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  • Lastly certain populations of immune cells may be Hh respons


    Lastly, certain populations of immune cells may be Hh responsive. Although PC have not been demonstrated in healthy liver-resident macrophages or lymphocytes, macrophages in injured livers have been shown to produce Hh ligands[58], [100], [101] and treating liver-derived macrophages with neutralising GDC-0349 to Hh ligands inhibits them from becoming M2 polarised in vitro.[58], [101] Similarly, NKT cells (the predominant liver lymphocyte sub-population in healthy adult livers) are highly responsive to Hh, which promotes NKT cell viability, proliferation and skews their differentiation towards a phenotype that enhances both immune tolerance and fibrogenesis.[57], [102]
    Hedgehog in liver regeneration A growing body of evidence demonstrates that activation of the Hh pathway is crucial for liver regeneration. The best-studied animal model for evaluating acute regeneration is surgical removal of 70% of the healthy liver (partial hepatectomy [PH]) in adult rodents. Hh ligand expression increases transiently but significantly following PH in rodents. Further, inhibiting Hh pathway induction with a direct pharmacologic antagonist of Smo decreased both recovery of liver mass and overall survival.[54], [65] Interestingly, similar results were found when a targeted molecular approach was used to inhibit Smo and block Hh pathway activity in liver pericytes, identifying Hh-responsive HSCs as central players in liver regeneration. Patients undergoing extensive liver resection to de-bulk metastatic cancer are at risk of liver failure due to massive loss of functional hepatic mass. To prevent this potentially-fatal outcome, a two-stage hepatectomy is often performed, with the first step being segmental portal vein ligation, followed by a PH to stimulate compensatory growth of the non-occluded liver section. To expedite the regenerative response, a modified two-step approach (dubbed, associating liver partition and portal vein ligation for staged hepatectomy [ALPPS]) has been developed in which transection along the demarcation between occluded and non-occluded liver replaces the PH step. Compensatory liver growth is much faster after ALPSS than portal vein ligation alone, and it was recently reported that Ihh is massively upregulated in the liver and blood of patients and mice subjected to ALPPS. Interestingly, mice subjected to portal vein ligation with simultaneous administration of systemic Ihh, performed as well as mice subjected to ALPPS, supporting the other preclinical evidence that Hh signalling plays a major role in promoting acute liver regeneration. Consistent with this concept, not only does the production of Hh ligands increase after PH, but the bioavailability of those ligands also changes. In the extracellular matrix of the healthy adult liver, the proteoglycan glypican-3 binds normally to Ihh to prevent Ihh from binding to Patch in order to constrain activation of the Hh pathway. After PH, the binding of Ihh to glypican-3 dramatically decreases, returning to its baseline levels only when the liver recovers its initial size. Thus, the bioavailability of Hh ligands increases rapidly and remains elevated for a period of time following PH, which is accompanied by striking changes in hepatic Hh pathway activity. The kinetics of this process have been mapped after PH in rodents.[54], [65], [104] Briefly, hepatic expression of Shh and Ihh ligands and Gli1/Gli2 transcription factors (the downstream effectors of the canonical Hh signalling pathway) increases transiently after PH, with peak Hh pathway activity corresponding to the period of active hepatocyte replication. Interestingly, Ihh induction seems to occur slightly before, and slightly after, hepatocyte DNA proliferative activity peaks, while maximal Shh expression coincides with the time window during which hepatocyte replication and accumulation of α-SMA producing myofibroblasts are maximal. Sinusoidal lining cells, particularly activated endothelial cells and inflammatory cells, appear to be major sources of Hh ligands, but hepatocytes isolated from mice after PH also produce these factors, suggesting that PH may evoke transient stress and/or de-differentiation in residual mature hepatocytes. While more research is necessary to clarify the latter issue, available data indicate that Smo-dependent nuclear accumulation of Gli-2 protein occurs initially in hepatocytes after PH, followed 24 h later by nuclear accumulation of Gli-2 in cells that co-express progenitor markers. Further, conditional disruption of Smo in α-SMA-expressing cells revealed that Hh pathway activity in myofibroblastic cells is required for post-PH matrix remodelling, progenitor cell expansion, and proliferative responses in hepatocytes and ductular cells. Thus, multiple converging lines of evidence demonstrate that coordinated transient activation of the Hh pathway is critically important to reconstruct healthy liver tissue following partial liver resection. One appealing translation of this knowledge to improve current clinical practice might be to treat patients with Hh stimulants. For example, recombinant Ihh before extended hepatectomy or after transplantation of small-for-size liver grafts to optimise liver regeneration and avoid post-surgical liver failure. However, because maturation of liver epithelial cells is inhibited when Hh pathway activity is high, further study is essential to define safe doses and durations of pathway activation in these contexts.