Fibroblast activation protein (FAP) is best known for its heightened expression in tumour stroma. This atypical serine protease has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. FAP expression is difficult to detect in non-diseased adult organs, but is greatly upregulated in sites of tissue remodelling, which include liver fibrosis, lung fibrosis, atherosclerosis, arthritis, tumours and embryonic tissues. Due to its restricted expression pattern and dual enzymatic activities, FAP is emerging as a unique therapeutic target. However, methods to exploit and target this protease are advancing more rapidly than knowledge of the fundamental biology of FAP. This review highlights this imbalance, emphasising the need to better define the substrate repertoire and expression patterns of FAP to elucidate its role in biological and pathological processes.

Fibroblast activation protein-␣ (FAP) can hydrolyze the postproline bond. We identified endogenous substrates of FAP in fibroblasts that were previously naive to both FAP and its proteolytic activity. FAP-dependent cleavage sites were identified in many extracellular matrix (ECM) and ECM-associated proteins including collagens and lysyl oxidase-like-1, and CSF-1, CXCL-5 and C1qT6. Quantitative proteomic analysis implicated FAP in ECM-cell interactions, coagulation and metabolism. This study greatly expands the repertoire of FAP substrates and shows that FAP has a role in coagulation in the mouse.

Canonical Hedgehog (Hh) signaling in vertebrate cells occurs following Smoothened activation/translocation into the primary cilia (Pc), followed by a GLI transcriptional response. Nonetheless, GLI activation can occur independently of the canonical Hh pathway. Using a murine model of liver injury, we previously identified the importance of canonical Hh signaling within the Pc+ liver progenitor cell (LPC) population and noted that SMO-independent, GLI-mediated signals were important in multiple Pc-ve GLI2+ intrahepatic populations. This study extends these observations to human liver tissue, and analyses the effect of GLI inhibition on LPC viability/gene expression. Human donor and cirrhotic liver tissue specimens were evaluated for SHH, GLI2 and Pc expression using immunofluorescence and qRT-PCR. Changes to viability and gene expression in LPCs in vitro were assessed following GLI inhibition. Identification of Pc (as a marker of canonical Hh signaling) in human cirrhosis was predominantly confined to the ductular reaction and LPCs. In contrast, GLI2 was expressed in multiple cell populations including Pc-ve endothelium, hepatocytes, and leukocytes. HSCs/myofibroblasts (>99%) expressed GLI2, with only 1.92% displaying Pc. In vitro GLI signals maintained proliferation/viability within LPCs and GLI inhibition affected the expression of genes related to stemness, hepatocyte/biliary differentiation and Hh/Wnt signaling. At least two mechanisms of GLI signaling (Pc/SMO-dependent and Pc/SMO-independent) mediate chronic liver disease pathogenesis. This may have significant ramifications for the choice of Hh inhibitor (anti-SMO or anti-GLI) suitable for clinical trials. We also postulate GLI delivers a pro-survival signal to LPCs whilst maintaining stemness.

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Hospitals in England experience extremely high levels of bed occupancy in the winter. In these circumstances, vaccine-preventable hospitalisations due to seasonal respiratory infections have a high cost because of the missed opportunity to treat other patients on the waiting list. This paper estimates the number of hospitalisations that current vaccines against influenza, pneumococcal disease (PD), COVID-19, and a hypothetical Respiratory Syncytial Virus (RSV) vaccine, could prevent in the winter among older adults in England. Their costs were quantified using a conventional reference costing method and a novel opportunity costing approach considering the net monetary benefit (NMB) obtained from alternative uses of the hospital beds freed-up by vaccines. The influenza, PD and RSV vaccines could collectively prevent 72,813 bed days and save over £45 million in hospitalisation costs. The COVID-19 vaccine could prevent over 2 billion bed days and save £1.3 billion. However, the value of hospital beds freed up by vaccination is likely to be 1.1–2 times larger (£48–93 million for flu, PD and RSV; £1.4–2.8 billion for COVID-19) when quantified in opportunity cost terms. Considering opportunity costs is key to ensuring maximum value is obtained from preventative budgets, as reference costing may significantly underestimate the true value of vaccines.