{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T02:02:31Z","timestamp":1793325751424,"version":"4.5.0"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T00:00:00Z","timestamp":1671667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01 DK126662"],"award-info":[{"award-number":["R01 DK126662"]}]},{"name":"National Institutes of Health","award":["R01 DK129241"],"award-info":[{"award-number":["R01 DK129241"]}]},{"name":"National Institutes of Health","award":["NIH P30 DK106912"],"award-info":[{"award-number":["NIH P30 DK106912"]}]},{"name":"National Institutes of Health","award":["P30 DK106912"],"award-info":[{"award-number":["P30 DK106912"]}]},{"name":"PKD Foundation","award":["R01 DK126662"],"award-info":[{"award-number":["R01 DK126662"]}]},{"name":"PKD Foundation","award":["R01 DK129241"],"award-info":[{"award-number":["R01 DK129241"]}]},{"name":"PKD Foundation","award":["NIH P30 DK106912"],"award-info":[{"award-number":["NIH P30 DK106912"]}]},{"name":"PKD Foundation","award":["P30 DK106912"],"award-info":[{"award-number":["P30 DK106912"]}]},{"name":"Kansas Research and Translation Core Center","award":["R01 DK126662"],"award-info":[{"award-number":["R01 DK126662"]}]},{"name":"Kansas Research and Translation Core Center","award":["R01 DK129241"],"award-info":[{"award-number":["R01 DK129241"]}]},{"name":"Kansas Research and Translation Core Center","award":["NIH P30 DK106912"],"award-info":[{"award-number":["NIH P30 DK106912"]}]},{"name":"Kansas Research and Translation Core Center","award":["P30 DK106912"],"award-info":[{"award-number":["P30 DK106912"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>ADPKD is a genetic disorder with a molecular complexity that remains poorly understood. In this study, we sampled renal cells to construct a comprehensive and spatiotemporally resolved gene expression atlas in whole Pkd1 mutant polycystic mouse kidneys at single-cell resolution. We characterized cell diversity and identified novel collecting duct (CD) cell subtypes in cystic kidneys. We further found that CD cells appear to take different cell fate trajectories, and the first and the most important step might take place around day 14 in Pkd1 homozygous kidneys. After that day, increased numbers of CD cells showed highly proliferative and fibrotic characteristics, as detected in later-stage Pkd1 homozygous kidneys, both of which should contribute to cyst growth and renal fibrosis. With a newly developed modeling algorithm, called CellChat Explorer, we identify cell-to-cell communication networks mediated by the ligand receptor, such as MIF-CD44\/CD74, in cystic kidneys, and confirm them via the expression patterns of ligands and receptors in four major cell types, which addresses the key question as to whether and how Pkd1 mutant renal epithelial cells affect their neighboring cells. The allele-specific gene expression profiles show that the secretion of cytokines by Pkd1 mutant epithelial cells may affect the gene expression profiles in recipient cells via epigenetic mechanisms, and vice versa. This study can be used to drive precision therapeutic targeting of ADPKD.<\/jats:p>","DOI":"10.3390\/cells12010045","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T03:02:15Z","timestamp":1671764535000},"page":"45","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Single-Cell and CellChat Resolution Identifies Collecting Duct Cell Subsets and Their Communications with Adjacent Cells in PKD Kidneys"],"prefix":"10.3390","volume":"12","author":[{"given":"Linda Xiaoyan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9784-0481","authenticated-orcid":false,"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Physical Medicine & Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewud","family":"Agborbesong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie Xia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5928-9820","authenticated-orcid":false,"given":"James P.","family":"Calvet","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaogang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1056\/NEJM199307293290508","article-title":"Autosomal dominant polycystic kidney disease","volume":"329","author":"Gabow","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1046\/j.1523-1755.2000.00250.x","article-title":"Estimating prevalence in single-gene kidney diseases progressing to renal failure","volume":"58","author":"Levy","year":"2000","journal-title":"Kidney Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.molmed.2014.01.004","article-title":"Polycystin-1: A master regulator of intersecting cystic pathways","volume":"20","author":"Fedeles","year":"2014","journal-title":"Trends Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1172\/JCI76972","article-title":"Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner","volume":"125","author":"Gainullin","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0272-6386(12)80768-2","article-title":"Clinical manifestations of autosomal dominant polycystic kidney disease in patients older than 50 years","volume":"15","author":"Milutinovic","year":"1990","journal-title":"Am. J. Kidney Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14283","DOI":"10.1073\/pnas.1412323111","article-title":"Cyst formation following disruption of intracellular calcium signaling","volume":"111","author":"Kuo","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Li, X. (2015). The Role of Calcium and Cyclic AMP in PKD. Polycystic Kidney Disease, Exon Publications.","DOI":"10.15586\/codon.pkd.2015"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nrneph.2015.39","article-title":"Vasopressin and disruption of calcium signalling in polycystic kidney disease","volume":"11","author":"Chebib","year":"2015","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/ki.1991.80","article-title":"C-myc as an inducer of polycystic kidney disease in transgenic mice","volume":"39","author":"Trudel","year":"1991","journal-title":"Kidney Int."},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/ki.2011.87","article-title":"WNT\/beta-catenin signaling in polycystic kidney disease","volume":"80","author":"Wuebken","year":"2011","journal-title":"Kidney Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1038\/ncb1326","article-title":"Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2","volume":"7","author":"Li","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.molmed.2011.06.003","article-title":"mTOR signaling in polycystic kidney disease","volume":"17","author":"Natoli","year":"2011","journal-title":"Trends Mol. Med."},{"key":"ref_14","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_15","first-page":"e23650","article-title":"Regulation of STATs by polycystin-1 and their role in polycystic kidney disease","volume":"2","author":"Weimbs","year":"2013","journal-title":"JAKSTAT"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Liu, W., Fan, L.X., Zhou, X., Sweeney, W.E., Avner, E.D., and Li, X. (2012). HDAC6 regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation in renal epithelial cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049418"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8281","DOI":"10.7150\/thno.47315","article-title":"RNA helicase p68 inhibits the transcription and post-transcription of Pkd1 in ADPKD","volume":"10","author":"Zhang","year":"2020","journal-title":"Theranostics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1681\/ASN.2013020176","article-title":"Smac-mimetic-induced epithelial cell death reduces the growth of renal cysts","volume":"24","author":"Fan","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1172\/JCI80467","article-title":"Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease","volume":"125","author":"Chen","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.kint.2018.06.025","article-title":"CD8(+) T cells modulate autosomal dominant polycystic kidney disease progression","volume":"94","author":"Kleczko","year":"2018","journal-title":"Kidney Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1172\/JCI64401","article-title":"Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease","volume":"123","author":"Zhou","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eabb3154","DOI":"10.1126\/sciadv.abb3154","article-title":"Cross-talk between CDK4\/6 and SMYD2 regulates gene transcription, tubulin methylation, and ciliogenesis","volume":"6","author":"Li","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1097\/01.ASN.0000028643.17901.42","article-title":"Genetics and pathogenesis of polycystic kidney disease","volume":"13","author":"Igarashi","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"F356","DOI":"10.1152\/ajprenal.00422.2013","article-title":"Tissue-specific regulation of the mouse Pkhd1 (ARPKD) gene promoter","volume":"307","author":"Williams","year":"2014","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1126\/science.aar2131","article-title":"Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease","volume":"360","author":"Park","year":"2018","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"giaa151","DOI":"10.1093\/gigascience\/giaa151","article-title":"SoupX removes ambient RNA contamination from droplet-based single-cell RNA sequencing data","volume":"9","author":"Young","year":"2020","journal-title":"Gigascience"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.cels.2019.03.003","article-title":"DoubletFinder: Doublet Detection in Single-Cell RNA Sequencing Data Using Artificial Nearest Neighbors","volume":"8","author":"McGinnis","year":"2019","journal-title":"Cell Syst."},{"key":"ref_30","first-page":"2579","article-title":"Visualizing Data using t-SNE","volume":"86","year":"2008","journal-title":"J. Mach. Learn. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/nbt.4314","article-title":"Dimensionality reduction for visualizing single-cell data using UMAP","volume":"37","author":"Becht","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_32","first-page":"226","article-title":"A Density-Based Algorithm for Discovering Clusters in Large Spatial Databases with Noise","volume":"96","author":"Ester","year":"1996","journal-title":"KDD-96 Proc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nbt.2859","article-title":"The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells","volume":"32","author":"Trapnell","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1126\/science.aax0249","article-title":"Single-cell transcriptional diversity is a hallmark of developmental potential","volume":"367","author":"Gulati","year":"2020","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/j.kint.2017.03.031","article-title":"Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease","volume":"92","author":"Hwang","year":"2017","journal-title":"Kidney Int."},{"key":"ref_37","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_38","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1681\/ASN.2011010084","article-title":"Macrophages promote cyst growth in polycystic kidney disease","volume":"22","author":"Karihaloo","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"baz046","DOI":"10.1093\/database\/baz046","article-title":"PanglaoDB: A web server for exploration of mouse and human single-cell RNA sequencing data","volume":"2019","author":"Franzen","year":"2019","journal-title":"Database"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"E9989","DOI":"10.1073\/pnas.1710964114","article-title":"Transcriptomes of major renal collecting duct cell types in mouse identified by single-cell RNA-seq","volume":"114","author":"Chen","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3936","DOI":"10.4049\/jimmunol.1302366","article-title":"Critical Roles for PU.1, GATA1, and GATA2 in the expression of human FcepsilonRI on mast cells: PU.1 and GATA1 transactivate FCER1A, and GATA2 transactivates FCER1A and MS4A2","volume":"192","author":"Inage","year":"2014","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e13722","DOI":"10.7554\/eLife.13722","article-title":"The cell proliferation antigen Ki-67 organises heterochromatin","volume":"5","author":"Sobecki","year":"2016","journal-title":"Elife"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1101\/gr.211615.116","article-title":"Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci","volume":"27","author":"Yu","year":"2017","journal-title":"Genome Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1186\/s12935-019-0986-8","article-title":"Overexpression of CENPF correlates with poor prognosis and tumor bone metastasis in breast cancer","volume":"19","author":"Sun","year":"2019","journal-title":"Cancer Cell Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1136\/jmedgenet-2014-102691","article-title":"The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes","volume":"52","author":"Waters","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1681\/ASN.2013040398","article-title":"Strategies targeting cAMP signaling in the treatment of polycystic kidney disease","volume":"25","author":"Torres","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Li, X. (2015). Role of Inflammation in Polycystic Kidney Disease. Polycystic Kidney Disease, Exon Publications.","DOI":"10.15586\/codon.pkd.2015"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"109648","DOI":"10.1016\/j.cellsig.2020.109648","article-title":"Molecular pathways involved in injury-repair and ADPKD progression","volume":"72","author":"Formica","year":"2020","journal-title":"Cell. Signal."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"135","DOI":"10.2215\/CJN.05760513","article-title":"Collecting duct principal cell transport processes and their regulation","volume":"10","author":"Pearce","year":"2015","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1161\/HYPERTENSIONAHA.115.06987","article-title":"Impact of Angiotensin Type 1A Receptors in Principal Cells of the Collecting Duct on Blood Pressure and Hypertension","volume":"67","author":"Chen","year":"2016","journal-title":"Hypertension"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s11906-016-0638-5","article-title":"Role of the Collecting Duct Renin Angiotensin System in Regulation of Blood Pressure and Renal Function","volume":"18","author":"Ramkumar","year":"2016","journal-title":"Curr. Hypertens. Rep."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/45\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:48:07Z","timestamp":1760147287000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/45"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,22]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cells12010045"],"URL":"https:\/\/doi.org\/10.3390\/cells12010045","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,22]]}}}