Neurogenin 3 Expressing Cells in the Human Exocrine Pancreas Have the Capacity for Endocrine Cell Fate

Abstract

Neurogenin 3 (NGN3) is necessary and sufficient for endocrine differentiation during pancreatic development and is expressed by a population of progenitor cells that give rise exclusively to hormone-secreting cells within islets. NGN3 protein can be detected in the adult rodent pancreas only following certain types of injury, when it is transiently expressed by exocrine cells undergoing reprogramming to an endocrine cell fate. Here, NGN3 protein can be detected in 2% of acinar and duct cells in living biopsies of histologically normal adult human pancreata and 10% in cadaveric biopsies of organ donor pancreata. The percentage and total number of NGN3+ cells increase during culture without evidence of proliferation or selective cell death. Isolation of highly purified and viable NGN3+ cell populations can be achieved based on coexpression of the cell surface glycoprotein CD133. Transcriptome and targeted expression analyses of isolated CD133+ / NGN3+ cells indicate that they are distinct from surrounding exocrine tissue with respect to expression phenotype and Notch signaling activity, but retain high level mRNA expression of genes indicative of acinar and duct cell function. NGN3+ cells have an mRNA expression profile that resembles that of mouse early endocrine progenitor cells. During in vitro differentiation, NGN3+ cells express genes in a pattern characteristic of endocrine development and result in cells that resemble beta cells on the basis of coexpression of insulin C-peptide, chromogranin A and pancreatic and duodenal homeobox 1. NGN3 expression in the adult human exocrine pancreas marks a dedifferentiating cell population with the capacity to take on an endocrine cell fate. These cells represent a potential source for the treatment of diabetes either through ex vivo manipulation, or in vivo by targeting mechanisms controlling their population size and endocrine cell fate commitment.

Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to Reverse Diabetes

“…Results of immunostaining indicate that Oct4 (Pou5f1) and Sox17 may only be co-expressed very transiently after overnight re-feeding (Figure S5B, RF12hr) followed by robust expansion of Sox17 + Pdx1 + and then Pdx1 + Ngn3 + cells at RF1d (Figure 4D and see also Figure S5B for all time points). Although Ngn3+ cells were also detectable in AL mice, they were mainly located outside or on the edge of the islets, in agreement with what was reported in previous studies (Baeyens et al, 2014; Gomez et al, 2015) (Figure 4D). The number of Ngn3+ cells was increased both inside and outside the islets during the FMD and re-feeding (Figure 4D).…”

Progenitor cell niches in the human pancreatic duct system and associated pancreatic duct glands: an anatomical and immunophenotyping study

“…; Gomez et al. ) and confirm the presence of endocrine features in ductal cells in adult human pancreas. Ductal Sox9 + cells are occasionally found in strict continuity with pancreatic islets, as reported elsewhere (Zhao et al.…”

“…A restricted Sox9 + sub‐population also expressed Ngn3, indicating features associated with the endocrine specification (Gomez et al. ). These observations indicate that PDGs represent the niche of a heterogeneous population of committed progenitor cells.…”

STAT Signaling Modifies Ascl1 Chromatin Binding and Limits Neural Regeneration from Muller Glia in Adult Mouse Retina

“…Additionally, ID proteins can bind directly with HES proteins to maintain neural progenitors in an undifferentiated state (Bai et al, 2007;Boareto et al, 2017;Nam and Benezra, 2009). ID proteins have also been shown to play an important role in other organ systems, such as the pancreas, where they can bind Hes1 and participate in the dedifferentiation and fate switching of exocrine cells to endocrine fates (Gomez et al, 2015). JAK/STAT signaling is known to bias progenitors toward a glial fate in other regions of the nervous system as well (Bonni et al, 1997;Guillemot, 2007;He et al, 2005).…”