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Stochastic priming and spatial cues orchestrate heterogeneous clonal contribution to mouse pancreas organogenesis.
Larsen HL, Martín-Coll L, Nielsen AV, Wright CVE, Trusina A, Kim YH, Grapin-Botton A
(2017) Nat Commun 8: 605
MeSH Terms: Acinar Cells, Animals, Cell Differentiation, Cell Lineage, Cell Proliferation, Computer Simulation, Gene Expression Profiling, Mice, Organogenesis, Pancreas, Single-Cell Analysis
Show Abstract · Added October 3, 2017
Spatiotemporal balancing of cellular proliferation and differentiation is crucial for postnatal tissue homoeostasis and organogenesis. During embryonic development, pancreatic progenitors simultaneously proliferate and differentiate into the endocrine, ductal and acinar lineages. Using in vivo clonal analysis in the founder population of the pancreas here we reveal highly heterogeneous contribution of single progenitors to organ formation. While some progenitors are bona fide multipotent and contribute progeny to all major pancreatic cell lineages, we also identify numerous unipotent endocrine and ducto-endocrine bipotent clones. Single-cell transcriptional profiling at E9.5 reveals that endocrine-committed cells are molecularly distinct, whereas multipotent and bipotent progenitors do not exhibit different expression profiles. Clone size and composition support a probabilistic model of cell fate allocation and in silico simulations predict a transient wave of acinar differentiation around E11.5, while endocrine differentiation is proportionally decreased. Increased proliferative capacity of outer progenitors is further proposed to impact clonal expansion.
2 Communities
0 Members
0 Resources
11 MeSH Terms
c-Myc downregulation is required for preacinar to acinar maturation and pancreatic homeostasis.
Sánchez-Arévalo Lobo VJ, Fernández LC, Carrillo-de-Santa-Pau E, Richart L, Cobo I, Cendrowski J, Moreno U, Del Pozo N, Megías D, Bréant B, Wright CV, Magnuson M, Real FX
(2018) Gut 67: 707-718
MeSH Terms: Acinar Cells, Animals, Cell Differentiation, Disease Models, Animal, Down-Regulation, Homeostasis, Mice, Pancreas, Pancreatic Neoplasms, Proto-Oncogene Proteins c-myc, Transcription Factors
Show Abstract · Added February 7, 2017
BACKGROUND AND AIMS - c-Myc is highly expressed in pancreatic multipotent progenitor cells (MPC) and in pancreatic cancer. The transition from MPC to unipotent acinar progenitors is associated with c-Myc downregulation; a role for c-Myc in this process, and its possible relationship to a role in cancer, has not been established.
DESIGN - Using coimmunoprecipitation assays, we demonstrate that c-Myc and Ptf1a interact. Using reverse transcriptase qPCR, western blot and immunofluorescence, we show the erosion of the acinar programme. To analyse the genomic distribution of c-Myc and Ptf1a and the global transcriptomic profile, we used ChIP-seq and RNA-seq, respectively; validation was performed with ChIP-qPCR and RT-qPCR. Lineage-tracing experiments were used to follow the effect of c-Myc overexpression in preacinar cells on acinar differentiation.
RESULTS - c-Myc binds and represses the transcriptional activity of Ptf1a c-Myc overexpression in preacinar cells leads to a massive erosion of differentiation. In adult mice: (1) c-Myc binds to Ptf1a, and Tcf3 is downregulated; (2) Ptf1a and c-Myc display partially overlapping chromatin occupancy but do not bind the same E-boxes; (3) at the proximal promoter of genes coding for digestive enzymes, we find reduced PTF1 binding and increased levels of repressive chromatin marks and PRC2 complex components. Lineage tracing of committed acinar precursors reveals that c-Myc overexpression does not restore multipotency but allows the persistence of a preacinar-like cell population. In addition, mutant KRas can lead to c-Myc overexpression and acinar dysregulation.
CONCLUSIONS - c-Myc repression during development is crucial for the maturation of preacinar cells, and c-Myc overexpression can contribute to pancreatic carcinogenesis through the induction of a dedifferentiated state.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
1 Communities
2 Members
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11 MeSH Terms
PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance.
Roy N, Takeuchi KK, Ruggeri JM, Bailey P, Chang D, Li J, Leonhardt L, Puri S, Hoffman MT, Gao S, Halbrook CJ, Song Y, Ljungman M, Malik S, Wright CV, Dawson DW, Biankin AV, Hebrok M, Crawford HC
(2016) Genes Dev 30: 2669-2683
MeSH Terms: Acinar Cells, Animals, Carcinoma, Pancreatic Ductal, Cell Transformation, Neoplastic, Gene Deletion, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Mice, Pancreatic Neoplasms, Tissue Array Analysis, Trans-Activators, Tumor Cells, Cultured
Show Abstract · Added February 7, 2017
Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.
© 2016 Roy et al.; Published by Cold Spring Harbor Laboratory Press.
2 Communities
1 Members
0 Resources
13 MeSH Terms
Pancreatic Inflammation Redirects Acinar to β Cell Reprogramming.
Clayton HW, Osipovich AB, Stancill JS, Schneider JD, Vianna PG, Shanks CM, Yuan W, Gu G, Manduchi E, Stoeckert CJ, Magnuson MA
(2016) Cell Rep 17: 2028-2041
MeSH Terms: Acinar Cells, Adenoviridae, Alleles, Animals, Cellular Reprogramming, Diabetes Mellitus, Experimental, Doxycycline, Gene Expression Profiling, Homeodomain Proteins, Immunity, Inflammation, Insulin-Secreting Cells, Macrophages, Metaplasia, Mice, Transgenic, Organ Size, Pancreas, Pancreatic Ducts, Reproducibility of Results, Transcription Factors, Transgenes
Show Abstract · Added November 18, 2016
Using a transgenic mouse model to express MafA, Pdx1, and Neurog3 (3TF) in a pancreatic acinar cell- and doxycycline-dependent manner, we discovered that the outcome of transcription factor-mediated acinar to β-like cellular reprogramming is dependent on both the magnitude of 3TF expression and on reprogramming-induced inflammation. Overly robust 3TF expression causes acinar cell necrosis, resulting in marked inflammation and acinar-to-ductal metaplasia. Generation of new β-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages. The new β-like cells were able to reverse streptozotocin-induced diabetes 6 days after inducing 3TF expression but failed to sustain their function after removal of the reprogramming factors.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
3 Communities
2 Members
2 Resources
21 MeSH Terms
Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A.
Hoang CQ, Hale MA, Azevedo-Pouly AC, Elsässer HP, Deering TG, Willet SG, Pan FC, Magnuson MA, Wright CV, Swift GH, MacDonald RJ
(2016) Mol Cell Biol 36: 3033-3047
MeSH Terms: Acinar Cells, Animals, Cell Differentiation, Gene Expression Profiling, Gene Expression Regulation, Gene Knockout Techniques, Homeostasis, Mice, Pancreas, Exocrine, Protein Unfolding, Sequence Analysis, RNA, Transcription Factors, Transcription, Genetic, Unfolded Protein Response
Show Abstract · Added November 1, 2016
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.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
2 Communities
2 Members
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14 MeSH Terms
Prox1-Heterozygosis Sensitizes the Pancreas to Oncogenic Kras-Induced Neoplastic Transformation.
Drosos Y, Neale G, Ye J, Paul L, Kuliyev E, Maitra A, Means AL, Washington MK, Rehg J, Finkelstein DB, Sosa-Pineda B
(2016) Neoplasia 18: 172-84
MeSH Terms: Acinar Cells, Animals, Cell Transformation, Neoplastic, Ceruletide, Heterozygote, Homeodomain Proteins, Humans, Inflammation, Metaplasia, Mice, Pancreas, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Tumor Suppressor Proteins
Show Abstract · Added April 11, 2016
The current paradigm of pancreatic neoplastic transformation proposes an initial step whereby acinar cells convert into acinar-to-ductal metaplasias, followed by progression of these lesions into neoplasias under sustained oncogenic activity and inflammation. Understanding the molecular mechanisms driving these processes is crucial to the early diagnostic and prevention of pancreatic cancer. Emerging evidence indicates that transcription factors that control exocrine pancreatic development could have either, protective or facilitating roles in the formation of preneoplasias and neoplasias in the pancreas. We previously identified that the homeodomain transcription factor Prox1 is a novel regulator of mouse exocrine pancreas development. Here we investigated whether Prox1 function participates in early neoplastic transformation using in vivo, in vitro and in silico approaches. We found that Prox1 expression is transiently re-activated in acinar cells undergoing dedifferentiation and acinar-to-ductal metaplastic conversion. In contrast, Prox1 expression is largely absent in neoplasias and tumors in the pancreas of mice and humans. We also uncovered that Prox1-heterozygosis markedly increases the formation of acinar-to-ductal-metaplasias and early neoplasias, and enhances features associated with inflammation, in mouse pancreatic tissues expressing oncogenic Kras. Furthermore, we discovered that Prox1-heterozygosis increases tissue damage and delays recovery from inflammation in pancreata of mice injected with caerulein. These results are the first demonstration that Prox1 activity protects pancreatic cells from acute tissue damage and early neoplastic transformation. Additional data in our study indicate that this novel role of Prox1 involves suppression of pathways associated with inflammatory responses and cell invasiveness.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
0 Communities
2 Members
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14 MeSH Terms
The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma.
Krah NM, De La O JP, Swift GH, Hoang CQ, Willet SG, Chen Pan F, Cash GM, Bronner MP, Wright CV, MacDonald RJ, Murtaugh LC
(2015) Elife 4:
MeSH Terms: Acinar Cells, Adenocarcinoma, Animals, Carcinoma in Situ, Carcinoma, Pancreatic Ductal, Cell Transdifferentiation, Disease Models, Animal, Gene Expression Profiling, Humans, Mice, Transcription Factors
Show Abstract · Added August 4, 2015
Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.
1 Communities
1 Members
0 Resources
11 MeSH Terms
Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice.
Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stangé G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CV, Van de Casteele M, German MS, Bouwens L, Heimberg H
(2014) Nat Biotechnol 32: 76-83
MeSH Terms: Acinar Cells, Animals, Cell Differentiation, Cell Proliferation, Ciliary Neurotrophic Factor, Diabetes Mellitus, Epidermal Growth Factor, Hyperglycemia, Insulin-Secreting Cells, Mice, Mice, Inbred NOD, Signal Transduction
Show Abstract · Added February 3, 2014
Reprogramming of pancreatic exocrine cells into cells resembling beta cells may provide a strategy for treating diabetes. Here we show that transient administration of epidermal growth factor and ciliary neurotrophic factor to adult mice with chronic hyperglycemia efficiently stimulates the conversion of terminally differentiated acinar cells to beta-like cells. Newly generated beta-like cells are epigenetically reprogrammed, functional and glucose responsive, and they reinstate normal glycemic control for up to 248 d. The regenerative process depends on Stat3 signaling and requires a threshold number of Neurogenin 3 (Ngn3)-expressing acinar cells. In contrast to previous work demonstrating in vivo conversion of acinar cells to beta-like cells by viral delivery of exogenous transcription factors, our approach achieves acinar-to-beta-cell reprogramming through transient cytokine exposure rather than genetic modification.
3 Communities
2 Members
0 Resources
12 MeSH Terms
The plastic pancreas.
Ziv O, Glaser B, Dor Y
(2013) Dev Cell 26: 3-7
MeSH Terms: Acinar Cells, Carcinoma, Pancreatic Ductal, Cell Death, Cell Dedifferentiation, Cell Differentiation, Cellular Reprogramming, Endocrine Cells, Humans, Pancreas, Pancreatitis, Regeneration, Stem Cells
Show Abstract · Added August 14, 2013
Pancreas homeostasis is based on replication of differentiated cells in order to maintain proper organ size and function under changing physiological demand. Recent studies suggest that acinar cells, the most abundant cell type in the pancreas, are facultative progenitors capable of reverting to embryonic-like multipotent progenitor cells under injury conditions associated with inflammation. In parallel, it is becoming apparent that within the endocrine pancreas, hormone-producing cells can lose or switch their identity under metabolic stress or in response to single gene mutations. This new view of pancreas dynamics suggests interesting links between pancreas regeneration and pathologies including diabetes and pancreatic cancer.
Copyright © 2013 Elsevier Inc. All rights reserved.
0 Communities
0 Members
1 Resources
12 MeSH Terms
Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration.
Pan FC, Bankaitis ED, Boyer D, Xu X, Van de Casteele M, Magnuson MA, Heimberg H, Wright CV
(2013) Development 140: 751-64
MeSH Terms: Acinar Cells, Animals, Body Weights and Measures, Cell Differentiation, Gene Knock-In Techniques, Mice, Microscopy, Confocal, Multipotent Stem Cells, Organogenesis, Pancreas, Recovery of Function, Signal Transduction, Tamoxifen, Time Factors, Transcription Factors
Show Abstract · Added January 10, 2014
Pancreatic multipotent progenitor cells (MPCs) produce acinar, endocrine and duct cells during organogenesis, but their existence and location in the mature organ remain contentious. We used inducible lineage-tracing from the MPC-instructive gene Ptf1a to define systematically in mice the switch of Ptf1a(+) MPCs to unipotent proacinar competence during the secondary transition, their rapid decline during organogenesis, and absence from the mature organ. Between E11.5 and E15.5, we describe tip epithelium heterogeneity, suggesting that putative Ptf1a(+)Sox9(+)Hnf1β(+) MPCs are intermingled with Ptf1a(HI)Sox9(LO) proacinar progenitors. In the adult, pancreatic duct ligation (PDL) caused facultative reactivation of multipotency factors (Sox9 and Hnf1β) in Ptf1a(+) acini, which undergo rapid reprogramming to duct cells and longer-term reprogramming to endocrine cells, including insulin(+) β-cells that are mature by the criteria of producing Pdx1(HI), Nkx6.1(+) and MafA(+). These Ptf1a lineage-derived endocrine/β-cells are likely formed via Ck19(+)/Hnf1β(+)/Sox9(+) ductal and Ngn3(+) endocrine progenitor intermediates. Acinar to endocrine/β-cell transdifferentiation was enhanced by combining PDL with pharmacological elimination of pre-existing β-cells. Thus, we show that acinar cells, without exogenously introduced factors, can regain aspects of embryonic multipotentiality under injury, and convert into mature β-cells.
3 Communities
2 Members
1 Resources
15 MeSH Terms