GATA factors in pancreas development and disease

Abstract

There is an urgent need for the development of novel therapeutics options for diabetic patients given the high prevalence of diabetes worldwide and that, currently, there is no cure for this disease. The transplantation of pancreatic islets that contain insulin-producing cells is a promising therapeutic alternative, particularly for type 1 diabetes. However, the shortage of organ donors constitutes a major limitation for this approach; thus, developing alternative sources of insulin-producing cells is of critical importance. In the last decade, our knowledge of the molecular mechanisms controlling embryonic pancreas development has significantly advanced.More importantly, this knowledge has provided the basis for the in vitro generation of insulin-producing cells from stem cells. Recent studies have revealed that GATA transcription factors are involved in various stages of pancreas formation and in the adult ß cell function. Here, we review the fundamental role of GATA transcription factors in pancreas morphogenesis and their association with congenital diseases associated with pancreas.

Direct conversion of human fibroblasts to pancreatic epithelial cells through transient progenitor states is controlled by temporal activation of defined factors

“…2f , bottom ). This is in agreement with previously reported GATA4 expression in the pancreatic progenitor state that is subsequently restricted to mature acinar cells during pancreatic maturation (Villamayor et al , 2020). Thus, our results give a mechanistic insight into how pancreatic identity is established and maintained through specific temporal suppression of Shh signaling.…”

“…1 was highly stage-specific, showing dramatic upregulation at four-week and downregulation at six-week timepoint. Previous studies have shown that GATA4 is required for pancreatic cell fate maintenance during pancreas development (Villamayor et al , 2020) but not for pancreatic cell fate specification since the mice with pancreas-specific Gata4 deletion develop a pancreas (Xuan et al , 2012). Importantly, GATA4 is essential for maintenance of pancreatic progenitor cell fate by downregulation of Shh signaling (Xuan et al , 2016).…”

“…1g-j ). The pools were further refined based on the previous literature about pancreas development (Petersen et al , 2018, Villamayor et al , 2020, Solar et al , 2009, Schaffer et al , 2010, Shih et al , 2012, Hale et al , 2014), resulting in eight and six TFs for acinar and ductal cells, respectively (conditions 5 and 7; Supplementary Fig. 1b ; see Methods for details).…”

“…3c ). Interestingly, HHEX is known to be one of the earliest markers of the foregut progenitor cells that is required for formation of pancreas (Bort et al , 2004, Zhao et al , 2012) and for the specification of hepatopancreatic ductal system (Villamayor et al , 2020). Furthermore, TF footprinting analysis by TOBIAS framework (Bentsen et al , 2020) showed dynamic epigenome reprogramming of fibroblast chromatin during iPEC conversion with decrease in chromatin accessibility observed for TFs that maintain the somatic cell identity of the fibroblasts (JUNB, FOSL1) and increase for early endoderm specification TFs like SOX17, FOXA2, and HHEX, as well as pancreas-lineage determining TFs such as HNF6, HNF1B and SOX9 ( Fig.…”

Cell Lineage Infidelity in PDAC Progression and Therapy Resistance

“…At this stage, cell lineage allocation to the main pancreatic fates (endocrine, acinar, and ductal) begins ( Zhou et al, 2007 ; Pan and Wright, 2011 ). The tip domains will end up producing acinar progenitors, whilst the trunk will produce bipotent ones ( Figure 1 ) ( Zhou et al, 2007 ; Pan and Wright, 2011 ; Villamayor et al, 2020 ). After E16.5, expansion of the acinar tissue is mainly driven by acinar cell replication rather than de novo formation of acini.…”