HEИндивидуална стипендия2022–2024

PlasticLiver · Mechanisms of cell plasticity in the liver

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период: 2022-12-01 → 2024-11-30
Финансиране от ЕС: 222 728 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Механизмите за възстановяване на чернодробните клетки се изследват чрез пример с редкия синдром на Алажиле. Разбирането на тези процеси е важно за разработването на терапии, които биха могли да заменят трансплантацията на орган.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Mechanisms of cell plasticity in the liver

The liver is known as a robust organ. Its regenerative capacity has been recognized already in ancient Greek mythology in the story of Prometheus. Unlike other regenerative tissues that contain dedicated stem cells (e.g., skin, intestine), the liver can regenerate cells from mature differentiated cells, which upon stimuli reprogram their fate and even switch into another cell type. However, some disease conditions hamper this remarkable cell plasticity and the liver’s capacity to recover. Deeper fundamental understanding of endogenous regenerative processes is therefore crucial for the development of any promising therapeutic strategy to avoid the most drastic solution, which is a liver transplant. This project studied mechanisms of cell plasticity in the liver, in the context of cholestatic liver diseases, exemplified by the rare disease Alagille syndrome. Because of gene mutations affecting the Notch signalling pathway, Alagille syndrome presents with a range of phenotypes in many organs, including a severe underdevelopment of intrahepatic bile ducts at birth, resulting in cholestasis, jaundice, pruritus (skin itching), and other complications. The severity of the Alagille syndrome liver phenotype varies broadly and, astonishingly, some individuals recover bile ducts with full function later in life. Bile ducts are a tree-like structure in the liver, branching from the centre of the organ. They collect bile from the organ periphery and carry it out of the liver, relying on a proper arrangement of cells in the bile duct epithelium. Previous studies in a mouse model of the disease showed that bile duct regeneration is spatially heterogeneous, with the bile ducts recovering differently in the centre and at the periphery of the organ, suggesting distinct mechanisms at play. This project aimed to determine mechanisms that contribute to the recovery of bile ducts and underlie the regional heterogeneity of this process by using state-of-the-art gene expression profiling methods and advanced microscopy approaches in mouse models. With these data, we aimed to identify molecular pathways for potential intervention in the treatment of cholestatic liver.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

The liver can regenerate thanks to a unique cell plasticity in which “terminally differentiated cells” change identity. Hepatocytes, the most abundant cell type sustaining liver metabolism, can transdifferentiate into a completely different cell type to repair the bile duct epithelium, which entails not only a fate switch but also a conversion of epithelial polarity. Despite this regenerative capacity, bile duct diseases present a major clinical challenge, often requiring a liver transplant. Activating and controlling endogenous regenerative programs, which preliminary data suggest are liver region-specific, is thus a promising therapeutic strategy but requires a deeper understanding of the underlying mechanisms. Based on regional differences in the quality of regenerated bile ducts in a mouse model of Alagille syndrome, I hypothesize that bile ducts in the hilar region regenerate via cholangiocyte proliferation, yielding well-formed epithelia, while bile ducts at the organ periphery develop de novo via hepatocyte transdifferentiation, yielding malformed bile ducts with aberrant polarity. Because there are multiple cell sources for liver repair, PlasticLiver aims to account for spatial and within-cell type heterogeneity in the liver during bile duct regeneration. Taking advantage of a novel cutting-edge approach for high resolution barcode lineage tracing and gene expression profiling co-developed in my host lab, I will resolve region-specific cell sources and mechanisms in developing and regenerating livers of a mouse model of Alagille syndrome. Moreover, combining generated single cell gene expression data and microscopy analysis of healthy and regenerated tissues, I will identify molecular mechanisms and potential targets to improve epithelial polarity in regenerated peripheral bile ducts. Ultimately, PlasticLiver will yield fundamental mechanistic insights into cell fate decisions and why liver, but no other organs, uses this type of cellular plasticity.

Оригинален текст от CORDIS (на английски).

Участници

KAROLINSKA INSTITUTET · STOCKHOLMКоординаторШвеция