Perpetuation of stellate cell
activation—mechanisms and implications
After the initial liver injury, stellate cells initiate activation
followed by a process of perpetuation, leading to accumula-
tion of ECM and culminating in the formation of scar tissue.
Perpetuation of stellate cell activation is a tightly orches-
trated process that includes a number of functional responses
including proliferation, fibrogenesis, chemotaxis, contractil-
ity, matrix degradation, retinoid loss, and cytokine/chemokine
expression (Fig. 4).
Proliferation
PDGF is most potent stellate cell mitogen during liver
injury. An increase in available PDGF and stellate cell
responsiveness due to increased expression of PDGF receptor
Volume 3, October 2013
Comprehensive Physiology Hepatic Stellate Cells and Liver Fibrosis

(A) Normal liver

Portal triad
Bile duct Hepatocytes

HSC

Sinusoidal space of Disse

Terminal
Portal vein Sinusoidal endothelial cells KC hepatic
vein

Hepatic
arteriole

(B) Fibrotic liver

HSC activation Loss of hepatocyte

and proliferation microvilli

Loss of endothelial fenestrations Distortion

of veins

Increase in fibril-forming
collagen in space of Disse

Fibril-forming collagens (types I, III, and V)

Basement membrane collagens (type IV and VI)
Glycoconjugates (laminin, fibronectin, glycosaminoglycans, and tensacin)

Hernandez-Gea V, Friedman SL. 2011.

Annu. Rev. Pathol. Mech. Dis. 6:425–56
Figure 3 Matrix and cellular alteration in hepatic fibrosis. Normal liver parenchyma contains epithelial cells (hepatocytes) and
nonparenchymal cells: fenestrated sinusoidal endothelium, hepatic stellate cells (HSCs), and Kupffer cells (KCs). (A) Sinusoids are
separated from hepatocytes by a low-density basement membrane-like matrix confined to the space of Disse, which ensures metabolic
exchange. Upon injury, the stellate cells become activated and secrete large amounts of extracellular matrix (ECM), resulting in
progressive thickening of the septa. (B) Deposition of ECM in the space of Disse leads to the loss of both endothelial fenestrations and
hepatocyte microvilli, which results in both the impairment of normal bidirectional metabolic exchange between portal venous flow
and hepatocytes and the development of portal hypertension.

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Hepatic Stellate Cells and Liver Fibrosis Comprehensive Physiology

Initiation Perpetuation

Injury Proliferation
Contractility
Oxidative stress
Apoptotic bodies PDGF
ET–1
LPS VEGF NO
Paracrine stimuli FGF Fibrogenesis
TGF-β1/
CTGF

MMP-2&9; MT-1-MMP

TIMP-1,2 Altered matrix

Reversion degradation
PDGF
Chemokines

Resolution
Chemokines Adenosine
TLR ligands
HSC
TIMP-1,2 chemotaxis
TRAIL
Fas T cells
B cells
NK cells
Apoptosis NK-T cells
Inflammatory
signaling

Figure 4 Pathways of hepatic stellate cell activation and loss during liver injury and resolution.
Features of stellate cell activation can be distinguished between those that stimulate initiation and those
that contribute to perpetuation. Initiation is provoked by soluble stimuli that include oxidant stress signals
(reactive oxygen intermediates), apoptotic bodies, lipopolysaccharide (LPS), and paracrine stimuli from
neighboring cell types including hepatic macrophages (Kupffer cells), sinusoidal endothelium, and
hepatocytes. Perpetuation follows, characterized by a number of specific phenotypic changes including
proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, and inflammatory
signaling. During resolution of hepatic fibrosis, there is both programmed cell death (apoptosis) to
clear fibrogenic cells, as well as reversion to a more quiescient phenotype. FGF, fibroblast growth
factor; ET-1, endothelin-1; NK, natural killer; NO, nitric oxide; MT, membrane type. Reprinted, with
permission, from (66).

results in rapid proliferation and an overall increase in
the absolute number of stellate cells with a profibrogeneic
phenotype (24, 220, 317). Tumor necrosis factor (TNF) alpha
signaling also contributes to PDGF-mediated stellate cell
proliferation primarily through the TNF receptor 1 (291).
Stellate cells are also responsive to a wide array of factors
including, VEGF (327), thrombin, EGF, keratinocytre growth
factor (282), and bFGF (328). Among those, VEGF is one of
the major cytokines secreted by activated HSCs, which drives
both angiogenesis and fibrogenesis, as described above (44,
135, 159). VEGF production is dependent on the overex-
pression of COX-2 protein via phospho-p42/44 MAP kinase
activation (329). Overall, HSCs contribute to both wound
healing and tumor growth, a conclusion underscored by sev-
eral studies implicating this cell type in the development and
growth of both primary and metastatic tumors (47, 134, 209).
Tissue inhibitors of matrix metalloproteinases (TIMPs)
are profibrogenic by inhibiting matrix degradation, and pro-
moting stellate cell survival. Increased TIMP-1 expression
by stellate cells also drives stellate cell proliferation in an
AKT-dependent manner (61). This mechanism might con-
tribute to the antiproliferative effects of activated Vitamin
D, 1,25(OH)(2)D(3) (1). Vitamin D receptor is expressed by
quiescent stellate cells (79), and its expression is downregu-
lated with activation. Consequently, treatment of stellate cells
with 1,25(OH)(2)D(3) dampens proliferation via cyclin D1
suppression and decreases expression of type I collagen and
TIMP-1 while simultaneously increasing MMP-9 expression.
Patients with liver disease exhibit vitamin D deficiency, and
appropriate supplementation might prove to be a useful ther-
apeutic intervention (225).
MicroRNAs are small 19-24 noncoding RNA sequences
that can regulate posttransciptional gene expression by
sequence-specific binding to the 3 -UTR of mRNAs to pro-
mote their degradation. The role of miRNAs in fibrosis pro-
gression is being clarified, as miRNA levels change in livers
of patients with fibrotic disease and in stellate cells during
activation (93, 99, 112, 196, 197, 205, 243, 307). In stellate

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Comprehensive Physiology
cells, miRNAs control proliferation and fibrogenesis
by regulating protein expression of proproliferative and
profibrogenic signaling pathways. In particular, miR-27a and
-27b and miR29b are upregulated in activated stellate cells,
whereas their suppression leads to decreased proliferation and
an increase in lipid droplets indicative of the quiescent pheno-
type (205, 244). miR-27a -27b directly target the 3 -UTR of
retinoid X receptor α (RXRα) to inhibit its expression. RXRα
can decrease DNA synthesis, leading to growth arrest in stel-
late cells (100). Furthermore, RXRα regulates adipogenesis
by activation of peroxisome proliferator-activated receptor γ
(PPARγ) which is a master regulator of stellate cell activation
(297). RXRα expression is decreased in stellate cell activa-
tion and its expression in activated stellate cells increases with
inactivation of miR-27a -27b, indicating a direct interaction
between RXRα and miR27a -27b (128). In contrast, miR-
195 is downregulated during stellate cell proliferation and
its expression is induced upon treatment with IFN-β, which
exhibits antifibrotic effects independent of its antiviral activ-
ity. Treatment with IFN-β downregulates cyclin E1 and upreg-
ulates p21 in a miR-195 specific manner thereby promoting
cell cycle arrest and decreased stellate cell proliferation (265).
Fibrogenesis
Production of ECM, in particular collagen type I, is a hallmark
of activated stellate cells. Production of collagen type I by
stellate cells is regulated both transcriptionally and posttran-
sciptionally (2, 37, 73, 117-119, 167, 175, 214, 238, 279,280,
295). TGF-β1 is major driver of this process through autocrine
and paracrine stimulation of ECM production (see above).
The other well-characterized fibrogenic cytokine towards stel-
late cells is connective tissue growth factor (CTGF/CCN2).
Levels of CTGF are increased in liver injury and the cytokine
promotes a range of profibrotic activities toward stellate cells,
mediated by a G-coupled protein receptor (78, 92, 111). CTGF
represents a very appealing target for antifibrotic therapy,
since unlike antagonism of TGF-β1, CTGF inhibition should
have no impact on hepatocyte growth or confer a risk of car-
cinogenesis.
There is a growing list of other factors that contribute
to fibrogenesis, including signaling molecules, chemokines,
and cellular stressors (250). For example, osteopontin, an
ECM cytokine expressed by stellate cells, activates collagen
I expression via integrin α(V)β(3) engagement and activa-
tion of the PI3K/pAkT/NFκB signaling pathways (300). Fur-
thermore, the recent identification of receptors to profibro-
genic chemokines on stellate cells including CXCR4 (108),
CCR1, CCR5 (262), CXCR2 (281), and CCR2 (263), add
to the repertoire of signals promoting stellate cell activation.
The targetability of chemokine receptors with small molecule
inhibitors makes them ideal candidates for antifibrotic ther-
apies. Recently, blockade of IL-17A has been proposed as
a potential strategy for cirrhosis treatment due to its induc-
tion (together with its receptor) in response to liver injury.
IL-17A may promote fibrosis by activating inflammatory and
Volume 3, October 2013
Hepatic Stellate Cells and Liver Fibrosis
liver resident cells and inducing collagen type I production
in HSCs through engagement of the signal transducer and
activator of transcription 3 signaling pathway (181).
As discussed above, (see “Proliferation”) miRNAs play
a significant role in stellate cell biology and can modulate
collagen synthesis. MiR-29b binds directly to the 3 -UTR of
collagen-IαI and -IV, thereby inhibiting its translation. miR-
29b expression is repressed by TGF-β, and its overexpression
inhibits TGF-β induced collagen expression via a SMAD-
independent mechanism, while HGF, which exhibits antifi-
brotic effects in stellate cells, induces miR-29b expression
(244, 266). MiR-21, whose expression is enhanced during
fibrotic disease, is also controlled by TGF-β signaling. TGF-
β functions via 2 distinct mechanisms to increase miR-21
production. Smad3 induces miR-21 transcription, while both
Smad2 and Smad3 enhance miR-21 maturation.
Chemotaxis
Stellate cell chemotaxis is an important event in the gener-
ation of fibrotic septae by allowing activated cells to align
within regions of injury. Stellate cells migrate primarily
towards chemoattractant cytokines (chemokines), and they
express a range of chemokine receptors and their cognate
chemokine ligands. Notably, stellate cells migrate towards
PDGF (113, 142), VEGF, Ang-1 (199), TGF-β1 , EGF (323),
b-FGF (59), CCL2 (176), and CXCR4 (254), and CXCR3
specific ligands (23). The mechanism of chemotaxis includes
a cytoskeletal remodeling with cell spreading at the tip, move-
ment of the cell body towards the stimulus, and retraction of
trailing protrusions (180). Oxidant signaling contributes to
these responses. Specifically, numerous chemoattractant sig-
nals (PDGF, VEGF, and CCL2) increase NADPH oxidase-
dependent intracellular ROS and activation of the ERK1/2
and JNK1/2 pathways (50, 212). Furthermore, generation of
intracellular superoxide anion or H2 O2 by treatment with
menadione promotes cell migration even in the absence of
specific chemoattractants (198).
Hypoxia is another broad activator of stellate cell migra-
tion, which functions via two distinct mechanisms. After
induction of hypoxic conditions, mitochondrial-generated
ROS activate the ERK1/2 and JNK1/2 pathways, driving
migration. Sustained hypoxia leads to a HIF-1α-dependent
increased production and secretion of VEGF by stellate cells,
promoting their mobility (200).
Since stellate cell mobilization is also required for tis-
sue wound healing, it has been reported that the space of
Disse microenvironment, per se, is another key factor in reg-
ulating the migratory behavior of stellate cells. ECM com-
ponents including MMP-2 and type I collagen are able to
induce stellate cell migration (208, 323). Cellular fibronectin
containing an alternatively spliced domain A (EIIA) is upreg-
ulated during liver injury. Signaling specifically by the EIIA
fibronectin variant though integrin receptor α(9)β(1) on stel-
late cells promotes formation of lamellipodia and cellular
motility, further implicating ECM signaling in stellate cell
1481
Hepatic Stellate Cells and Liver Fibrosis Comprehensive Physiology

biology (210). The hyaluronic acid receptor (CD44) is also Retinoid loss
increased in liver injury and repair, promoting both activation
Recently, there has been a renewed focus on the role
and migration of stellate cells (140). Interestingly, a specific
of retinoid loss in stellate cell activation and collagen
splice variant (CD44v6) is responsible for up to 50% of this
production. Stellate cell activation is characterized by the loss
migration, confirming the idea that activated stellate cells may
of perinuclear retinoid droplets (65, 70); however, their func-
depend, to some degree, on CD44v6 and hyaluronic acid for
tion in activation and fibrogenesis is only now being revealed.
migration.
Stellate cells are the largest reserve of retinoids in the body
(∼60%) and conversion of retinol into retinyl ester is a hall-
mark of stellate cell activation. The abundance of vitamin A
Contraction in stellate cells is heterogenous depending on the intralobular
position of the cell (80) and may be indicative of alternate acti-
Stellate cell contraction is thought to be a primary determi-
vation states. Quiescent stellate cells that are isolated based
nant of portal hypertension in patients with end-stage liver
on their collagen 1 expression display an increase in CYP251
disease. The factors leading to portal hypertension include
retinoid catabolizing cytochrome, a decrease in retinyl esters,
increased blood flow, increased intrahepatic resistance, and
and a more activated phenotype compared to cells isolated
disrupted liver architecture. During injury, the hepatic sinu-
based on their buoyancy in gradient centrifugation (45).
soids undergo both morphological and functional changes
LRAT, which catalyzes the esterification of retinol into
mediated by HSCs. Dramatic remodeling occurs, character-
retinyl ester, is the sole acyltransferase found in the liver. With
ized by deposition of collagen matrix, loss of fenestrations
stellate cell activation, LRAT expression is lost. Addition-
and increased density of contractile HSCs (293). Addition-
ally, treatment with IL-1 promotes decreased LRAT expres-
ally, there is an imbalance of vasoactive forces characterized
sion (139). Despite its apparent role in stellate cell activation,
by deficient nitric oxide production and an increase in vaso-
mice deficient in LRAT neither display spontaneous fibrogen-
constrictive substances including ET-1, angiotensinogen II,
esis, nor do they exhibit increased fibrogenesis in liver injury
eicosanoids, atrial natriuretic peptide, somatostatin, and car-
models, indicating that perhaps retinoid loss is a marker of
bon monoxide (237, 239, 240, 292). Together, these factors
activation, but is not crucial for stellate cell activation (144).
lead to an increase in sinusoidal resistance and portal hyper-
However, treatment with retinoic acid can decrease stellate
tenstion.
cell activation as reflected in reduced collagen I, MMP-9, and
The final step in the induction of cellular contraction
α-SMA by inhibiting expression of TGF-β (98).
is phosphorylation of MLC-2, resulting from a calcium-
In contrast to the lack of dependence on LRAT for fibro-
dependent and a calcium-sensitive pathway. In the calcium-
genesis by stellate cells, mice deficient in LRAT are protected
dependent pathway, typically in skeletal and cardiac muscle,
from chemical hepatocarcinogenesis. An increase in active
release of Ca2+ from the endoplasmic/sarcoplasmic reticulum
retinoids due to their lack of conversion to retinol storage
leads to activation of myosin light-chain kinase (MLCK) by
form leads to an overall antiproliferative effect, increased p21
calmodulin and subsequent phosphorylation of MLC. Alter-
levels, and inhibition of tumor progression (144, 272).
natively, in the Ca2+ -sensitive pathway, the dominant path-
An additional link between retinoid metabolism to stel-
way in stellate cell mediated contraction and smooth mus-
late cell activation has emerged through the recognition that
cle cells, Rho-kinase inactivates the myosin binding subunit
this process requires cellular autophagy (104). Specifically,
by phosphorylation, thereby preventing it from dephospho-
hydrolysis of retinyl esters liberates fatty acids that are metab-
rylating MLC and inhibiting contraction. The net effect of
olized by β-oxidation, generating the substrates that are essen-
Rho-kinase activation is increased phosphorylated-MLC and
tial for fueling the energy-intensive pathways of cellular acti-
contraction (168).
vation. The free retinol can be detected in the extracellular
Adenosine plays an important role in stellate cell dif-
milieu under these conditions (72), but pathways enabling
ferentiation, proliferation, and type I collagen production.
its cellular egress are not known. Similar to stellate cells,
Despite these profibrotic effects, however, adenosine inhibits
autophagy contributes to the intracellular catabolism of lipids
stellate cell contraction (as well as chemotaxis) via loss of
in hepatocytes, fibroblasts (274), and neurons (150, 151).
actin stress fibers. Engagement of the A2a receptor by adeno-
Moreover, inhibition of autophagy in hepatocytes leads to
sine promotes PKA activity and Rho A inhibition (276),
reduced rates of β-oxidation and marked lipid accumulation
which establishes a rationale for Rho antagonism as a strat-
in cytosolic lipid droplets (274).
egy for treatment of portal hypertension (132). Adenosine
therefore promotes both injurious and protective effects on
Matrix degradation
stellate cells and understanding these different functions will
be important in the development of antifibrotic agents. Inter- Fibrosis is a dynamic process of matrix production and degra-
estingly, the antifibrotic activities of caffeine, now validated dation. Fibrotic progression is characterized by the replace-
in several large cohorts (43, 187, 211), may reflect the com- ment of normal basement membrane, collagen type IV, with
pound’s effect in reducing adenosine signaling in stellate scar forming collagen type I. Early matrix degradation is an
cells (38). important step in fibrosis and may be essential for stellate cell

1482 Volume 3, October 2013

Comprehensive Physiology
migration to sites of injury. Stellate cells are the prominent
source for MMP-2, MMP-9, and MMP-13 (7, 96, 183, 302),
which function as either interstitial collagenases (MMP-13)
or gelatinases (MMP-2 and -9).
Despite the dependence of fibrosis progression on MMPs,
these molecules paradoxically exhibit antifibrotic properties,
and their expression is suppressed with fibrotic progression.
MMP-2 inhibits collagen type I production by stellate cells
and mice lacking MMP-2 therefore exhibit increased fibro-
sis (229). Furthermore, MMP-2 is able to regulate stellate
cell apoptosis by cleavage of the extracellular domain of N-
cadherin, further supporting its antifibrotic role (97). Some of
the paradoxical activity of MMPs in vivo may be explained by
their simultaneous activation of macrophages (87) a feature
often overlooked in interpreting their contribution to fibrosis.
Regulation of MMP expression occurs through several mech-
anisms. TIMPs, which are prominently expressed by stellate
cells, bind MMPs, inactivating them. Additionally, with pro-
gressive fibrosis, MMP-9 and MMP-13 are repressed at the
chromatin level and access by the transcription factors NF-κB
and AP-1 is inhibited. Impaired histone acetylation is associ-
ated with permanently silenced genes, and activated stellate
cells have a global increase in histone deacetlyase-4 leading
to decreases in acetylation in the MMP-9 and -13 promoter
regions and gene repression (226).
While the source of enzymes that degrade ECM in liver
has been elusive, findings increasingly point to subsets of
macrophages that have fibrolytic potential. Indeed, a recent
study has characterized a specific subtype of macrophages
that express the surface marker Ly-6C as a recruited cellular
subset that secretes a range of proteases that have the capacity
to degrade ECM (230, 231).
Immunoregulation
In recent years stellate cells have emerged as a promi-
nent determinant of hepatic immunoregulation during injury.
They express of a battery of chemokines including CCL2
(277), CCL5 (260), CXCL2, CCL21 (22), CXCL8, CXCL9,
CXCL10, CXCL12, and CX3CL3 which have been shown to
recruit neutrophils, macrophages/monocytes, NK/NKT cells,
DCs, and T-cells, thereby establishing their role in immune
cell infiltration. Many of these chemokines also function inde-
pendent of immune cells and modulate cellular differentiation,
survival, proliferation, and apoptosis.
Stellate cells can control immune cell function through
three interrelated mechanisms (283, 288): (i) cell surface
expression of chemokines and/or delivery of chemokines to
endothelial cells promotes lymphocyte adhesion and subse-
quent migration and activated stellate cells specifically pro-
mote ICAM-1 and VCAM-1 dependent adhesion and migra-
tion (107); (ii) increased expression of stellate cell derived
chemokines establishes a chemoattractant gradient between
the peripheral blood and the liver, thus driving immune cell
migration into the liver; and (iii) stellate cell interaction
with immune cells has a direct role in promoting/inhibiting
Volume 3, October 2013
Hepatic Stellate Cells and Liver Fibrosis
their maturation within the liver. For example, stellate cells
can inhibit the priming of naı̈ve T cells in a cell contact-
dependent CD54 mechanism. Incubation of stellate cells
with DCs and OT-1 T-cells inhibits T cell proliferation and
reduces CD25 and CD44 activation markers (255). The abil-
ity of stellate cells to inhibit T cell proliferation is depen-
dent on their activation state, since quiescent stellate cells
do not possess this inhibitory function. Proteomics analy-
sis reinforces this immune suppressive role (127). In the
transplantation setting, endotoxin-stimulated stellate cells are
important immune regulators by inducing selective expan-
sion of tolerance-promoting Tregs to reduce inflammation
and alloimmunity (46).
Pattern recognition receptors, particularly TLR4, con-
tribute significantly to stellate cell responses. Stimulation
of stellate cells with the TLR4 ligands enhances TGF-β
signaling and production of inflammatory and chemotactic
cytokines (CCL2, IL-6), leading to a more profibrogenic
phenotype (94, 185, 213, 264). Additionally, stellate cell
TLR3 activation confers antifibrotic activities by stimulating
interleukin-10 production (30).
During late stage fibrosis when portal hypertension is
present there is an increased bacterial load delivery from the
gut to the liver due to increased intestinal permeability, leading
to an increase in LPS and TLR4 activation by stellate cells.
Treatment of mice with the intestinal decontaminant rifax-
imin, decreases portal pressure, fibrosis, and angiogenesis in
a TLR4-specific manner (331). Specifically, rifaximin treat-
ment inhibits production of stellate cell derived fibronectin.
LSECs are the key mediators during angiogenesis. Stellate
cell derived fibronectin is able to induce LSEC migration, and
tubulogenesis, thereby contributing to the pathogenic effects
of LPS (331).
The stellate cell’s capabilities now extend to their role
in DC development (109). DCs exposed to stellate cells or
their supernatants express low CD11c, CD86, and major his-
tocompatibility complex class II, which elicits an inferior
allostimulatory function compared with conventional DC.
From the complementary point of view, the inflamma-
tory response can also modulate stellate cell activation and
fibrogenesis. Therefore, a positive feedback loop exists in
which inflammatory and fibrogenic cells stimulate each other
in amplifying fibrosis. Thus, cell types regulating progression
and resolution of fibrosis include macrophages (a pivotal cell
with the potential for both a pro- and antifibrotic capacity
by secreting/regulating TGF-β1, PDGF, MMPs, and TIMPs)
(230, 231), natural killer cells (antifibrotic activity by inhibit-
ing and/or killing activated stellate cells) (77, 189), T-cells
(responsible for initiating/maintaining the adaptive immune
response and may induce liver injury upon CCL3/MIP1α
recruitment of CCR1 expressing CD4+ T cells) (286), B-cells
(fibrosis promotion in an antibody- and T cell-independent
manner) (201), DCs (involved in both proinflammatory and
immunogenic responses) (42, 131), as well as endothelial cells
(antigen-presenting cells for CD4+ and CD8+ T populations
with antigen clearance activity) (146).
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Hepatic Stellate Cells and Liver Fibrosis
Stellate Cells and Resolution of
Liver Fibrosis
Despite the historical conception of liver fibrosis as a passive
and irreversible process due to hepatocyte collapse (223,224),
the idea of fibrosis regression was proposed in the 1970s (217,
224) and demonstrated in the 1990s (17, 95). At a certain
stage of disease, fibrosis may become irreversible, likely due
to significant collagen cross-linking and development of an
insoluble and relatively hypocellular matrix, which may coin-
cide with the appearance of clinical cirrhosis manifestations
(124). Since stellate cells are an important contributor to ECM
remodeling in liver fibrosis, three possibilities may account
for regression of fibrosis, either their apoptosis, senescence,
or reversion to their quiescent stage.
Apoptosis of stellate cells during liver fibrosis recovery
contributes to a decrement in the number of activated stellate
cells (120, 123, 251). This situation coincides with a decrease
in TIMP-1 expression (122), which protects the cells from
apoptosis and inhibits the MMPs functions (192), favoring
the partial degradation of ECM (55). Of interest, the NF-κB
transcription factor plays a role in the stellate cell’s protec-
tion from apoptosis during liver fibrosis resolution, since its
inhibition can accelerate recovery from liver fibrosis (202).
Moreover, apoptosis can be spontaneously initiated in acti-
vated stellate cells via CD95L (Fas ligand) Bcl-2 and p53
(90). Finally, other cell populations can contribute to stellate
cell apoptosis. Hepatocytes can secrete NGF, which is apop-
totic towards stellate cells (228) (203). Natural killer cells
can also provoke stellate cell apoptosis through TRAIL and
NKG2D, a stellate cell membrane receptor that is specifically
expressed by activated stellate cells, rendering them suscepti-
ble to NK action (228). Kupffer cells can also induce stellate
cell apoptosis by a caspase-9-mediated mechanism (60).
Recent studies have now established that HSCs can undero
p53-mediated senescence in culture (258) and in vivo (155).
Initial studies in cultured HSCs suggested that as the cells
reached their replicative limit, they adopt a more inflammatory
and less fibrogenic phenotype (258). Based on these observa-
tions, elegant in vivo approaches confirmed the development
of senescence in HSCs in vivo (155, 169). Moreover, this
response is p53-dependent, because animals in which p53 is
specifically deleted in stellate cells have more fibrosis after
toxic liver injury (169). Remarkably, this senescence program
regulates the polarization of macrophages towards a pheno-
type that is protective against experimental carcinogenesis,
unearthing a noncell autonomous pathway of tumor suppres-
sion by p53 through its impact on the surrounding stromal
biology (169).
Until recently, reversion from activated to quiescent HSC
was only demonstrated in cultured cells. However, elegant
studies have now used genetic methods to document reversion
of activated cells to a quiescent phenotype in vivo (67, 143,
294). Reverted cells, however, have a heightened capacity to
reactivate, compared to those that have never activated. Quan-
titatively, reversion of activated stellate cells to quiescence is
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Comprehensive Physiology
likely to be a significant pathway in fibrosis regression that
involves approximately 50% of the stellate cell population,
and may in part be regulated by changes in PPARγ activity.
Conclusion
HSCs are among the most fascinating and versatile of cell
types in mammalian biology. While their contributions to hep-
atic injury and fibrosis has been well established for at least
two decades, clarifying this role further continues to bene-
fit from remarkable discoveries uncovering the signals that
control cell plasticity, survival, and intracellular signaling. A
growing range of genes, epigenetic changes, mediators, and
secretory proteins of stellate cells has been uncovered using
complementary methods of gene profiling and proteomics,
which has led to a more integrated understanding of the cell’s
regulation. Concurrently, genetic models including new meth-
ods to delete genes specifically in stellate cells further clarify
their roles in normal and injured liver. In aggregate, these dis-
coveries have enhanced the perceived importance of HSCs not
only to the fibrotic response in liver, but also to normal liver
homeostasis that includes blood flow regulation, regeneration,
and stem cell responses.
A key issue in studying HSCs is the choice of model
and species. Studies over the past 25 years have utilized both
rodent and human cells, as well as several methods to immor-
talize cultured cells, including SV40 T antigen gene transfec-
tion, spontaneous immortalization in low serum, or ectopic
telomerase gene expression. Whereas human cells have the
advantage of direct human disease relevance, they lack the
capacity for in vivo gene deletion using knockout technology,
which is now widely used for mouse models and isolated
stellate cells. This raises an important issue, as yet unan-
swered, whether the genotypes and phenotypes of rodent and
human stellate cells in normal and diseased liver are suffi-
ciently similar to allow investigators to rely on rodent studies
to understand and predict human disease targets. This concern
has become more pertinent based on a recent study indicating
that rodent models of inflammation bear little resemblance
to human disease (268). While one approach might be to
“humanize” mice so that they contain human stellate cells,
methods to achieve this goal would be tedious and would
likely require use of immunodeficient animals. An alternative
approach would be to perform comprehensive comparative
analysis of mRNAs, microRNAs, proteins, and/or epigenet-
ics between human and rodent cells from normal and injured
liver to determine how faithful rodent cells are to their human
counterparts. Based on studies to date, there is no evidence
that fibrogenic responses by stellate cells between species are
widely divergent, but the question has not yet been rigorously
addressed.
Despite progress in the field, several other key issues also
remain unresolved. The contribution of stellate cells to regen-
eration has long been assumed, but recent reports suggest
that HSC depletion has no effect on regeneration (54, 144).
Furthermore, use of transgenic animals has begun to trace
Volume 3, October 2013
Comprehensive Physiology
stellate cell fate during fibrosis regression (143, 230, 294) but
underlying mechanisms are still incomplete. Similarly, it is
increasingly clear that stellate cells and the fibrotic stroma
they generate in injured liver accelerate the risk of hepato-
cellular carcinoma, but methods to clarify pathways linking
fibrosis to cancer are only now emerging. Also unclear is the
full range of paracrine interactions in stellate cell crosstalk
with sinusoidal endothelial cells, biliary epithelial cells, and
immune cell subsets. Finally, although activation of HSCs
into contractile myofibroblasts is well recognized as the cen-
tral event in hepatic fibrosis, this insight has not yet translated
into an effective antifibrotic therapy for patients with chronic
fibrosing liver diseases. Future studies in animal models will
further clarify these vital roles, while their translation into
effective antifibrotic drugs for fibrotic liver disease is sure to
emerge in the coming years.
Acknowledgements
Work in the authors’ laboratory was supported by NIH Grants
DK56621, AA020709 (to S.L.F.), NIDDK F30-DK090986,
and T32-GM007280 (to Y.S.), and funds from the Alfonso
Martin Escudero Fundation (to J.E.P.).
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Further Reading
Friedman SL, Sheppard D, Duffield J and Violette S. Therapy for fibrotic
diseases: Nearing the starting line. Sci Transl Med, 5:167sr1, 2013.
Friedman SL, guest editor. Special issue on fibrosis. Biochim Biophys Acta.
2013 Mar 16. pii: S0925-4439(13)00077-X. doi: 10.1016/j.bbadis.
Volume 3, October 2013