Directed pancreatic acinar differentiation of mouse embryonic stem cells via embryonic signalling molecules and exocrine transcription factors.

Pluripotent embryonic stem cells (ESC) are a promising cellular system for generating an unlimited source of tissue for the treatment of chronic diseases and valuable in vitro differentiation models for drug testing. Our aim was to direct differentiation of mouse ESC into pancreatic acinar cells, which play key roles in pancreatitis and pancreatic cancer. To that end, ESC were first differentiated as embryoid bodies and sequentially incubated with activin A, inhibitors of Sonic hedgehog (Shh) and bone morphogenetic protein (BMP) pathways, fibroblast growth factors (FGF) and retinoic acid (RA) in order to achieve a stepwise increase in the expression of mRNA transcripts encoding for endodermal and pancreatic progenitor markers.

Pancreatic ductal adenocarcinoma and transcription factors: role of c-Myc.

Introduction: Deregulated expression/activation of transcription factors is a key event in the establishment and progression of human cancer. Furthermore, most oncogenic signaling pathways converge on sets of transcription factors that ultimately control gene expression patterns resulting in cancer development, progression, and metastasis.

Methods: Ductal pancreatic adenocarcinoma (PDA) is the main type of pancreatic cancer and the fourth leading cause of cancer mortality in the Western world.

Derepression of Polycomb targets during pancreatic organogenesis allows insulin-producing beta-cells to adopt a neural gene activity program.

The epigenome changes that underlie cellular differentiation in developing organisms are poorly understood. To gain insights into how pancreatic beta-cells are programmed, we profiled key histone methylations and transcripts in embryonic stem cells, multipotent progenitors of the nascent embryonic pancreas, purified beta-cells, and 10 differentiated tissues. We report that despite their endodermal origin, beta-cells show a transcriptional and active chromatin signature that is most similar to ectoderm-derived neural tissues.

The epigenetic regulators Bmi1 and Ring1B are differentially regulated in pancreatitis and pancreatic ductal adenocarcinoma.

Chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC) are associated with major changes in cell differentiation. These changes may be at the basis of the increased risk for PDAC among patients with chronic pancreatitis. Polycomb proteins are epigenetic silencers expressed in adult stem cells; up-regulation of Polycomb proteins has been reported to occur in a variety of solid tumours such as colon and breast cancer.

Mouse ES cells over-expressing the transcription factor NeuroD1 show increased differentiation towards endocrine lineages and insulin-expressing cells.

Embryonic stem (ES) cells which constitutively express the Pdx-1, Ngn-3, NeuroD1, Nkx2.2, and Nkx6.1 transcription factors were engineered by means of lentiviral vectors, following a multi-step infection procedure to successively generate ES cell lines expressing one, two, and three factors, respectively.

Murine embryonic stem cell-derived pancreatic acinar cells recapitulate features of early pancreatic differentiation.

Background & Aims: Acinar cells constitute 90% of the pancreas epithelium, are polarized, and secrete digestive enzymes. These cells play a crucial role in pancreatitis and pancreatic cancer. However, there are limited models to study normal acinar cell differentiation in vitro.

Pancreatic ductal adenocarcinoma: cellular origin, signaling pathways and stroma contribution.

Pancreatic cancer has a very poor prognosis, in part due to its diagnosis at late stages of the disease and to limited response to chemotherapy and radiotherapy. The vast majority of pancreatic cancers are classified as pancreatic ductal adenocarcinomas (PDACs). Despite advances in knowledge on the cellular origin of PDAC or the involvement of signal transduction pathways therein, many questions remain unanswered.

Viral-mediated coexpression of Pdx1 and p48 regulates exocrine pancreatic differentiation in mouse ES cells.

Embryonic stem cells (ES) can spontaneously activate a pancreatic differentiation program in vitro, although with low efficiency. The aim was to improve such process by using viral mediated gene transduction. In this study, we have examined the suitability of using viral vectors to express key transcriptional factors involved in pancreatic development.

PTF1alpha/p48 transcription factor couples proliferation and differentiation in the exocrine pancreas [corrected].

Background & Aims: The basic helix-loop-helix transcription factor pancreas-specific transcription factor 1alpha (PTF1alpha)/p48 is critical for committing cells to a pancreatic fate and for the maintenance of the differentiated state in acinar cells. The aim was to analyze the ability of p48 to modulate cell proliferation, its relationship with cell differentiation, and the mechanisms involved therein.

Methods: Pancreatic and nonpancreatic cells were transfected with p48 cDNA, and the effects on cell proliferation were examined.

Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice.

E2F transcription factors are thought to be key regulators of cell growth control. Here we use mutant mouse strains to investigate the function of E2F1 and E2F2 in vivo. E2F1/E2F2 compound-mutant mice develop nonautoimmune insulin-deficient diabetes and exocrine pancreatic dysfunction characterized by endocrine and exocrine cell dysplasia, a reduction in the number and size of acini and islets, and their replacement by ductal structures and adipose tissue.

Transforming growth factor (TGF)beta, fibroblast growth factor (FGF) and retinoid signalling pathways promote pancreatic exocrine gene expression in mouse embryonic stem cells.

Extracellular signalling cues play a major role in the activation of differentiation programmes. Mouse embryonic stem (ES) cells are pluripotent and can differentiate into a wide variety of specialized cells. Recently, protocols designed to induce endocrine pancreatic differentiation in vitro have been designed but little information is currently available concerning the potential of ES cells to differentiate into acinar pancreatic cells.