Hepatocyte Dedifferentiation Profiling In Alcohol-Related Liver Disease Identifies CXCR4 As A Driver Of Cell Reprogramming.

Background and Aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocytes markers and showing immature features. However, the mechanisms and the impact of hepatocyte dedifferentiation in liver disease are poorly understood. Methods: HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ALD). Hepatocyte- specific overexpression or deletion of CXCR4, and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity. Results: Here we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness and cancer gene programs. CXCR4 pathway was highly enriched in HB cells, and correlated with disease severity and hepatocyte dedifferentiation. In vitro , CXCR4 was associated with biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased hepatocyte specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression. Conclusions: This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH. Lay summary: Here we describe that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis.

The model of Palliative Care in the perinatal setting: a review of the literature.

BACKGROUND: The notion of Palliative Care (PC) in neonatal and perinatal medicine has largely developed in recent decades. Our aim was to systematically review the literature on this topic, summarise the evolution of care and, based on the available data, suggest a current standard for this type of care. METHODS: Data sources included Medline, the Cochrane Library, CINAHL, and the bibliographies of the papers retrieved. Articles focusing on neonatal/perinatal hospices or PC were included. A qualitative analysis of the content was performed, and data on the lead author, country, year, type of article or design, and direct and indirect subjects were obtained. RESULTS: Among the 1558 articles retrieved, we did not find a single quantitative empirical study. To study the evolution of the model of care, we ultimately included 101 studies, most of which were from the USA. Fifty of these were comments/reflections, and only 30 were classifiable as clinical studies (half of these were case reports). The analysis revealed a gradual conceptual evolution of the model, which includes the notions of family-centered care, comprehensive care (including bereavement) and early and integrative care (also including the antenatal period). A subset of 27 articles that made special mention of antenatal aspects showed a similar distribution. In this subset, the results of the four descriptive clinical studies showed that, in the context of specific programmes, a significant number of couples (between 37 and 87%) opted for PC and to continue with the pregnancy when the foetus has been diagnosed with a lethal illness. CONCLUSIONS: Despite the interest that PC has aroused in perinatal medicine, there are no evidence-based empirical studies to indicate the best model of care for this clinical setting. The very notion of PC has evolved to encompass perinatal PC, which includes, among other things, the idea of comprehensive care, and early and integrative care initiated antenatally.

CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons.

Cytidine 5'-diphosphocholine (CDP-choline) has been shown to reduce neuronal degeneration induced in central nervous system (CNS) injury. However, the precise mechanism underlying the neuroprotective properties of this molecule is still unknown. Excitotoxicity causes cell death in CNS injury (trauma or ischemia) and has also been involved in neurodegenerative diseases. We have examined whether CDP-choline prevents glutamate-mediated cell death, determined by trypan blue exclusion and lactate dehydrogenase activity assays. Pretreatment of rat cerebellar granule cells (CGCs) with CDP-choline causes a dose- and time-dependent reduction of glutamate-induced excitotoxicity. Cell death is prevented >50% when 100 microM CDP-choline is added 6 d before the glutamate excitotoxic insult but less than 20% when added concomitantly with glutamate. Pretreatment of CGCs with CDP-choline reduces almost completely (>80%) the number of apoptotic cells analyzed by flow cytometry, suggesting that CDP-choline exerts a neuroprotective effect by inhibiting the apoptotic pathway induced by glutamate.