Diabetes mellitus is a metabolic disorder characterized by dysfunction, loss, or insufficient mass of β cells. The main function of β cells is to produce and secrete insulin, the hormone responsible for the regulation of blood glucose levels. Type 1 diabetes (T1D) results from autoimmune destruction of β cells, while type 2 diabetes (T2D) mostly results from β-cell dysfunction or peripheral tissue resistance to insulin, often culminating in β-cell death. Thus, both forms of diabetes can benefit from restoration of β-cell mass. Currently, islet transplantation is the only way to provide new β cells to diabetic patients, but the scarcity of compatible cadaveric donors makes this approach available to only few patients; moreover, it requires lifelong immune suppression

Afelik, Solomon

Rovira, Meritxell

Genome Medicine

English

Diposit Digital de la Universitat de Barcelona

Afelik and Rovira Genome Medicine  (2017) 9:42 DOI 10.1186/s13073-017-0437-xCOMMENT Open AccessPancreatic β-cell regeneration: advances inunderstanding the genes and signalingpathways involvedSolomon Afelik1* and Meritxell Rovira2*Editorial summaryRecent advances in β-cell regeneration in vivo areproviding insights into the mechanisms involved inthe conversion of distinct pancreatic cell lineages intoβ cells. These mechanisms mostly involve reactivationof the gene encoding the pancreatic endocrinecell-specifying transcription factor neurogenin-3.bicarbonate-containing secretions to convey acinar-derivedThe promise of pancreatic β-cell regenerationDiabetes mellitus is a metabolic disorder characterized bydysfunction, loss, or insufficient mass of β cells. The mainfunction of β cells is to produce and secrete insulin, thehormone responsible for the regulation of blood glucoselevels. Type 1 diabetes (T1D) results from autoimmunedestruction of β cells, while type 2 diabetes (T2D) mostlyresults from β-cell dysfunction or peripheral tissue resist-ance to insulin, often culminating in β-cell death. Thus,both forms of diabetes can benefit from restoration of β-cell mass. Currently, islet transplantation is the only wayto provide new β cells to diabetic patients, but the scarcityof compatible cadaveric donors makes this approachavailable to only few patients; moreover, it requires life-long immune suppression [1].Great progress has been made in the field of in vitrodifferentiation of human embryonic and induced pluripo-tent stem cells toward insulin-producing cells, includingthe generation of stem cell-derived β cells from patientswith T1D, leading to an ongoing clinical trial to assesstheir safety in humans [2]. Recent advances in studies withanimal models are also beginning to provide compellingevidence to suggest in vivo β-cell regeneration as a viablealternative future approach to restoring β-cell mass in* Correspondence: safelik@uic.edu; mrovira@cmrb.eu1Division of Transplantation, Department of Surgery, University of Illinois atChicago, 840 South Wood Street, CSB 920 (Rm 502), Chicago, IL 60612, USA2Center of Regenerative Medicine in Barcelona (CMRB), Dr. Aiguader 88,08003 Barcelona, Spain© The Author(s). 2017 Open Access This articInternational License (http://creativecommonsreproduction in any medium, provided you gthe Creative Commons license, and indicate if(http://creativecommons.org/publicdomain/zediabetic patients. These advances have been based on pre-vious studies demonstrating the ability of particular genesand pathways to induce β-cell neogenesis in vivo fromdifferentiated adult pancreatic lineages such as acinarcells, ductal or centroacinar cells, and other endocrinesubtypes [1]. It is worth noting that in early developmentall pancreatic lineages, including acinar cells (whichproduce digestive enzymes), duct cells (which produceenzymes into the duodenum), and all the pancreatic endo-crine subtypes, differentiate from a common pool of multi-potent pancreatic progenitor cells (MPCs). MPCs becomepatterned into acinar progenitor cells and bi-potent ductal/endocrine progenitor cells. The activation of Ngn3 in thispool of bi-potent progenitors promotes the differentiationof all endocrine cells, while Ngn3-negative bi-potent pro-genitors mature as ductal cells.β-cell regeneration from pancreatic acinar, ductal,or β-cell lineages requires Ngn3 activationVarious pancreatic regeneration models have been devel-oped in both mice and rats to study β-cell regenerationin vivo. These models have been used successfully to re-program several pancreatic lineages into β cells by geneticmodifications of key transcription factors, highlighting theprominent role of such genes in β-cell regeneration. Theseare often genes involved in β-cell development during em-bryogenesis. Reactivation of the embryonic pancreaticendocrine cell-specifying gene Ngn3 appears to be criticalfor sustained β-cell regeneration in vivo in most β-cell re-generation models reported so far [3] (Fig. 1).While in vivo genetic manipulations are useful for ex-perimentation, they are not feasible for therapy inhumans. To translate these studies into therapy, it is ofparamount importance to identify signaling pathways orsmall molecules that can specifically target key β-cellreprogramming genes. Recently, several breakthroughpapers have described specific signaling pathways thatle is distributed under the terms of the Creative Commons Attribution 4.0.org/licenses/by/4.0/), which permits unrestricted use, distribution, andive appropriate credit to the original author(s) and the source, provide a link tochanges were made. The Creative Commons Public Domain Dedication waiverro/1.0/) applies to the data made available in this article, unless otherwise stated.Fig. 1 Illustration of cellular plasticity between the different pancreatic lineages and the signaling pathways involved in pancreatic β-cell regeneration.In the regenerative scenarios—acinar to β cell, ductal to β cell, and α to β cell—a transition state involving Ngn3 activation is necessary for thereprogramming to occur, with the exception of δ to β cell conversion (see [3] and main text for further details). a Acinar cells can be converted intoβ cells in vivo by overexpression of Ngn3, Pdx1, and MafA in mice (1). Hyperglycemia can inhibit (shown by a cross) in vivo reprogramming of acinarcells by Pdx1, Ngn3, and MafA. Furthermore, acinar cells can become β cells in vitro and in vivo after exposure to ciliary neurotrophic factor (CNTF) andepidermal growth factor (EGF) (2); this regenerative event is dependent on PKA/STAT3 signaling-mediated Ngn3 activation. b Ductal cells can bereprogrammed into β cells in vivo after genetic deletion of the ubiquitin ligase Fbxw7 (1). Such reprogramming can also be induced in vivo in miceafter treatment with gastrin, EGF, and medium hyperglycemia (2). Interestingly, this ductal to β cell conversion requires a progenitor-like intermediatestate that involves Ngn3 activation. c Similarly, α cells can be converted into β cells by ectopic activation of Pax4 in α cells in the adult pancreas, eitherby transgenic overexpression of Pax4 or indirectly by suppressing Arx (1). In a recent report, it was shown that treatment with an artemisinin (forexample, artemether) [9] or long-term administration of gamma-amino butyric acid (GABA) [8] results in robust conversion of α cells to β cells in vitroand in vivo (2). Both compounds act through the GABAA receptor; artemether treatment increases gephryin protein levels, which potentiates GABAAreceptor signaling while inhibiting mTOR signaling (shown by a cross). Strikingly, both artemisinin and GABA treatments inhibit Arx function orexpression, leading to induction of Pax4 expression, concomitantly inhibiting glucagon secretion and inducing insulin expression. Although the in vivoα to β switch in itself is independent of Ngn3, the conversion of endogenous α to β cells appears to trigger α-cell neogenesis from ductal cells byreactivation of Ngn3 in GABA-treated pancreas. d Finally, δ cells can be reprogrammed into β cells in early puberty, although this conversion isindependent of Ngn3 activationAfelik and Rovira Genome Medicine  (2017) 9:42 Page 2 of 4Afelik and Rovira Genome Medicine  (2017) 9:42 Page 3 of 4induce β-cell regeneration from differentiated pancreaticlineages in vivo.Notably, Baeyens and colleagues [4] translated know-ledge gained from in vitro studies to an in vivo mousemodel of β-cell regeneration. This study elegantlyshowed that treating alloxan-induced diabetic mice withepidermal growth factor (EGF) and ciliary neurotrophicfactor (CNTF) was sufficient to stimulate the conversionof acinar cells into β cells. Moreover, they provided evi-dence that this regenerative capacity is dependent onprotein kinase A/signal transducer and activator of tran-scription 3 (PKA/STAT3) signaling, mediating Ngn3 ac-tivation. Interestingly, a subsequent study has illustratedhow hyperglycemia can inhibit in vivo reprogrammingof acinar cells by the transcription factors Pdx1, Ngn3,and MafA [5], highlighting the significant role of glucoselevels in the plasticity and β-cell regenerative potentialof the exocrine pancreas. Altogether, these studies pro-vide critical knowledge for β-cell regeneration from pan-creatic acinar cells in vivo, with important therapeuticimplications given their vast numbers in the pancreas.Besides regenerating β cells from pancreatic acinarcells, there have been recent advances in reprogrammingβ cells from pancreatic ducts in vivo. Zhang and co-workers [6] recently described the effectiveness oflong-term administration of a low dose of the hormonegastrin (which is produced by the stomach and stimulatesthe release of gastric acid that helps to break down anddigest food) and epidermal growth factor (EGF) underconditions of medium levels of hyperglycemia to repro-gram Sox9+ ductal cells into β cells in an alloxan-induceddiabetic mouse model. In addition, a recent report demon-strated the effect of pro-inflammatory cytokines in indu-cing β-cell neogenesis in adult mouse duct cells byactivating Ngn3 through STAT3 phosphorylation [7], simi-lar to the requirement of STAT3 signaling for acinar to β-cell regeneration reported by Baeyens et al. [4]. As EGFand gastrin are known in other contexts to be involved inactivation of STAT3, it would be interesting to learn ifSTAT3-mediated Ngn3 activation plays a role in the ef-fects reported by Zhang et al. [6].While these key recent findings connect extracellularsignaling pathways to in vivo β-cell reprogramming ofacinar and ductal cells through Ngn3 activation, an im-pressive boost to the field of β-cell regeneration alsocomes from the discovery of the role of gamma-aminobutyric acid (GABA) receptor signaling in the conver-sion of α cells to β cells. Two complementary paperspublished this year [8, 9] beautifully illustrate how know-ledge acquired from genetic modification of Arx andPax4, key transcription factors involved in α to β cellconversion, inspired the design of a high-throughputscreen of small molecules to identify compounds thatcould either induce Pax4 or inhibit Arx expression in αcell lines in vitro. This led to the identification of theartemisinin antimalarial drug class (for example, arte-mether) as hit compounds that induce the conversion ofα to β cells through activation of GABAA receptor sig-naling in α cells [9]. Indeed, either artemisinin treatment[9] or long-term administration of GABA [8] results inrobust conversion of α cells to β cells both in vitro andin vivo. Strikingly, artemisinin or long-term GABA ad-ministration in vivo inhibits either Arx function or Arxexpression, respectively, leading to induction of Pax4 ex-pression. Hence, both drugs promote β-cell neogenesisfrom α cells in vivo in zebrafish and rodent models ofdiabetes, as well as in human islets in vitro. GABA treat-ment acts via the GABAA receptor in α cells, whereasartemisinins stabilize the neuronal assembly proteingephryin in this receptor, thus enhancing GABAA recep-tor signaling, and consequently inhibiting glucagonsecretion. This suggests that a reduced extracellular con-centration of glucagon is required for α to β cell conver-sion mediated by GABA receptor signaling.In all these regenerative scenarios (Fig. 1)—acinar to βcell, ductal to β cell, and α to β cell—the transition stateinvolving Ngn3 activation is necessary for the repro-gramming to occur. Even though the GABAA-receptor-signaling-mediated α to β switch per se is independentof Ngn3, the conversion of endogenous α to β cells ap-pears to trigger α-cell neogenesis from ductal cells by re-activation of Ngn3, such that knockdown of Ngn3 inGABA-treated pancreas exhibits a reduction in α to βcell conversion [8]. Interestingly, in a recent study byCheng and colleagues [10], a fasting-mimicking diet(FMD) in mice was shown to promote Ngn3-drivenβ-cell regeneration through the inhibition of PKA andmTOR kinases. Also in this study, exposure of healthyand T1D human islets to low-glucose and low-serum fast-ing-mimicking medium in vitro was found to significantlystimulate the secretion of insulin and to induce Sox2and Ngn3 expression. This may suggest that mediumor low glucose levels play an important role in pan-creatic lineage reprogramming into β cells throughthe activation of Ngn3.ConclusionsThese recent findings suggest that pharmacologicaltreatment with several compounds or growth factors orpresumably an FMD can promote plasticity and β-cellregeneration in the pancreas in animal models in vivo.The signaling pathways involved in such plasticity changedepending on the lineage source of the reprogramming(acinar, ductal, or α cells). Although there are common re-quirements for all of them, such as the acquisition of atransitional progenitor-like state with the activation ofNgn3, extracellular glucose and glucagon levels might alsoplay an important role. Thus, these recent findings openAfelik and Rovira Genome Medicine  (2017) 9:42 Page 4 of 4the door to potential new therapies to restore β-cell massin diabetic patients.AbbreviationsFMD: Fasting-mimicking diet; MPC: Multipotent pancreatic progenitor cell;T1D: Type 1 diabetes; T2D: Type 2 diabetesAcknowledgementsMR is supported by the Spanish Ministry of Economy, Industry andCompetitiveness SAF2015-73226-JIN (AEI/FEDER, UE) and CERCAProgramme/Generalitat de Catalunya. SA is supported by the AmericanDiabetes Association Junior Faculty Award, and the Chicago DiabetesProject (http://www.chicagodiabetesproject.org/).Authors’ contributionsBoth authors read and approved the final manuscript. The illustration in Fig. 1 isby MR.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in publishedmaps and institutional affiliations.References1. Benthuysen JR, Carrano AC, Sander M. Advances in β cell replacement andregeneration strategies for treating diabetes. J Clin Invest. 2016;126(10):3651–660.2. Millman JR, Pagliuca FW. Autologous pluripotent stem cell–derived β-likecells for diabetes cellular therapy. Diabetes. 2017;66(5):1111–20.3. Afelik S, Rovira M. Pancreatic β-cell regeneration: facultative or dedicatedprogenitors? Mol Cell Endocrinol. 2017;445:85–94.4. Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stangé G, et al. Transientcytokine treatment induces acinar cell reprogramming and regeneratesfunctional beta cell mass in diabetic mice. Nat Biotechnol. 2014;32(1):76–83.5. Cavelti-Weder C, Li W, Zumsteg A, Stemann-Andersen M, Zhang Y, YamadaT, et al. Hyperglycaemia attenuates in vivo reprogramming of pancreaticexocrine cells to beta cells in mice. Diabetologia. 2016;59(3):522–32.6. Zhang M, Lin Q, Qi T, Wang T, Chen CC, Riggs AD, et al. Growth factors andmedium hyperglycemia induce Sox9+ ductal cell differentiation into β cellsin mice with reversal of diabetes. Proc Natl Acad Sci U S A. 2016;113(3):650–5.7. Valdez IA, Dirice E, Gupta MK, Shirakawa J, Teo AK, Kulkarni RN. Proinflammatorycytokines induce endocrine differentiation in pancreatic ductal cells via STAT3-dependent NGN3 activation. Cell Rep. 2016;15(3):460–70.8. Ben-Othman N, Vieira A, Courtney M, Record F, Gjernes E, Avolio F, et al.Long-term GABA administration induces alpha cell-mediated beta-like cellneogenesis. Cell. 2017;168(1–2):85.e11.9. Li J, Casteels T, Frogne T, Ingvorsen C, Honoré C, Courtney M, et al.Artemisinins target GABAA receptor signaling and impair α cell identity. Cell.2017;168(1–2):86–100.e15.10. Cheng CW, Villani V, Buono R, Wei M, Kumar S, Yilmaz OH, et al. Fasting-mimicking diet promotes Ngn3-driven β-cell regeneration to reversediabetes. Cell. 2017;168(5):775–88.e12.Reproduced with permission of copyright owner.Further reproduction prohibited without permission.

Pancreatic β-cell regeneration: advances in understanding the genes and signaling pathways involved.

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Pancreatic β-cell regeneration: advances in understanding the genes and signaling pathways involved.

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