{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:51Z","timestamp":1787027871313,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2019YFA0802704"],"award-info":[{"award-number":["2019YFA0802704"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31771620"],"award-info":[{"award-number":["31771620"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006250","name":"Research Startup Fund of Southwest University","doi-asserted-by":"publisher","award":["SWU117064"],"award-info":[{"award-number":["SWU117064"]}],"id":[{"id":"10.13039\/501100006250","id-type":"DOI","asserted-by":"publisher"}]},{"name":"APC"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2, is characterized by progressive and exponential enlargement of renal and hepatic cysts. However, the epithelial dynamics that generate this growth pattern remain incompletely understood. Using Brainbow\/Confetti multicolor clonal lineage tracing in developmental and adult-onset ADPKD mouse models, we show that polycystin-deficient epithelial cells initiate clonal expansion at early stages of tubule dilation and continue to expand throughout cyst progression. Concurrently, cyst-lining cells undergo a progressive transition from columnar to flattened morphology, which amplifies luminal enlargement independent of cell number. Integrating these measures, we developed a mathematical model demonstrating that the combination of this clonal expansion and epithelial cell shape remodeling is sufficient to produce the exponential growth trajectory observed in ADPKD. Together, these findings define the core epithelial mechanisms that drive cyst initiation and expansion, and may provide a mathematical framework for the emergent exponential growth of cysts.<\/jats:p>","DOI":"10.3390\/cells15030297","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T17:20:14Z","timestamp":1770225614000},"page":"297","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Epithelial Dynamics of Cystogenesis in Genetic Models of Autosomal Dominant Polycystic Kidney Disease"],"prefix":"10.3390","volume":"15","author":[{"given":"Mengyan","family":"Sun","sequence":"first","affiliation":[{"name":"Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohui","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingqiang","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Luo","sequence":"additional","affiliation":[{"name":"Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaole","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8403-9603","authenticated-orcid":false,"given":"Ming","family":"Ma","sequence":"additional","affiliation":[{"name":"Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"The European Polycystic Kidney Disease Consortium (1994). The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell, 77, 881\u2013894.","DOI":"10.1016\/0092-8674(94)90137-6"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1126\/science.272.5266.1339","article-title":"PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein","volume":"272","author":"Mochizuki","year":"1996","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/S0092-8674(00)81793-6","article-title":"The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I","volume":"87","author":"Qian","year":"1996","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0092-8674(00)81570-6","article-title":"Somatic inactivation of Pkd2 results in polycystic kidney disease","volume":"93","author":"Wu","year":"1998","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1681\/ASN.V1071524","article-title":"Somatic PKD2 mutations in individual kidney and liver cysts support a \u201ctwo-hit\u201d model of cystogenesis in type 2 autosomal dominant polycystic kidney disease","volume":"10","author":"Pei","year":"1999","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S1097-2765(00)80135-5","article-title":"Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease","volume":"2","author":"Watnick","year":"1998","journal-title":"Mol. Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1038\/nm1675","article-title":"A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1","volume":"13","author":"Piontek","year":"2007","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/j.cub.2007.08.034","article-title":"Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease","volume":"17","author":"Davenport","year":"2007","journal-title":"Curr. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/ng0697-179","article-title":"PKD1 interacts with PKD2 through a probable coiled-coil domain","volume":"16","author":"Qian","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R378","DOI":"10.1016\/S0960-9822(02)00877-1","article-title":"Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease","volume":"12","author":"Pazour","year":"2002","journal-title":"Curr. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1097\/01.ASN.0000029587.47950.25","article-title":"The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia","volume":"13","author":"Yoder","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1038\/ng.2715","article-title":"Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease","volume":"45","author":"Ma","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3698","DOI":"10.1038\/s41467-024-48025-6","article-title":"Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease","volume":"15","author":"Zhang","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Li, X. (2015). The Role of Calcium and Cyclic AMP in PKD. Polycystic Kidney Disease, Codon Publications.","DOI":"10.15586\/codon.pkd.2015"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nrneph.2016.108","article-title":"Roles of mTOR complexes in the kidney: Implications for renal disease and transplantation","volume":"12","author":"Fantus","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/nm.3092","article-title":"Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy","volume":"19","author":"Rowe","year":"2013","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1681\/ASN.2015030231","article-title":"2-Deoxy-d-Glucose Ameliorates PKD Progression","volume":"27","author":"Chiaravalli","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1681\/ASN.2013111179","article-title":"Inactivation of integrin-\u03b21 prevents the development of polycystic kidney disease after the loss of polycystin-1","volume":"26","author":"Lee","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1681\/ASN.2020071094","article-title":"TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease","volume":"32","author":"Cordido","year":"2021","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Li, X. (2015). Epigenetics in ADPKD: Understanding Mechanisms and Discovering Treatment. Polycystic Kidney Disease, Codon Publications.","DOI":"10.15586\/codon.pkd.2015.ch12"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2751","DOI":"10.1172\/JCI90921","article-title":"Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease","volume":"127","author":"Li","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1046\/j.1523-1755.2003.00185.x","article-title":"Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort","volume":"64","author":"Chapman","year":"2003","journal-title":"Kidney Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1056\/NEJMoa054341","article-title":"Volume progression in polycystic kidney disease","volume":"354","author":"Grantham","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1681\/ASN.2013080864","article-title":"Scattered Deletion of PKD1 in Kidneys Causes a Cystic Snowball Effect and Recapitulates Polycystic Kidney Disease","volume":"26","author":"Leonhard","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.kint.2018.12.023","article-title":"Long-term trajectory of kidney function in autosomal-dominant polycystic kidney disease","volume":"95","author":"Yu","year":"2019","journal-title":"Kidney Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1093\/hmg\/ddn039","article-title":"Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1","volume":"17","author":"Shibazaki","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1038\/s41588-021-00946-4","article-title":"Renal plasticity revealed through reversal of polycystic kidney disease in mice","volume":"53","author":"Dong","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.gde.2020.01.003","article-title":"Control of cell shape during epithelial morphogenesis: Recent advances","volume":"63","author":"Gillard","year":"2020","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1681\/ASN.2018050518","article-title":"Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease","volume":"29","author":"Cassini","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4040","DOI":"10.4161\/cc.22375","article-title":"CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD","volume":"11","author":"Bukanov","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/S0140-6736(07)60601-1","article-title":"Autosomal dominant polycystic kidney disease","volume":"369","author":"Torres","year":"2007","journal-title":"Lancet"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.cell.2010.09.016","article-title":"Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells","volume":"143","author":"Snippert","year":"2010","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/dvg.20397","article-title":"A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs","volume":"46","author":"Means","year":"2008","journal-title":"Genesis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1242\/dev.02732","article-title":"Intraflagellar transport is essential for endochondral bone formation","volume":"134","author":"Haycraft","year":"2007","journal-title":"Development"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1006\/dbio.2002.0597","article-title":"Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: A tool for temporally regulated gene activation\/inactivation in the mouse","volume":"244","author":"Hayashi","year":"2002","journal-title":"Dev. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1172\/JCI22850","article-title":"Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation","volume":"115","author":"Nishio","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13794","DOI":"10.1038\/s41598-024-62776-8","article-title":"Improved predictions of total kidney volume growth rate in ADPKD using two-parameter least squares fitting","volume":"14","author":"Hu","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1038\/s42003-024-06868-1","article-title":"Multiscale and multimodal evaluation of autosomal dominant polycystic kidney disease development","volume":"7","author":"Saande","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1016\/j.ekir.2024.04.002","article-title":"Deep Learning-Based Automated Imaging Classification of ADPKD","volume":"9","author":"Kim","year":"2024","journal-title":"Kidney Int. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/ng.860","article-title":"A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation","volume":"43","author":"Fedeles","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/dvg.20207","article-title":"Transgenic mice expressing tamoxifen-inducible Cre for somatic gene modification in renal epithelial cells","volume":"44","author":"Leonhard","year":"2006","journal-title":"Genesis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.stem.2007.03.002","article-title":"Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss","volume":"1","author":"Ruzankina","year":"2007","journal-title":"Cell Stem Cell"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/297\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T05:12:47Z","timestamp":1770354767000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/297"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,4]]},"references-count":42,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cells15030297"],"URL":"https:\/\/doi.org\/10.3390\/cells15030297","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,4]]}}}