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Age\u2010related ovarian fibrosis partially contributes to this phenotype as short\u2010term treatment with anti\u2010fibrotic compounds improves ovulation in reproductively old mice. However, age\u2010dependent changes that are intrinsic to the follicle may also be relevant. In this study, we used a mouse model to demonstrate that reproductive aging is associated with impaired cumulus expansion which is accompanied by altered morphokinetic behavior of cumulus cells as assessed by time\u2010lapse microscopy. The extracellular matrix integrity of expanded cumulus\u2013oocyte complexes is compromised with advanced age as evidenced by increased penetration of fluorescent nanoparticles in a particle exclusion assay and larger open spaces on scanning electron microscopy. Reduced hyaluronan (HA) levels, decreased expression of genes encoding HA\u2010associated proteins (e.g., <jats:italic>Ptx3<\/jats:italic> and <jats:italic>Tnfaip6<\/jats:italic>), and increased expression of inflammatory genes and matrix metalloproteinases underlie this loss of matrix integrity. Importantly, HA levels are decreased with age in follicular fluid of women, indicative of conserved reproductive aging mechanisms. These findings provide novel mechanistic insights into how defects in cumulus expansion contribute to age\u2010related infertility and may serve as a target to extend reproductive longevity.<\/jats:p>","DOI":"10.1111\/acel.14004","type":"journal-article","created":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T08:35:40Z","timestamp":1697618140000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Cumulus expansion is impaired with advanced reproductive age due to loss of matrix integrity and reduced hyaluronan"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-6342","authenticated-orcid":false,"given":"Elnur","family":"Babayev","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Feinberg School of Medicine Northwestern University  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanakarn","family":"Suebthawinkul","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Feinberg School of Medicine Northwestern University  Chicago Illinois USA"},{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine Chulalongkorn University  Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilan","family":"Gokyer","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Feinberg School of Medicine Northwestern University  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendena S.","family":"Parkes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, &amp; Therapeutics, Institute for Reproductive and Developmental Sciences University of Kansas Medical Center  Kansas City Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Rivas","sequence":"additional","affiliation":[{"name":"Virginia Tech\u2010Wake Forest University School of Biomedical Engineering and Sciences Wake Forest School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Ellen","family":"Pavone","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Feinberg School of Medicine Northwestern University  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam R.","family":"Hall","sequence":"additional","affiliation":[{"name":"Virginia Tech\u2010Wake Forest University School of Biomedical Engineering and Sciences Wake Forest School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele T.","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, &amp; Therapeutics, Institute for Reproductive and Developmental Sciences University of Kansas Medical Center  Kansas City Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca E.","family":"Duncan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Feinberg School of Medicine Northwestern University  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10815\u2010010\u20109481\u20109"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.111.097345"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13259"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.9875"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioab241"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrd.23313"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.710033"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP\u201016\u20100129"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009\u20100006"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0012\u20101606(90)90172\u2010f"},{"key":"e_1_2_11_12_1","first-page":"201","volume-title":"Equine diagnostic ultrasound","author":"Carnevale E. 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