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Cell Cycle. 2011 June 1; 10(11): 1764–1771.
Published online 2011 June 1. doi:  10.4161/cc.10.11.15828
PMCID: PMC3142460

Hepatic stellate cells and astrocytes

Stars of scar formation and tissue repair

Abstract

Scar formation inhibits tissue repair and regeneration in the liver and central nervous system. Activation of hepatic stellate cells (HSCs) after liver injury or of astrocytes after nervous system damage is considered to drive scar formation. HSCs are the fibrotic cells of the liver, as they undergo activation and acquire fibrogenic properties after liver injury. HSC activation has been compared to reactive gliosis of astrocytes, which acquire a reactive phenotype and contribute to scar formation after nervous system injury, much like HSCs after liver injury. It is intriguing that a wide range of neuroglia-related molecules are expressed by HSCs. We identified an unexpected role for the p75 neurotrophin receptor in regulating HSC activation and liver repair. Here we discuss the molecular mechanisms that regulate HSC activation and reactive gliosis and their contributions to scar formation and tissue repair. Juxtaposing key mechanistic and functional similarities in HSC and astrocyte activation might provide novel insight into liver regeneration and nervous system repair.

Key words: p75 neurotrophin receptor, transforming growth factor-β, neurotrophins, epidermal growth factor, extracellular matrix, collagen, chondroitin sulfate proteoglycans, matrix metalloproteinases, scar, neurons, hepatocytes

Introduction

After injury, tissue repair is inhibited by cells that, upon activation from a quiescent state, deposit growth factors and cytokines that control cell survival in an autocrine and paracrine manner. Understanding the molecular mechanisms that govern the proliferation and activation of cells that regulate scar formation can provide insights into tissue repair and regeneration. Hepatic stellate cells (HSCs) regulate tissue repair after injury, while astrocytes do so after nervous system injury. HSCs and astrocytes share striking morphological and functional similarities. They both have spindled star-like shapes, as reflected in their names, which are derived from the Latin (stella) and Greek (astron) words for “star.” Like astrocytes, HSCs express glial fibrillary acidic protein (GFAP), a cytoskeletal protein well known for its role in astrocyte gliosis1 (Fig. 1A). Interestingly, HSCs and astrocytes are perivascular cells; both are intimately associated with the vasculature and help regulate the blood-tissue barrier, which can be critical in tissue homeostasis and reaction to injury.2

Figure 1
Expression of GFAP in HSCs and astrocytes. Differentiation of HSCs into activated myofibroblasts (left) is a hallmark of fibrotic liver disease of different etiologies, such as viral hepatitis and chronic alcohol consumption.96 In chronic liver disease, ...

HSCs fulfill a critical and dynamic function in regulating the liver's response to injury. In a normal healthy liver, HSCs are quiescent, a state in which they serve primarily to store vitamin A. In response to liver injury or disease, HSCs differentiate into myofibroblast-like cells and undergo changes in gene expression, morphology (e.g., increased size), proliferation and extracellular matrix (ECM) production.3 Activated HSC myofibroblasts are characterized by the presence of specific cytoskeletal stress fibers, including α-smooth muscle actin, and by upregulated expression and secretion of profibrogenic factors such as transforming growth factorβ (TGFβ), ECM proteins such as collagens I and III, the ECM-remodeling enzymes matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases.4,5

Astrocytes are glial cells found in gray and white matter in the brain and spinal cord. Their finely branching processes envelope all cellular components throughout the CNS to maintain nervous system functions. After CNS injury or disease, astrocytes become reactive, leading to cellular hypertrophy, upregulation of the intermediate filament GFAP (Fig. 1B), changes in gene expression, some proliferation and inhibitory ECM production, leading to so-called reactive astrogliosis.68 Beside GFAP, activated astrocytes show enhanced expression of vimentin and re-expression of nestin, all of which contribute to formation of the intermediate filament network. Activated astrocytes secrete cytokines, such as interleukin (IL) 1 and IL-6; growth factors, such as TGFβ; ciliary neurotrophic factor and nerve growth factor (NGF); and ECM proteins, such as laminin and chondroitin sulfate proteoglycans (CSPGs).811

HSCs and astrocytes have both protective and damaging functions in tissue repair (Fig. 2). Activated HSCs and astrocytes can promote inflammation and cytokine release. HSCs secrete a scar-forming matrix that inhibits hepatocyte proliferation and liver regeneration,5,12,13 and the scar-forming matrix released by astrocytes inhibits axonal regeneration.6 Both HSC activation and astrocyte reactivity appear to be necessary for and contribute to tissue repair.1418 Despite such striking similarities, HSC activation and reactive astrogliosis are not completely analogous. In this commentary, we highlight the molecular mechanisms that regulate the activation of HSCs and astrocytes and their effects on inhibitory or repair-promoting cross-talk with hepatocytes and neurons.

Figure 2
Dual role of HSCs and astrocytes in tissue repair. HSC activation and reactive astrogliosis after tissue injury each lead to deposition of growth factors, cytokines and ECM proteins that control cell survival, proliferation, growth and regeneration in ...

Molecular Mediators of Scar Formation Fibrosis in the Liver vs. Reactive Gliosis in the Nervous System

Scar formation is characterized by matrix deposition and localized inflammation. In the liver, fibrotic scarring is created by excess collagen secreted by activated HSCs. The dense collagen meshwork of the scar presents a barrier to hepatocyte growth and proliferation and inhibits liver regeneration after injury. In the CNS, scarring after traumatic injury is carried out by reactive astrocytes, which secrete a CSPG matrix that can persist for months.7 CSPGs, along with myelin-based growth inhibitors, inhibit axonal growth and nerve regeneration after CNS injury.

A crucial question in both liver fibrosis and reactive gliosis is what causes HSCs to become activated and astrocytes to become reactive and initiate scar formation. Finding the molecular “scar inducers” that activate HSCs and astrocytes is important for identifying therapeutic targets for liver and nervous system injuries. One common major profibrotic factor that promotes HSC and astrocyte activation and scar formation is TGFβ.19 In the liver, activation of HSCs by TGFβ stimulates these cells to produce and secrete collagen matrix. In activated HSCs, TGFβ expression increases, which initiates an autocrine signaling loop that perpetuates HSC activation. TGFβ secreted by activated HSCs stops hepatocyte proliferation, another barrier to liver regeneration.13 The importance of TGFβ in HSC activation has been confirmed in vivo, as TGFβ1-null mice show minimal collagen expression in the liver after acute injury.20 In HSCs and astrocytes, the major signaling molecule downstream of TGFβ is the transcription factor Smad3. In an in vivo model of acute liver injury and in vitro in culture-activated HSCs, Smad3 signaling is not necessary for HSC activation, as assessed by alpha-smooth muscle actin expression; however, it is essential for maximal expression of collagen type I in activated HSCs and for inhibition of HSC proliferation.21,22 In Smad3-null mice, scar formation is reduced after cortical stab wound injury. Thus, TGFβ signaling through Smad3 in astrocytes may contribute to scar formation after brain injury.23

In the CNS, TGFβ expression increases in astrocytes after injury and localizes in areas of gliotic scar formation.7,24 Accordingly, astroglial overexpression of TGFβ1 strongly upregulates ECM proteins in transgenic mice25 and increases CSPG expression by astrocytes in vitro.26 Neutralization of TGFβ activity with antibodies against TGFβ1 and TGFβ2 reduces gliotic scarring after brain injury in vivo.27 CSPGs are upregulated by reactive astrocytes soon after CNS injury, such as spinal cord injury.7 Although vascular leakage had been associated with scar formation, the vascular derived signal that regulates TGFβ signaling and CSPG upregulation was unknown. We showed that the blood protein fibrinogen, which leaks into the CNS immediately after blood-brain barrier disruption or vascular damage,28,29 serves as an early signal for the induction of glial scar formation via the TGFβ/Smad signaling pathway.30 Fibrinogen is a carrier of latent TGFβ and induces phosphorylation of Smad2 in astrocytes that leads to inhibition of neurite outgrowth. After cortical injury, mice genetically or pharmacologically depleted of fibrinogen have much lower levels of active TGFβ, reduced astrocytosis and less deposition of the CSPG neurocan. Therefore, fibrinogen initiates scar formation in the CNS by regulating the bioavailability of active TGFβ at sites of vascular damage.30 In the CNS, fibrin is deposited early before the secretion of CSPGs.30 Similarly, in the liver fibrin deposition precedes collagen secretion after injury. Moreover, impaired fibrin clearance results in persistent activation of HSCs.31 It is therefore possible that fibrinogen might be regulating the bioavailability of active TGFβ and thus collagen deposition after liver damage.

Beside TGFβ, other inducers of scar formation in the liver and CNS after injury include IL-1, IL-6, interferon γ and fibroblast growth factor 2. In HSCs, IL-6 promotes collagen secretion,32 while IL-1α may help promote changes in secretion of matrix-remodeling enzymes by activated HSCs.33 Fibroblast growth factor 2 has no effect on HSC activation but may have a role in regulating collagen production.34 IL-1β is upregulated immediately after CNS injury and in turn upregulates GFAP expression in astrocytes,35 a hallmark of the transition to a reactive state. Transgenic expression of IL-6 or tumor necrosis factor α in the CNS can induce spontaneous astrogliosis, which can have both deleterious effects on CNS function36,37 and beneficial effects after CNS injury.38,39 Administration of interferon γ increases gliotic scarring after traumatic brain injury.40 Fibroblast growth factor 2 is a major regulator of GFAP induction in astrocytes, suggesting that it promotes their transition to a reactive state.41

Other molecular pathways underlying scar formation in the CNS or liver have also been unraveled. Epidermal growth factor (EGF) is a major inducer of scar formation by astrocytes in the CNS and regulates hepatocyte proliferation in the liver. In primary astrocytes, treatment with EGF triggers the regulation of many genes associated with the reactive phenotype.42 In cultured astrocytes, treatment with TGFα, EGF and heparin-binding EGF, all of which are ligands for the EGF receptor, increases CSPG secretion.26,43 The transcription factor Sox9 is involved in astrocyte production of pro- and antiregenerative matrix molecules. Overexpression of Sox9 induces the expression of key enzymes involved in CSPG synthesis but does not increase the expression of laminin, fibronectin or other ECM proteins. Correspondingly, SOX9 knockdown in primary astrocytes reduces expression of key CSPG synthesis enzymes and increases the expression of laminin and fibronectin. Thus, SOX9 levels may be pivotal in determining the balance of pro- and antiregenerative ECM proteins produced by astrocytes.44 The role of SOX9 in liver scar formation has not been investigated.

A further major difference between scar formation in CNS injury versus liver injury is the physical area that the scarring encompasses. In CNS injury, the scar forms around the injury site, with reactive astrocytes surrounding the damaged tissue.6,45 The molecular regulation of the boundary is not understood. This localized scar formation may confine the postinjury inflammatory response to the damaged area, thereby minimizing damage to surrounding healthy tissue. In contrast, fibrotic scarring in the liver is often widespread, as many hepatic diseases and injuries are caused by systemic sources (e.g., viral hepatitis, chronic alcohol consumption) that activate HSCs throughout the liver.

Regulation of Blood-tissue Homeostasis by Astrocytes and HSCs

Activated HSCs remodel the sinusoidal wall46 as well as necrotic areas, suggesting a possible function in blood-tissue homeostasis. Astrocytes fulfill a similar function in inducing and maintaining the blood-brain barrier.47 Local neuronal activity leads to dynamic changes in cerebral blood flow and astrocytes are emerging as a key player in coordinating this neurovascular coupling.48 Interestingly, activated HSCs regulate the contractility of blood vessels and their resistance to blood pressure.49,50 Metallothionein, a functional marker of the blood-brain barrier, is strongly expressed in HSCs during their activation under prolonged culture conditions,2 further suggesting a role for HSCs in blood-tissue homeostasis.

Neuroglial Characteristics of HSCs

HSCs are thought to be fibroblastic mesenchymal cells,51,52 based upon the robust induction of α-smooth muscle actin, matrix molecules and matrix metalloproteinases during their activation.53 However, HSCs also express many neuroglia-related molecules that contribute to their function. HSCs express all four neurotrophins, the TrkB and TrkC receptors, the p75 neurotrophin receptor (p75NTR), neuroglia-related cytoskeletal proteins such as GFAP and nestin, and a variety of molecules and receptors involved in neurotransmission and neuroendocrine signaling (Table 1). Additionally, HSCs can respond to several neurotransmitters, including acetylcholine and serotonin (Table 1) and HSC processes can make synapse-like contacts with nerves.54 Further evidence of the neural features of HSCs comes from in vitro studies with a pharmacologic inhibitor of the hedgehog pathway. Hedgehog, which provides neural survival signals required in developing and adult brain,55 was shown to signal cell activation and viability of HSCs.56 Although the exact functions of these neuroglial molecules in HSCs are not fully known, they have been implicated in functions as diverse as differentiation,17 proliferation,57 apoptosis58 and chemotaxis.59

Table 1
Functions of neuroglial-related molecules expressed in HSCs

We have shown that p75NTR regulates HSC activation to myofibroblasts.17 p75NTR is a member of the TNF receptor superfamily of proteins originally studied for its role in neuronal death and survival.60 It is widely expressed throughout the body,61 and its expression can be upregulated by injury or disease, including liver cirrhosis.58,62 p75NTR acts through the small GTPase Rho to promote HSC differentiation into an activated myofibroblast state in a neurotrophin ligand-independent manner.17 Unlike primary HSCs isolated from wildtype mice, HSCs from p75NTR−/− mice showed impaired differentiation into an activated form in culture. This ability was restored by adenoviral delivery of full-length p75NTR or its intracellular domain. p75NTR−/− HSCs also exhibited loss of Rho activation, which was completely restored by adenoviral delivery of constitutively active Rho. Additionally, inhibiting p75NTR-mediated Rho activation with the peptide inhibitor TAT-Pep5 prevented activation of wildtype HSCs—further evidence that a p75NTR/Rho signaling pathway is important in HSC differentiation.

The role of p75NTR/Rho signaling in later stages of liver injury is unknown. Although p75NTR signaling in HSCs contributes to hepatocellular growth after injury, p75NTR may have a dual role in liver injury and repair. Indeed, p75NTR can mediate HSC apoptosis upon stimulation with the neurotrophin ligand NGF.17,58,63 At early stages of liver injury, p75NTR may regulate HSC differentiation through the Rho signaling pathway, and HSCs may secrete hepatocyte growth factor (HGF) to support hepatocyte proliferation. At later stages, however, secretion of pro-NGF or NGF by regenerating hepatocytes may lead to ligand-induced p75NTR-mediated activation of apoptotic pathways in HSCs.64 Thus, p75NTR signaling in HSCs may act in a paracrine manner to regulate liver regeneration after injury. The bioavailability of neurotrophins and the balance between pro- and mature NGF might regulate the biological function of p75NTR in liver repair.

Another molecular mechanism proposed for p75NTR-mediated HSC activation65 involves thyroid hormones implicated in liver cirrhosis. Binding of thyroid hormone receptor α1 to thyroid response elements in the p75NTR promoter induces p75NTR transcription.65 The resulting increased levels of p75NTR activate Rho signaling involved in the transdifferentiation of HSCs to myofibroblasts.65 Interestingly, thyroid hormone regulates several aspects of astrocyte differentiation and maturation, including the production of ECM proteins and growth factors.66 The role of p75NTR in liver regeneration was also confirmed in the chloride tetracarbon model of liver cirrhosis.67 In this study, the involvement of p75NTR in the regenerative response was attributed to regulation of hepatic myofibroblast apoptosis and proliferation by p75NTR.67 Moreover, p75NTR is a marker of mesenchymal progenitors of HSCs at an early stage of liver development.68 p75NTR-positive progenitor cells also express Jagged1, a Notch ligand that is crucial for inducing hepatoblasts to differentiate into cholangiocytes. Thus, p75NTR could participate in the commitment of liver progenitors and the differentiation of liver mesenchymal cells.68

p75NTR/Rho signaling also contributes to neuron growth and nerve regeneration. p75NTR-mediated activation of Rho inhibits the regeneration of injured nerves.69 TAT-Pep5 alleviates this growth inhibition and promotes neurite extension.69 The function of p75NTR in astrocytes is poorly understood. p75NTR mRNA is expressed in primary astrocytes and is further upregulated by treatment with NGF, a p75NTR ligand.70 In astrocyte cultures, activation of p75NTR by NGF attenuates proliferation induced by mitogens such as EGF or serum.71 In astrocytes in the intact adult rat CNS, p75NTR expression is restricted to a small population72,73 but is induced after different types of injury.71,74,75 p75NTR is strongly upregulated by excitotoxic damage,74 cerebral ischemia75 and seizures.76

The role of astrocytic p75NTR in these pathological conditions is unknown.77 Regulation of apoptosis has been excluded, as p75NTR expression does not correlate with apoptosis during development or in injury models.74,77,78 However, p75NTR is expressed in cycling cells, suggesting a role in regulating the cell cycle, as cell cycle transitions are necessary for cell differentiation and activation.77 A potential in vivo function of p75NTR in astrocytes has been substantiated by gene expression profiles of highly invasive and noninvasive tumor cell populations isolated from a human malignant glioma cell line after implantation into the brain of immunocompromised mice.79 p75NTR was a critical regulator of glioma invasion through the regulation of RhoA activity and cytoskeletal rearrangement.79 Interestingly, neurotrophin-dependent regulation of intramembrane proteolysis of p75NTR is required for p75NTR-mediated glioma invasion.80 Indeed, p75NTR undergoes intramembrane proteolysis in malignant gliomas, whose highly invasive nature in vivo is markedly impaired by implantation of glioma cells expressing cleavage-resistant chimeric forms of p75NTR or by subcutaneous injection of γ-secretase inhibitors.80 Although the exact role of p75NTR in cancer is poorly understood, p75NTR has been implicated in the metastatic progression of melanomas, and specifically those that metastasize to the brain.8184

The Dual Roles of HSC Activation and Reactive Astrogliosis in Tissue Repair

Although many studies have documented the damaging roles of HSCs and astrocytes in tissue injury, these cells can also promote tissue repair. In the initial stages after liver injury, HSC activation is critical, as it leads to the generation of a provisional ECM scaffold and release of growth factors, such as HGF, that promote hepatocyte proliferation. HSCs are a major source of HGF.13,85 Moreover, activated HSCs are intimately associated with regenerating hepatocyte clusters through cell-to-cell contacts,86,87 which are believed to promote three-dimensional growth of hepatocytes after injury. In mice that are heterozygous for the transcription factor Foxf1, defective HSC activation impairs liver regeneration after injury.16 Mice that lack p75NTR, which is critical for HSC activation, have exacerbated liver pathology and decreased hepatocyte proliferation in a genetic model of liver injury.17

Like HSCs, reactive astrocytes have also been viewed as a negative component of the inflammatory response to brain injury. Reactive astrocytes secrete TGFβ, which induces scar formation and may contribute to cytotoxic death of neurons and glial cells by releasing nitric oxide.6 However, in numerous studies of cultured neurons, TGFβ afforded protection against various toxins and injurious agents.88,89 In addition, reactive astrocytes support neuronal survival by releasing neurotrophic factors such as NGF and ciliary neurotrophic factor.9,10,90

Reactive astrogliosis can also play a positive role in the response to CNS injury. Selective ablation of reactive astrocytes after spinal cord injury in mice increases neuronal degeneration and the amount and duration of inflammation, suggesting that the gliotic scar compartmentalizes and minimizes inflammation at the injury site.14 These findings highlight a cytoprotective role of astrocytes after injury. In mice, conditional knockout of Stat3, an important intracellular mediator of cytokine-induced astrocyte reactivity, leads to widespread inflammatory cell infiltration, demyelination and limited functional recovery after spinal cord injury,15,91 further suggesting a protective role for reactive astrogliosis. Thus, HSC activation in liver injury and reactive astrogliosis in CNS injury seem to have dual roles. The balance of positive and negative effects of HSCs and astrocytes may be related to the stage and context of injury.

What the Liver and the Nervous System Can Learn from Each Other

Although parallels exist between the injury responses involved in HSC activation and reactive gliosis, the processes of scar formation after liver injury and after CNS injury are not totally analogous. Can we use knowledge about cell activation and scar formation in one organ to infer what may occur after injury in the other? Ideally, one would like to be able to manipulate scar formation to increase the opportunity for healing. In both CNS and hepatic injury, there are two major goals of treatment: to remove the scar using chemical or mechanical inhibitors of growth and to promote tissue regeneration and repair by fostering the growth of the key cell type (i.e., hepatocytes or neurons) that is most important for functional recovery of the tissue.

Combination therapy is a promising approach. In the nervous system, one strategy to promote repair is a neurotrophic factor-producing cell graft in the injured area combined with ways to alleviate the inhibitory effects of myelin-based growth inhibitors and CSPG matrix.92,93 A novel method to remove CSPGs from the gliotic scar was developed in transgenic mice, in which astrocytes were genetically modified to secrete a chondroitinase that digests CSPGs.94 This technique, in conjunction with other therapies, holds promise for the treatment of CNS injury. A similar technique might be used to promote collagen removal from the injured liver; an HSC-specific promoter could be valuable for cell-specific gene therapy. Therapies for liver fibrosis aim at selectively inducing apoptosis of activated HSCs to remove the source of scar-forming matrix. Such therapies may potentially be used in conjunction with HGF to promote hepatocyte proliferation.

Investigators in both the liver field and the nervous system field have explored the de-differentiation of activated/reactive cells. HSC activation can be reversed in vitro;95 however, it is not known whether it can be reversed in vivo. With further research, HSC and astrocyte “deactivation” may prove to be promising therapeutically. It would be especially interesting to see whether the two processes overlap in their molecular mechanisms. The identification of pathways that underlie HSC activation and astrogliosis is giving deep insights into the contribution of HSCs and astrocytes to scar formation after injury and offer a platform for the development of novel therapeutic targets. The parallels between scar formation in the liver and in the nervous system could stimulate researchers in both fields to unravel novel paradigms by looking beyond their tissue of choice.

Acknowledgments

We thank Benjamin D. Sachs for discussions, John Carol for graphics and Stephen Ordway for editorial assistance. Supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke Grants R01NS051470, R01NS52189 and R01NS066361 to K.A., the Pilot/Feasibility grant from the UCSF Liver Center (P30 DK026743) to K.A., the German Research Foundation (DFG) postdoctoral fellowship to C.S., and a National Multiple Sclerosis Society postdoctoral fellowship to N.L.M.

Abbreviations

HSC
hepatic stellate cell
GFAP
glial fibrillary acidic protein
ECM
extracellular matrix
TGFβ
transforming growth factorβ
CNS
central nervous system
IL
interleukin
NGF
nerve growth factor
CSPG
chondroitin sulfate proteoglycan
EGF
epidermal growth factor
HGF
hepatocyte growth factor

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