Cumulus expansion is impaired with advanced reproductive age due to loss of matrix integrity and reduced hyaluronan

Elnur Babayev; Chanakarn Suebthawinkul; Dilan Gokyer; Wendena S. Parkes; Felipe Rivas; Mary Ellen Pavone; Adam R. Hall; Michele T. Pritchard; Francesca E. Duncan

doi:10.1111/acel.14004

Cumulus expansion is impaired with advanced reproductive age due to loss of matrix integrity and reduced hyaluronan

Elnur Babayev, Chanakarn Suebthawinkul, Dilan Gokyer, Wendena S. Parkes, Felipe Rivas, Mary Ellen Pavone, Adam R. Hall, Michele T. Pritchard^*, Francesca E. Duncan^*

^*Corresponding author for this work

Obstetrics and Gynecology

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Reproductive aging is associated with ovulatory defects. Age-related ovarian fibrosis partially contributes to this phenotype as short-term treatment with anti-fibrotic compounds improves ovulation in reproductively old mice. However, age-dependent 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-lapse microscopy. The extracellular matrix integrity of expanded cumulus–oocyte 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-associated proteins (e.g., Ptx3 and Tnfaip6), 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-related infertility and may serve as a target to extend reproductive longevity.

Original language	English (US)
Article number	e14004
Journal	Aging Cell
Volume	22
Issue number	11
DOIs	https://doi.org/10.1111/acel.14004
State	Published - Nov 2023

Funding

This work made use of the BioCryo facility of Northwestern University's NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-2025633), the IIN, and Northwestern's MRSEC program (NSF DMR-1720139). The authors thank core scientist Eric W. Roth for his help with electron microscopy experiments. The authors also thank Dr. Jacob M. Schauer from Northwestern University Feinberg School of Medicine Biostatistics Collaboration Center for his help with the statistical analysis. The graphical abstract was created with BioRender.com. This study was supported by the Eunice Kennedy Shriver National Institutes of Child Health and Development (R01 HD093726, M.T.P. and F.E.D.; and K12 HD050121, E.B.). A.R.H. received funding from R01GM134226 and P41EB020594. This work was also supported, in part, by the Bill & Melinda Gates Foundation (INV‐003385, F.E.D.). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. This work made use of the BioCryo facility of Northwestern University's NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS‐2025633), the IIN, and Northwestern's MRSEC program (NSF DMR‐1720139). The authors thank core scientist Eric W. Roth for his help with electron microscopy experiments. The authors also thank Dr. Jacob M. Schauer from Northwestern University Feinberg School of Medicine Biostatistics Collaboration Center for his help with the statistical analysis. The graphical abstract was created with BioRender.com .

Keywords

ART
IVF
aging
cumulus expansion
hyaluronic acid
ovary

ASJC Scopus subject areas

Aging
Cell Biology

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10.1111/acel.14004

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@article{cdea9bbdeeb04d68a8da85acf1a18f81,

title = "Cumulus expansion is impaired with advanced reproductive age due to loss of matrix integrity and reduced hyaluronan",

abstract = "Reproductive aging is associated with ovulatory defects. Age-related ovarian fibrosis partially contributes to this phenotype as short-term treatment with anti-fibrotic compounds improves ovulation in reproductively old mice. However, age-dependent 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-lapse microscopy. The extracellular matrix integrity of expanded cumulus–oocyte 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-associated proteins (e.g., Ptx3 and Tnfaip6), 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-related infertility and may serve as a target to extend reproductive longevity.",

keywords = "ART, IVF, aging, cumulus expansion, hyaluronic acid, ovary",

author = "Elnur Babayev and Chanakarn Suebthawinkul and Dilan Gokyer and Parkes, {Wendena S.} and Felipe Rivas and Pavone, {Mary Ellen} and Hall, {Adam R.} and Pritchard, {Michele T.} and Duncan, {Francesca E.}",

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year = "2023",

month = nov,

doi = "10.1111/acel.14004",

language = "English (US)",

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journal = "Aging Cell",

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AU - Babayev, Elnur

AU - Suebthawinkul, Chanakarn

AU - Gokyer, Dilan

AU - Parkes, Wendena S.

AU - Rivas, Felipe

AU - Pavone, Mary Ellen

AU - Hall, Adam R.

AU - Pritchard, Michele T.

AU - Duncan, Francesca E.

PY - 2023/11

Y1 - 2023/11

N2 - Reproductive aging is associated with ovulatory defects. Age-related ovarian fibrosis partially contributes to this phenotype as short-term treatment with anti-fibrotic compounds improves ovulation in reproductively old mice. However, age-dependent 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-lapse microscopy. The extracellular matrix integrity of expanded cumulus–oocyte 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-associated proteins (e.g., Ptx3 and Tnfaip6), 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-related infertility and may serve as a target to extend reproductive longevity.

AB - Reproductive aging is associated with ovulatory defects. Age-related ovarian fibrosis partially contributes to this phenotype as short-term treatment with anti-fibrotic compounds improves ovulation in reproductively old mice. However, age-dependent 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-lapse microscopy. The extracellular matrix integrity of expanded cumulus–oocyte 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-associated proteins (e.g., Ptx3 and Tnfaip6), 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-related infertility and may serve as a target to extend reproductive longevity.

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Cumulus expansion is impaired with advanced reproductive age due to loss of matrix integrity and reduced hyaluronan

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