Cellular stress drives pancreatic plasticity

Valdez, Ivan A.; Teo, Adrian Kee Keong; Kulkarni, Rohit

doi:10.1126/scitranslmed.3010577

Cited by 13 publications

(13 citation statements)

References 55 publications

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“…The adult pancreatic acinar cell, previously thought to be terminally and irreversibly differentiated, is now known to be surprisingly malleable (87)(88)(89)(90). We showed that two critical aspects of regulation by Ptf1a define the acinar cell identity.…”

Section: Discussionmentioning

confidence: 80%

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Hoang

Hale

Azevedo-Pouly

et al. 2016

Molecular and Cellular Biology

113

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Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo. Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes, some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation, and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma. Loss of cellular identity has long been associated with tissue injury and a first step in cancer progression (for examples, see references 1 and 2). Maintenance of a specific cellular phenotype depends on the continued transcription of cell-type-specific genes, largely through open chromatin architecture (3, 4) maintained by a small group of lineage-restricted DNA-binding transcription factors (TFs) (5, 6) that establish a unique transcriptional regulatory network (7). Many physiologic or pathophysiologic perturbations can affect the differentiated state of a cell quantitatively, but fewer affect the state of differentiation qualitatively. Qualitative changes involve the acquisition of characteristics of another cell type (or types), often defined by one or a few cell-specific markers, in addition to the diminution of the original phenotype. Despite progress with cellular reprogramming (for example, see reference 8), the molecular and genetic mechanisms that maintain cellular identity within the context of adult organs remain incompletely understood. In this report, we show that inactivation of the transcriptional regulatory gene Ptf1a in adult pancreatic acinar cells has pleiotropic effects on gene expression that cause quantitative and multigene qualitative changes of acinar differentiation.The acinar cell of the pancreas has been an informative model of terminal cellular differentiation (9). Common cellular processes are greatly exaggerated in support of the prodigious synthesis, processing, storage, and exocytosis of secretory proteins. The pancreatic acinar cell has the most ribosomes (10) and the highest rate of protein synthesis (11) of any mammalian somatic cell; it synthesizes, stores, and secretes its weight in protein daily. Specialized cellular functions ...

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Section: Discussionmentioning

confidence: 80%

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Hoang

Hale

Azevedo-Pouly

et al. 2016

Molecular and Cellular Biology

113

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“…The field of pancreatic plasticity is a dynamic and timely area of investigation that has been the focus of intense examination in recent years (Valdez et al, 2015). In this study, we have investigated the effect(s) of proinflammatory cytokine-induced stress on the differentiation potential of human and mouse ductal cells.…”

Section: Discussionmentioning

confidence: 99%

“…A growing and compelling line of evidence in rodents and humans suggests that pancreatic cell plasticity allows the generation of insulin-producing cells from non-beta cell sources, particularly during times of need (e.g. beta cell loss, pancreatic injury or metabolic stress) (Valdez et al, 2015). Various groups have argued for or against this phenomenon in an ongoing debate about the origin of the newly formed beta cells (Dor et al, 2004; Kopp et al, 2011; Kulkarni et al, 2004; Nir et al, 2007; Solar et al, 2009; Xiao et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…The remainder of the pancreas is made up of the exocrine portion and contains acinar and ductal cells, which are responsible for digestive enzyme and bicarbonate secretions. Pancreatic cell plasticity has been reported in most of these cells, both endocrine and exocrine, using a variety of models and experimental approaches (Valdez et al, 2015). Furthermore, numerous studies have reported that pancreatic cell interconversions are mediated via the emergence of NGN3, a key endocrine progenitor transcription factor necessary for endocrine cell specification (Rukstalis and Habener, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation

et al. 2016

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SUMMARY A major goal of diabetes research is to develop strategies that replenish pancreatic insulin-producing beta cells. One emerging strategy is to harness pancreatic plasticity—the ability of pancreatic cells to undergo cellular interconversions—a phenomenon implicated in physiological stress and pancreatic injury. Here we investigated the effects of inflammatory cytokine stress on the differentiation potential of ductal cells in a human cell line, in mouse ductal cells by pancreatic intraductal injection, and during the progression of autoimmune diabetes in the non-obese diabetic (NOD) mouse model. We find that inflammatory cytokine insults stimulate epithelial-to-mesenchymal transition (EMT) as well as the endocrine program in human pancreatic ductal cells via STAT3-dependent NGN3 activation. Furthermore, we show that inflammatory cytokines activate ductal-to-endocrine cell reprogramming in vivo independently of hyperglycemic stress. Together, our findings provide evidence that inflammatory cytokines direct ductal-to-endocrine cell differentiation, with implications for beta cell regeneration.

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“…While some investigators support the notion of committed progenitors, others propose that during injury, acinar cells dedifferentiate to act as facultative progenitor cells (Kong et al, 2011; Mills and Sansom, 2015). In theory, such facultative progenitors should demonstrate considerable plasticity in response to stress (Valdez et al, 2015). Another explanation for the regenerative capacities of the pancreas could be the presence of quiescent or reserve progenitors (Li and Clevers, 2010; Tian et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis

et al. 2016

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Summary The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.

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Cellular stress drives pancreatic plasticity

Cited by 13 publications

References 55 publications

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation

Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis

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