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Unravelling the developmental origins of cystic fibrosis-related diabetes.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Unravelling the developmental origins of cystic fibrosis-related diabetes.
Συγγραφείς: Cho A; McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada.; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada., Nostro MC; McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada. Cristina.Nostro@uhn.ca.; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Cristina.Nostro@uhn.ca.
Πηγή: Diabetologia [Diabetologia] 2026 Aug; Vol. 69 (8), pp. 2131-2142. Date of Electronic Publication: 2026 Jun 09.
Τύπος έκδοσης: Journal Article; Review
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0006777 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0428 (Electronic) Linking ISSN: 0012186X NLM ISO Abbreviation: Diabetologia Subsets: MEDLINE
Imprint Name(s): Original Publication: Berlin Springer Verlag
Ιατρικοί όροι (MeSH): Cystic Fibrosis*/complications , Cystic Fibrosis*/genetics , Cystic Fibrosis*/metabolism , Diabetes Mellitus*/etiology , Diabetes Mellitus*/metabolism , Diabetes Mellitus*/genetics, Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Pancreas/metabolism ; Pancreas/embryology ; Mutation/genetics ; Humans ; Animals
Περίληψη: Cystic fibrosis (CF)-related diabetes (CFRD) is a growing and evolving concern for people living with cystic fibrosis. As its own unique clinical entity, there is an urgent need to better understand this complex health challenge to improve the quality of life for people with CF. Unfortunately, many aspects of CFRD pathophysiology and pathogenesis remain unclear, resulting in a disparity in the standard of care provided. An emerging body of evidence supports that CFRD may have developmental origins, as people with CF present with pancreatic pathology and glucose abnormalities as early as in utero. This therefore suggests that the CF transmembrane conductance regulator (CFTR) gene mutations that cause CF may impair pancreatic organogenesis, thus leading to CFRD. This review consequently aims to summarise the existing evidence that may support a fundamentally vital role of CFTR in the development of the pancreas. From aspects of the endocrine and exocrine pancreas to scrutinising the broader islet microenvironment, the many constituents at play in pancreatic organogenesis are highlighted. Unravelling the deeper complexities of CFRD pathogenesis will not only clarify existing knowledge gaps but may transform the way future care is provided.
(© 2026. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Competing Interests: Acknowledgements: We thank J. F. Engelhardt (University of Alabama at Birmingham) for his thoughtful input on the manuscript. Funding: This work was supported by a Cystic Fibrosis Foundation award to MCN (NOSTRO23I0) and scholarships from Banting and Best Diabetes Centre and Ontario Graduate Scholarship to AC. Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: AC and MCN were responsible for the conceptualisation, writing, editing and final approval of this manuscript.
References: Lee J-A, Cho A, Huang EN et al (2021) Gene therapy for cystic fibrosis: new tools for precision medicine. J Transl Med 19(1):452. https://doi.org/10.1186/s12967-021-03099-4. (PMID: 10.1186/s12967-021-03099-4347176718556969)
Sankari A, Sharma S (2025) Cystic fibrosis. StatPearls Publishing, Treasure Island, FL, USA.
Guo J, Garratt A, Hill A (2022) Worldwide rates of diagnosis and effective treatment for cystic fibrosis. J Cyst Fibros 21(3):456–462. https://doi.org/10.1016/j.jcf.2022.01.009. (PMID: 10.1016/j.jcf.2022.01.00935125294)
US CF Foundation (2011) The Clinical and Functional TRanslation of CFTR (CFTR2). Available from: https://cftr2.org/ . Accessed 18 Jan 2026.
Andersen DH (1938) Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathologic study. Am J Dis Child 56(2):344–399. https://doi.org/10.1001/archpedi.1938.01980140114013. (PMID: 10.1001/archpedi.1938.01980140114013)
Cystic Fibrosis Canada (2023) 2023 Annual data report. Available from: https://cystic-fibrosis.cdn.prismic.io/cystic-fibrosis/Z9sI9jiBA97GirFZ_2023-Annual-Data-ReportWEB-2-.pdf . Accessed 5 Oct 2025.
Cystic Fibrosis Canada (2025) Cystic fibrosis impact report 2024-25. Available from: https://impact.cysticfibrosis.ca/?utm_source=LinkedIn&utm_medium=LaunchPost&utm_campaign=IR-24-25-EN#message . Accessed 5 Oct 2025.
Bell SC, Mall MA, Gutierrez H et al (2020) The future of cystic fibrosis care: a global perspective. Lancet Respir Med 8(1):65–124. https://doi.org/10.1016/S2213-2600(19)30337-6. (PMID: 10.1016/S2213-2600(19)30337-631570318)
Granados A, Chan CL, Ode KL, Moheet A, Moran A, Holl R (2019) Cystic fibrosis related diabetes: pathophysiology, screening and diagnosis. J Cyst Fibros 18(Suppl 2):S3–S9. https://doi.org/10.1016/j.jcf.2019.08.016. (PMID: 10.1016/j.jcf.2019.08.01631679726)
Al-Selwi Y, Shaw JA, Kattner N (2021) Understanding the pancreatic islet microenvironment in cystic fibrosis and the extrinsic pathways leading to cystic fibrosis related diabetes. Clin Med Insights Endocrinol Diabetes 14:11795514211048812. https://doi.org/10.1177/11795514211048813. (PMID: 10.1177/11795514211048813346757378524685)
Potter KJ, Coriati A, Hicks P et al (2023) Canadian cystic fibrosis-related diabetes clinical practice survey: analysis of current practices and gaps in clinical care. Can J Diabetes 47(3):263-271.e1. https://doi.org/10.1016/j.jcjd.2023.02.002. (PMID: 10.1016/j.jcjd.2023.02.00236872137)
Moran A, Brunzell C, Cohen RC et al (2010) Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care 33(12):2697–2708. https://doi.org/10.2337/dc10-1768. (PMID: 10.2337/dc10-1768211157722992215)
Putman MS, Norris AW, Hull RL et al (2023) Cystic fibrosis-related diabetes workshop: research priorities spanning disease pathophysiology, diagnosis, and outcomes. Diabetes Care 46(6):1112–1123. https://doi.org/10.2337/dc23-0380. (PMID: 10.2337/dc23-03803712594810234745)
Scully KJ, Marks BE, Putman MS (2024) Advances in diabetes technology to improve the lives of people with cystic fibrosis. Diabetologia 67(10):2143–2153. https://doi.org/10.1007/s00125-024-06223-3. (PMID: 10.1007/s00125-024-06223-33899539912012899)
Cohen A, Mass A, Reiter J, Zangen DH, Cohen-Cymberknoh M (2024) Long-term therapy with CFTR modulators consistently improves glucose metabolism in adolescents and adults with cystic fibrosis. Respir Med 228:107664. https://doi.org/10.1016/j.rmed.2024.107664. (PMID: 10.1016/j.rmed.2024.10766438759874)
Prentice B, Nicholson M, Lam GY (2023) Cystic fibrosis related diabetes (CFRD) in the era of modulators: a scoping review. Paediatr Respir Rev 46:23–29. https://doi.org/10.1016/j.prrv.2022.11.005. (PMID: 10.1016/j.prrv.2022.11.00536581478)
Sharpe H, Lam GY (2026) The evolving understanding of cystic fibrosis-related diabetes in the highly effective modulator therapy era: a scoping review. Diabetologia 69(4):855–871. https://doi.org/10.1007/s00125-025-06653-7. (PMID: 10.1007/s00125-025-06653-74158809612957650)
Vuralli D (2026) From pathophysiology to treatment: contemporary approaches to CFRD in the pediatric and adolescent population. Pediatr Diabetes 2026:5539725. https://doi.org/10.1155/pedi/5539725. (PMID: 10.1155/pedi/55397254155283512811412)
Norris AW, Ode KL, Merjaneh L et al (2019) Survival in a bad neighborhood: pancreatic islets in cystic fibrosis. J Endocrinol 241(1):R35–R50. https://doi.org/10.1530/JOE-18-0468. (PMID: 10.1530/JOE-18-0468307590726675675)
Malik SS, Padmanabhan D, Hull-Meichle RL (2023) Pancreas and islet morphology in cystic fibrosis: clues to the etiology of cystic fibrosis-related diabetes. Front Endocrinol 14:1269139. https://doi.org/10.3389/fendo.2023.1269139. (PMID: 10.3389/fendo.2023.1269139)
Bogdani M, Blackman SM, Ridaura C, Bellocq J-P, Powers AC, Aguilar-Bryan L (2017) Structural abnormalities in islets from very young children with cystic fibrosis may contribute to cystic fibrosis-related diabetes. Sci Rep 7(1):17231. https://doi.org/10.1038/s41598-017-17404-z. (PMID: 10.1038/s41598-017-17404-z292224475722914)
Hart NJ, Aramandla R, Poffenberger G et al (2018) Cystic fibrosis-related diabetes is caused by islet loss and inflammation. JCI Insight 3(8):e98240. https://doi.org/10.1172/jci.insight.98240.
Arrigo T, Cucinotta D, Nibali SC et al (1993) Longitudinal evaluation of glucose tolerance and insulin secretion in non-diabetic children and adolescents with cystic fibrosis: results of a two-year follow-up. Acta Paediatr 82(3):249–253. https://doi.org/10.1111/j.1651-2227.1993.tb12653.x. (PMID: 10.1111/j.1651-2227.1993.tb12653.x8495078)
Moran A, Diem P, Klein DJ, Levitt MD, Robertson RP (1991) Pancreatic endocrine function in cystic fibrosis. J Pediatr 118(5):715–723. https://doi.org/10.1016/s0022-3476(05)80032-0. (PMID: 10.1016/s0022-3476(05)80032-02019925)
Olivier AK, Yi Y, Sun X et al (2012) Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets. J Clin Invest 122(10):3755–3768. https://doi.org/10.1172/JCI60610. (PMID: 10.1172/JCI60610229966903534166)
Uc A, Olivier AK, Griffin MA et al (2015) Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass. Clin Sci Lond Engl 128(2):131–142. https://doi.org/10.1042/CS20140059. (PMID: 10.1042/CS20140059)
Yi Y, Norris AW, Wang K et al (2016) Abnormal glucose tolerance in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 194(8):974–980. https://doi.org/10.1164/rccm.201512-2518OC. (PMID: 10.1164/rccm.201512-2518OC274478405067820)
Kéri AF, Bajzát D, Andrásdi Z et al (2024) Early onset of abnormal glucose tolerance in patients with cystic fibrosis: a systematic review and meta-analysis. J Cyst Fibros 23(4):616–624. https://doi.org/10.1016/j.jcf.2024.02.010. (PMID: 10.1016/j.jcf.2024.02.01038458829)
Andersen DH (1958) Cystic fibrosis of the pancreas. J Chronic Dis 7(1):58–90. https://doi.org/10.1016/0021-9681(58)90185-1. (PMID: 10.1016/0021-9681(58)90185-113491678)
Imrie JR, Fagan DG, Sturgess JM (1979) Quantitative evaluation of the development of the exocrine pancreas in cystic fibrosis and control infants. Am J Pathol 95(3):697–708. (PMID: 4533302042306)
Gibson-Corley KN, Meyerholz DK, Engelhardt JF (2016) Pancreatic pathophysiology in cystic fibrosis. J Pathol 238(2):311–320. https://doi.org/10.1002/path.4634. (PMID: 10.1002/path.463426365583)
Shih HP, Wang A, Sander M (2013) Pancreas organogenesis: from lineage determination to morphogenesis. Annu Rev Cell Dev Biol 29:81–105. https://doi.org/10.1146/annurev-cellbio-101512-122405. (PMID: 10.1146/annurev-cellbio-101512-12240523909279)
Sambathkumar R, Migliorini A, Nostro MC (2018) Pluripotent stem cell-derived pancreatic progenitors and β-like cells for type 1 diabetes treatment. Physiol Bethesda Md 33(6):394–402. https://doi.org/10.1152/physiol.00026.2018. (PMID: 10.1152/physiol.00026.2018)
Prasadan K, Daume E, Preuett B et al (2002) Glucagon is required for early insulin-positive differentiation in the developing mouse pancreas. Diabetes 51(11):3229–3236. https://doi.org/10.2337/diabetes.51.11.3229. (PMID: 10.2337/diabetes.51.11.322912401714)
Ballian N, Brunicardi FC, Wang X-P (2006) Somatostatin and its receptors in the development of the endocrine pancreas. Pancreas 33(1):1–12. https://doi.org/10.1097/01.mpa.0000226894.16817.e8. (PMID: 10.1097/01.mpa.0000226894.16817.e816804406)
Dale DJ, Rutan CD, Mastracci TL (2024) Development of the pancreatic ducts and their contribution to organogenesis. Adv Anat Embryol Cell Biol 239:31–55. https://doi.org/10.1007/978-3-031-62232-8_2. (PMID: 10.1007/978-3-031-62232-8_23928348111934529)
Villasenor A, Cleaver O (2012) Crosstalk between the developing pancreas and its blood vessels: an evolving dialog. Semin Cell Dev Biol 23(6):685–692. https://doi.org/10.1016/j.semcdb.2012.06.003. (PMID: 10.1016/j.semcdb.2012.06.003227286684372237)
Migliorini A, Ge S, Atkins MH et al (2024) Embryonic macrophages support endocrine commitment during human pancreatic differentiation. Cell Stem Cell 31(11):1591-1611.e8. https://doi.org/10.1016/j.stem.2024.09.011. (PMID: 10.1016/j.stem.2024.09.01139406230)
Cozzitorto C, Mueller L, Ruzittu S et al (2020) A specialized niche in the pancreatic microenvironment promotes endocrine differentiation. Dev Cell 55(2):150-162.e6. https://doi.org/10.1016/j.devcel.2020.08.003. (PMID: 10.1016/j.devcel.2020.08.003328579517720791)
Marino CR, Matovcik LM, Gorelick FS, Cohn JA (1991) Localization of the cystic fibrosis transmembrane conductance regulator in pancreas. J Clin Invest 88(2):712–716. https://doi.org/10.1172/JCI115358. (PMID: 10.1172/JCI1153581713921295422)
Trezise AE, Chambers JA, Wardle CJ, Gould S, Harris A (1993) Expression of the cystic fibrosis gene in human foetal tissues. Hum Mol Genet 2(3):213–218. https://doi.org/10.1093/hmg/2.3.213. (PMID: 10.1093/hmg/2.3.2137684639)
Hyde K, Reid CJ, Tebbutt SJ, Weide L, Hollingsworth MA, Harris A (1997) The cystic fibrosis transmembrane conductance regulator as a marker of human pancreatic duct development. Gastroenterology 113(3):914–919. https://doi.org/10.1016/s0016-5085(97)70187-2. (PMID: 10.1016/s0016-5085(97)70187-29287984)
Engström M, Westholm E, Wendt A, Eliasson L (2025) The role of islet CFTR in the development of cystic fibrosis-related diabetes: a semi-systematic review. J Cyst Fibros 24(4):724–732. https://doi.org/10.1016/j.jcf.2025.04.006. (PMID: 10.1016/j.jcf.2025.04.00640254519)
Sun X, Yi Y, Yan Z et al (2019) In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis. Sci Transl Med 11(485):eaau7531. https://doi.org/10.1126/scitranslmed.aau7531. (PMID: 10.1126/scitranslmed.aau7531309181146489481)
Evans IA, Sun X, Liang B et al (2024) In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets. JCI Insight 9(8):e157229. https://doi.org/10.1172/jci.insight.157229. (PMID: 10.1172/jci.insight.1572293864693511141870)
Johansson KA, Dursun U, Jordan N et al (2007) Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Dev Cell 12(3):457–465. https://doi.org/10.1016/j.devcel.2007.02.010. (PMID: 10.1016/j.devcel.2007.02.01017336910)
Meier JJ, Köhler CU, Alkhatib B et al (2010) Beta-cell development and turnover during prenatal life in humans. Eur J Endocrinol 162(3):559–568. https://doi.org/10.1530/EJE-09-1053. (PMID: 10.1530/EJE-09-105320022941)
Piper K, Brickwood S, Turnpenny LW et al (2004) Beta cell differentiation during early human pancreas development. J Endocrinol 181(1):11–23. https://doi.org/10.1677/joe.0.1810011. (PMID: 10.1677/joe.0.181001115072563)
Rall LB, Pictet RL, Williams RH, Rutter WJ (1973) Early differentiation of glucagon-producing cells in embryonic pancreas: a possible developmental role for glucagon. Proc Natl Acad Sci U S A 70(12):3478–3482. https://doi.org/10.1073/pnas.70.12.3478. (PMID: 10.1073/pnas.70.12.34784519640427263)
Vuguin PM, Kedees MH, Cui L et al (2006) Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation. Endocrinology 147(9):3995–4006. https://doi.org/10.1210/en.2005-1410. (PMID: 10.1210/en.2005-1410166275794287247)
Lee YC, Damholt AB, Billestrup N et al (1999) Developmental expression of proprotein convertase 1/3 in the rat. Mol Cell Endocrinol 155(1–2):27–35. https://doi.org/10.1016/s0303-7207(99)00119-7. (PMID: 10.1016/s0303-7207(99)00119-710580836)
Wilson ME, Kalamaras JA, German MS (2002) Expression pattern of IAPP and prohormone convertase 1/3 reveals a distinctive set of endocrine cells in the embryonic pancreas. Mech Dev 115(1–2):171–176. https://doi.org/10.1016/s0925-4773(02)00118-1. (PMID: 10.1016/s0925-4773(02)00118-112049785)
Lee Y-S, Lee C, Choung J-S, Jung H-S, Jun H-S (2018) Glucagon-like peptide 1 increases β-cell regeneration by promoting α- to β-cell transdifferentiation. Diabetes 67(12):2601–2614. https://doi.org/10.2337/db18-0155. (PMID: 10.2337/db18-015530257975)
Prasadan K, Shiota C, Xiangwei X, Ricks D, Fusco J, Gittes G (2016) A synopsis of factors regulating beta cell development and beta cell mass. Cell Mol Life Sci CMLS 73(19):3623–3637. https://doi.org/10.1007/s00018-016-2231-0. (PMID: 10.1007/s00018-016-2231-027105622)
Hull RL, Gibson RL, McNamara S et al (2018) Islet interleukin-1β immunoreactivity is an early feature of cystic fibrosis that may contribute to β-cell failure. Diabetes Care 41(4):823–830. https://doi.org/10.2337/dc17-1387. (PMID: 10.2337/dc17-1387294376985860832)
Brooks EP, Sussel L (2023) Not the second fiddle: α cell development, identity, and function in health and diabetes. J Endocrinol 258(2):e220297. https://doi.org/10.1530/JOE-22-0297. (PMID: 10.1530/JOE-22-02973717182810524258)
Huang WQ, Guo JH, Yuan C et al (2017) Abnormal CFTR affects glucagon production by islet α cells in cystic fibrosis and polycystic ovarian syndrome. Front Physiol 8:835. https://doi.org/10.3389/fphys.2017.00835. (PMID: 10.3389/fphys.2017.00835292041215698272)
Edlund A, Pedersen MG, Lindqvist A, Wierup N, Flodström-Tullberg M, Eliasson L (2017) CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells. Sci Rep 7(1):90. https://doi.org/10.1038/s41598-017-00098-8. (PMID: 10.1038/s41598-017-00098-8282738905428348)
Hillman M, Eriksson L, Mared L, Helgesson K, Landin-Olsson M (2012) Reduced levels of active GLP-1 in patients with cystic fibrosis with and without diabetes mellitus. J Cyst Fibros Off J Eur Cyst Fibros Soc 11(2):144–149. https://doi.org/10.1016/j.jcf.2011.11.001. (PMID: 10.1016/j.jcf.2011.11.001)
Gharib SA, Vemireddy R, Castillo JJ et al (2024) Cystic fibrosis-related diabetes is associated with reduced islet protein expression of GLP-1 receptor and perturbation of cell-specific transcriptional programs. Sci Rep 14(1):25689. https://doi.org/10.1038/s41598-024-76722-1. (PMID: 10.1038/s41598-024-76722-13946343411514218)
Rotti PG, Xie W, Poudel A et al (2018) Pancreatic and islet remodeling in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) knockout ferrets. Am J Pathol 188(4):876–890. https://doi.org/10.1016/j.ajpath.2017.12.015. (PMID: 10.1016/j.ajpath.2017.12.015293666805963477)
Mohammed SM, Bone RN, Aquino JDC, Mirmira RG, Evans-Molina C, Ismail HM (2024) Changes in immunofluorescence staining during islet regeneration in a cystic fibrosis-related diabetes (CFRD) ferret model. Islets 16(1):2436696. https://doi.org/10.1080/19382014.2024.2436696. (PMID: 10.1080/19382014.2024.24366963964136511633224)
Edlund A, Esguerra JLS, Wendt A, Flodström-Tullberg M, Eliasson L (2014) CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic beta-cells. BMC Med 12:87. https://doi.org/10.1186/1741-7015-12-87. (PMID: 10.1186/1741-7015-12-87248856044035698)
Di Fulvio M, Bogdani M, Velasco M et al (2020) Heterogeneous expression of CFTR in insulin-secreting β-cells of the normal human islet. PloS One 15(12):e0242749. https://doi.org/10.1371/journal.pone.0242749. (PMID: 10.1371/journal.pone.0242749332643327710116)
White MG, Maheshwari RR, Anderson SJ et al (2020) In situ analysis reveals that CFTR is expressed in only a small minority of β-cells in normal adult human pancreas. J Clin Endocrinol Metab 105(5):1366–1374. https://doi.org/10.1210/clinem/dgz209. (PMID: 10.1210/clinem/dgz209317488117341165)
Pandol SJ (2010) The exocrine pancreas. Morgan & Claypool Life Sciences, San Rafael, CA, USA.
Wilschanski M, Novak I (2013) The cystic fibrosis of exocrine pancreas. Cold Spring Harb Perspect Med 3(5):a009746. https://doi.org/10.1101/cshperspect.a009746. (PMID: 10.1101/cshperspect.a009746236373073633181)
Tyler SR, Rotti PG, Sun X et al (2019) PyMINEr finds gene and autocrine-paracrine networks from human islet scRNA-Seq. Cell Rep 26(7):1951-1964.e8. https://doi.org/10.1016/j.celrep.2019.01.063. (PMID: 10.1016/j.celrep.2019.01.063307594026394844)
Mastracci TL, Apte M, Amundadottir LT et al (2023) Integrated physiology of the exocrine and endocrine compartments in pancreatic diseases: workshop proceedings. Diabetes 72(4):433–448. https://doi.org/10.2337/db22-0942. (PMID: 10.2337/db22-09423694031710033248)
Ma Z, Zhang X, Zhong W et al (2023) Deciphering early human pancreas development at the single-cell level. Nat Commun 14(1):5354. https://doi.org/10.1038/s41467-023-40893-8. (PMID: 10.1038/s41467-023-40893-83766017510475098)
De Vas MG, Kopp JL, Heliot C, Sander M, Cereghini S, Haumaitre C (2015) Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors. Dev Camb Engl 142(5):871–882. https://doi.org/10.1242/dev.110759. (PMID: 10.1242/dev.110759)
Sharon N, Chawla R, Mueller J et al (2019) A peninsular structure coordinates asynchronous differentiation with morphogenesis to generate pancreatic islets. Cell 176(4):790-804.e13. https://doi.org/10.1016/j.cell.2018.12.003. (PMID: 10.1016/j.cell.2018.12.003306617596705176)
Merkwitz C, Blaschuk OW, Schulz A et al (2013) The ductal origin of structural and functional heterogeneity between pancreatic islets. Prog Histochem Cytochem 48(3):103–140. https://doi.org/10.1016/j.proghi.2013.09.001. (PMID: 10.1016/j.proghi.2013.09.00124100070)
Rotti PG, Evans IA, Zhang Y et al (2022) Lack of CFTR alters the ferret pancreatic ductal epithelial secretome and cellular proteome: implications for exocrine/endocrine signaling. J Cyst Fibros Off J Eur Cyst Fibros Soc 21(1):172–180. https://doi.org/10.1016/j.jcf.2021.04.010. (PMID: 10.1016/j.jcf.2021.04.010)
Sun X, Yi Y, Xie W et al (2017) CFTR influences beta cell function and insulin secretion through non-cell autonomous exocrine-derived factors. Endocrinology 158(10):3325–3338. https://doi.org/10.1210/en.2017-00187. (PMID: 10.1210/en.2017-00187289775925659686)
Rotti PG, Yi Y, Gasser G et al (2024) CFTR represses a PDX1 axis to govern pancreatic ductal cell fate. iScience 27(12):111393. https://doi.org/10.1016/j.isci.2024.111393. (PMID: 10.1016/j.isci.2024.1113933968702211647141)
Aplin AC, Aghazadeh Y, Mohn OG, Hull-Meichle RL (2024) Role of the pancreatic islet microvasculature in health and disease. J Histochem Cytochem Off J Histochem Soc 72(11–12):711–728. https://doi.org/10.1369/00221554241299862. (PMID: 10.1369/00221554241299862)
Brissova M, Shostak A, Fligner CL et al (2015) Human islets have fewer blood vessels than mouse islets and the density of islet vascular structures is increased in type 2 diabetes. J Histochem Cytochem 63(8):637–645. https://doi.org/10.1369/0022155415573324. (PMID: 10.1369/0022155415573324262161394530394)
Kao D-I, Lacko LA, Ding B-S et al (2015) Endothelial cells control pancreatic cell fate at defined stages through EGFL7 signaling. Stem Cell Rep 4(2):181–189. https://doi.org/10.1016/j.stemcr.2014.12.008. (PMID: 10.1016/j.stemcr.2014.12.008)
Magenheim J, Ilovich O, Lazarus A et al (2011) Blood vessels restrain pancreas branching, differentiation and growth. Dev Camb Engl 138(21):4743–4752. https://doi.org/10.1242/dev.066548. (PMID: 10.1242/dev.066548)
Aghazadeh Y, Poon F, Sarangi F et al (2021) Microvessels support engraftment and functionality of human islets and hESC-derived pancreatic progenitors in diabetes models. Cell Stem Cell 28(11):1936–1949.e8. https://doi.org/10.1016/j.stem.2021.08.001. (PMID: 10.1016/j.stem.2021.08.00134480863)
Agerskov RH, Nyeng P (2024) Innervation of the pancreas in development and disease. Dev Camb Engl 151(2):dev202254. https://doi.org/10.1242/dev.202254. (PMID: 10.1242/dev.202254)
Borden P, Houtz J, Leach SD, Kuruvilla R (2013) Sympathetic innervation during development is necessary for pancreatic islet architecture and functional maturation. Cell Rep 4(2):287–301. https://doi.org/10.1016/j.celrep.2013.06.019. (PMID: 10.1016/j.celrep.2013.06.019238502893740126)
Croizier S, Prevot V, Bouret SG (2016) Leptin controls parasympathetic wiring of the pancreas during embryonic life. Cell Rep 15(1):36–44. https://doi.org/10.1016/j.celrep.2016.02.088. (PMID: 10.1016/j.celrep.2016.02.088270521644982372)
Yang YHC, Kawakami K, Stainier DY (2018) A new mode of pancreatic islet innervation revealed by live imaging in zebrafish. eLife 7:e34519. https://doi.org/10.7554/eLife.34519. (PMID: 10.7554/eLife.34519299163646039180)
Cosentino C, Regazzi R (2021) Crosstalk between macrophages and pancreatic β-cells in islet development, homeostasis and disease. Int J Mol Sci 22(4):1765. https://doi.org/10.3390/ijms22041765. (PMID: 10.3390/ijms22041765335789527916718)
Banaei-Bouchareb L, Gouon-Evans V, Samara-Boustani D et al (2004) Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice. J Leukoc Biol 76(2):359–367. https://doi.org/10.1189/jlb.1103591. (PMID: 10.1189/jlb.110359115178709)
Coderre L, Debieche L, Plourde J, Rabasa-Lhoret R, Lesage S (2021) The potential causes of cystic fibrosis-related diabetes. Front Endocrinol 12:702823. https://doi.org/10.3389/fendo.2021.702823. (PMID: 10.3389/fendo.2021.702823)
Wang Z, Dong S, Zhou W (2024) Pancreatic stellate cells: key players in pancreatic health and diseases (Review). Mol Med Rep 30(1):109. https://doi.org/10.3892/mmr.2024.13233. (PMID: 10.3892/mmr.2024.132333869525411082724)
Li J, Chen B, Fellows GF, Goodyer CG, Wang R (2021) Activation of pancreatic stellate cells is beneficial for exocrine but not endocrine cell differentiation in the developing human pancreas. Front Cell Dev Biol 9:694276. https://doi.org/10.3389/fcell.2021.694276. (PMID: 10.3389/fcell.2021.694276344902478418189)
Yan Z, Stewart ZA, Sinn PL et al (2015) Ferret and pig models of cystic fibrosis: prospects and promise for gene therapy. Hum Gene Ther Clin Dev 26(1):38–49. https://doi.org/10.1089/humc.2014.154. (PMID: 10.1089/humc.2014.154256751434367511)
Veres A, Faust AL, Bushnell HL et al (2019) Charting cellular identity during human in vitro β-cell differentiation. Nature 569(7756):368–373. https://doi.org/10.1038/s41586-019-1168-5. (PMID: 10.1038/s41586-019-1168-5310686966903417)
Breunig M, Merkle J, Melzer MK et al (2021) Differentiation of human pluripotent stem cells into pancreatic duct-like organoids. STAR Protoc 2(4):100913. https://doi.org/10.1016/j.xpro.2021.100913. (PMID: 10.1016/j.xpro.2021.100913349179728669107)
Darrigrand J-F, Isaacson A, Spagnoli FM (2025) Generation of human iPSC-derived pancreatic organoids to study pancreas development and disease. F1000Research 14:575. https://doi.org/10.12688/f1000research.162496.1. (PMID: 10.12688/f1000research.162496.14075632312314479)
Simsek S, Zhou T, Robinson CL et al (2016) Modeling cystic fibrosis using pluripotent stem cell-derived human pancreatic ductal epithelial cells. Stem Cells Transl Med 5(5):572–579. https://doi.org/10.5966/sctm.2015-0276. (PMID: 10.5966/sctm.2015-0276270344114835252)
Atkins MH, Scarfò R, McGrath KE et al (2022) Modeling human yolk sac hematopoiesis with pluripotent stem cells. J Exp Med 219(3):e20211924. https://doi.org/10.1084/jem.20211924. (PMID: 10.1084/jem.2021192434928315)
Menendez L, Yatskievych TA, Antin PB, Dalton S (2011) Wnt signaling and a Smad pathway blockade direct the differentiation of human pluripotent stem cells to multipotent neural crest cells. Proc Natl Acad Sci U S A 108(48):19240–19245. https://doi.org/10.1073/pnas.1113746108. (PMID: 10.1073/pnas.1113746108220841203228464)
Park TS, Hirday R, Ali A et al (2023) Protocol to generate endothelial cells, pericytes, and fibroblasts in one differentiation round from human-induced pluripotent stem cells. STAR Protoc 4(2):102292. https://doi.org/10.1016/j.xpro.2023.102292. (PMID: 10.1016/j.xpro.2023.1022923714986010189549)
Kristidis P, Bozon D, Corey M et al (1992) Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet 50(6):1178–1184. (PMID: 13760161682557)
Jia S, Taylor-Cousar JL (2023) Cystic fibrosis modulator therapies. Annu Rev Med 74:413–426. https://doi.org/10.1146/annurev-med-042921-021447. (PMID: 10.1146/annurev-med-042921-02144735973718)
Grant Information: NOSTRO23I0 Cystic Fibrosis Foundation
Contributed Indexing: Keywords: Cystic fibrosis; Cystic fibrosis transmembrane conductance regulator; Cystic fibrosis-related diabetes; Development; Microenvironment; Organogenesis; Pancreas; Review
Substance Nomenclature: 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
Entry Date(s): Date Created: 20260609 Date Completed: 20260628 Latest Revision: 20260628
Update Code: 20260628
DOI: 10.1007/s00125-026-06768-5
PMID: 42262528
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1432-0428
DOI:10.1007/s00125-026-06768-5