The simple truth is seldom true and never simple: Dual role for p75NTR in transdifferentation and cell death of hepatic stellate cells

Authors


  • Potential conflict of interest: Nothing to report.

Passino MA, Adams RA, Sikorski SL, Akassoglou K. Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR. Science 2007;315:1853–1856. (Reproduced with permission.)

Abstract

Differentiation of hepatic stellate cells (HSCs) to extracellular matrix- and growth factor-producing cells supports liver regeneration through promotion of hepatocyte proliferation. We show that the neurotrophin receptor p75NTR, a tumor necrosis factor receptor superfamily member expressed in HSCs after fibrotic and cirrhotic liver injury in humans, is a regulator of liver repair. In mice, depletion of p75NTR exacerbated liver pathology and inhibited hepatocyte proliferation in vivo. p75 NTR−/− HSCs failed to differentiate to myofibroblasts and did not support hepatocyte proliferation. Moreover, inhibition of p75NTR signaling to the small guanosine triphosphatase Rho resulted in impaired HSC differentiation. Our results identify signaling from p75NTR to Rho as a mechanism for the regulation of HSC differentiation to regeneration-promoting cells that support hepatocyte proliferation in the diseased liver.

Comment

Neurotrophins (NTs) were discovered in the nervous system where they exert functions including neuronal survival and growth, apoptosis, and synaptic modulation.1 NTs are also active in non-neural tissues. Herein, they influence differentiation, tissue remodeling, proliferation, and migration of cells.2 In the liver, stellate cells contain NTs and express NT receptors, in particular p75NTF.3–6 Regenerating hepatocytes4 and cultured stellate cells6 secrete nerve growth factor (NGF).

There are 4 NTs in mammalians: NGF, brain-derived neurotrophin (BDNF), neurotrophin 3 (NT3), and neurotrophin 4/5 (NT4/5) which exert their biological effects through the high-affinity NT receptors TrkA (tropomyosin-related tyrosine kinase A), TrkB, and TrkC, and through the “low” affinity pan-neurotropin receptor p75NTR that belongs to the tumor necrosis factor (TNF) receptor superfamily.7 The p75NTR carries a cytoplasmic death-domain and a Chopper domain that are starting points for pathways that lead to apoptosis. Full-length p75NTR binds all 4 mature NTs. However, when p75NTR heterodimerizes with Trk receptors, it binds mature NTs with much higher affinity.7 p75NTR also binds uncleaved pro-NGF and pro-BDNT with high affinity.8 Binding of pro-NTs requires the presence of sortilin, which serves as a co-receptor for pro-NTs.9 Pro-NTs can be secreted as such, or can be converted into mature NTs by enzymatic cleaving.8 Besides pro-NTs and NTs, myelin-based growth inhibitors (MBGIs) such as Nogo-66, “myelin-associated glycoprotein”, and “oligodendrocyte myelin glycoprotein”, as well as prion protein, rabies-virus glycoprotein, and amyloid precursor protein serve as unconventional ligands. The MBGIs require the presence of Nogo Receptor and the membrane protein Lingo-1 to signal.10 Finally, p75NTR can also signal in the absence of ligands, presumably when the receptor oligomerizes, or when it forms other complexes.10

The intracellular signaling pathways activated by p75NTR can be subdivided into 3 broad categories: (1) pathways that lead to apoptosis, which include the NRIF/TNF receptor-associated factor/Rac/c-Jun N-terminal kinase pathway; (2) pathways that promote cell survival, which include nuclear factor-κB, phosphoinositide 3-kinase/Akt, and Ras/mitogen-activated protein kinase; and (3) pathways that modulate the cytoskeleton and lead to cellular regeneration, such as the RhoA/Rho kinase pathway.7, 10

Which are the target cells for NTs in the liver? Part of the truth was unveiled by Trim et al. who reported that activated hepatic stellate cells carry p75NTR and undergo apoptosis in response to NGF secreted by neighboring regenerating hepatocytes.4, 5 In their view, p75NTR is the Achilles' heel of stellate cells. It makes them vulnerable to NGF-induced apoptosis. This process may self-limit hepatic fibrogenesis.

Passino et al. reveal a different aspect of the truth. Activation of Rho/Rho kinase signaling via p75NTR is a conditio sine qua non for in vivo transition of mouse hepatic stellate cells into myofibroblast-like cells that are important cellular sources of hepatocyte growth factor (HGF). The authors have used the plasminogen knockout (plg−/−) mouse model.11 In the liver, plasminogen deficiency leads to fibrin deposits and concomitant necrosis of hepatocytes trapped in the fibrin cloth. Passino et al. crossed these mice with p75NTR-deficient mice. The plg−/− p75NTR−/− double knockouts have more hepatocyte damage than do the single plg−/− knockouts. In double knockouts, replacement of damaged hepatocytes by new hepatocytes is affected by lesser secretion of HGF by stellate cells. In wild-type or plg−/− mice, early-activated stellate cells up-regulate expression of p75NGF and secrete HGF. HGF drives healthy hepatocytes into proliferation. In p75NTF−/− mice, stellate cells remain quiescent. They do not secrete much HGF. Hence, regeneration of hepatocytes is attenuated. The mechanism by which p75NTR induces secretion of HGF is indirect. In a ligand-independent way, p75NTR activates the Rho/Rho kinase pathway which enhances actin filament formation and phosphorylation of cofilin. This pathway contributes to the transition of quiescent stellate cells into myofibroblast-like cells.12

How can the studies by Trim et al. be reconciled with those of Passino et al.? Stellate cell transdifferentiation is a gradual process that can be broadly subdivided into an initiation phase and a perpetuation phase (Fig. 1). We propose that during early initiation, p75NTR receptor is up-regulated. The signal that induces this process is unknown. In late initiation, p75NTR participates in the transdifferention of stellate cells via activation of the Rho/Rho kinase pathway. This activation could be brought about by oligomerization of the unliganded receptor, or by unconventional ligands that bind to it. In the perpetuation phase, p75NTR shows its Janus face. By dimerization with one of the Trk receptors or by association with a protein such as sortilin, p75NTR becomes a high-affinity death receptor and kills off the cells on which it is expressed. The merits of the work by Trim et al. and by Passino et al. are that they have unveiled a new fascinating regulatory network in the liver. Who takes on its further dissection?

Figure 1.

Live or let die? p75NTR determines the cell fate of hepatic stellate cells. Quiescent stellate cells express very little if any p75NTR receptor. (A) Early priming to activation implies increased expression of p75NTR receptor. Mechanisms that induce expression of p75NTR are unknown. (B) Further initiation of stellate cell activation leads to hypothetical homodimerization or hetero-oligomerization of the receptor. This induces ligand-independent activation of the Rho/Rho kinase signaling pathway, which further fuels transdifferentiation of quiescent cells into myofibroblasts. (C) During perpetuation of transdifferentiation, secretion of pro-NGF or NGF by regenerating hepatocytes leads to ligand-induced activation of apoptotic pathways in stellate cells.

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