ACINPLAST

Acinar cell plasticity in the adult mouse pancreas

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 Obiettivo del progetto (Objective)

'Cellular metaplasia may occur by transdifferentiation of one mature cell type into another, sometimes via an intermediate state of dedifferentiation. This type of cellular plasticity seems to be found in adult pancreatic acinar cells. The loss of differentiation may turn the acinar cells in facultative stem cells in the adult pancreas. Both in regeneration of exocrine as well as endocrine tissue and in pancreatic disease states, this type of acinar-derived precursor cells has found to be implicated. Therefore, the different steps in acinar cell transdifferentiation and the signalling pathways and molecular mechanisms governing the process need to be investigated in depth. Before, we have developed an in vitro system to dissect different steps in acinar cell transdifferentiation starting from purified mouse acinar cells. This system permits to accurately evaluate changes in gene and protein expression during the different stages of acinar cell transdifferentiation, and when perturbing specific signalling mechanisms (using chemical inhibitors, RNA interference or using cells from genetically modified mice). Our study will be focused on Notch and Ras signalling events, and the role of caveolae as a higher hierarchical platform to integrate these signalling pathways. Results will be further validated in an in vivo experimental model of acino-to-ductal transdifferentiation, based on ligation of pancreatic ducts. We will also investigate a possible molecular switch of RBPs (recombining binding protein suppressor of hairless RBP-Jk and its paralogue RBP-L) and the genes targeted by it, when the cultured acinar cells convert into precursor-like cells. Knowledge on acinar cell plasticity can be used to prevent acinar cell de- and transdifferentiation in pancreatitis and pancreatic cancer, and can exploited for forced transdifferentiation towards endocrine beta-cells.'

Introduzione (Teaser)

Pancreatic cancer is the fourth most frequent cause of cancer deaths. Studying metaplasia can help prevent the cell processes involved in its manifestation.

Descrizione progetto (Article)

Metaplasia in the pancreatic acinar cell compartment, implicated in pancreatitis, is often a forerunner of tumour lesions and neoplasia in pancreatic cancer. Cellular metaplasia may take place when one mature cell type transdifferentiates into another. However, dedifferentiation is the first phase in the metaplasia. This kind of cellular plasticity seems to be found in adult pancreatic acinar cells. Since this loss of differentiation may turn the acinar cells into facultative stem cells, the different steps in this process and the molecular mechanisms governing it must be thoroughly investigated.

The 'Acinar cell plasticity in the adult mouse pancreas' (Acinplast) project used an in vitro model of acino-ductal metaplasia to better understand the molecular mechanisms that govern this process. Research looked at which signalling pathways eventually contribute to dedifferentiation. Results indicate very early activation of Ras signalling and of its downstream MAPK and PI3K pathways. In addition, in the metaplastic process the cells take on characteristics that are similar to precursor cells and start to express stem cell markers.

The project outcome will not only offer insight into acinar cell plasticity, but results will also be valuable in combating another disease. It has been shown that this cellular plasticity can be used optimally for forced transdifferentiation towards endocrine beta-cells, the cell type destroyed in diabetes (type 1). With dedifferentiation of the acinar cells, exocrine acinar and endocrine beta-cells can be guided into the endocrine lineage. This was achieved with rat acinar cells, using a conversion and interference approach. This points to the discovery of a new source of beta-cells to be used for cell replacement therapy.