TY - JOUR
T1 - Fibroinflammatory signatures increase with age in the human ovary and follicular fluid
AU - Machlin, Jordan H.
AU - Barishansky, Seth J.
AU - Kelsh, John
AU - Larmore, Megan J.
AU - Johnson, Brian W.
AU - Pritchard, Michele T.
AU - Pavone, Mary Ellen
AU - Duncan, Francesca E.
N1 - Funding Information:
Funding: This work was supported by grants from Friends of Prentice (F.E.D. and M.E.P), the Eunice Kennedy Shriver National Institutes of Child Health and Development (R01 HD093726, F.E.D. and M.T.P), and the Master of Science in Reproductive Science and Medicine program at Northwestern University.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - The female reproductive system ages before any other organ system in the body. This phenomenon can have tangible clinical implications leading to infertility, miscarriages, birth defects and systemic deterioration due to estrogen loss. “Fibroinflammation” is a hallmark of aging tissues; there is an increase in inflammatory cytokines and fibrotic tissue in the aging ovarian stroma. We systematically evaluated immunomodulatory factors in human follicular fluid, which, like the stroma, is a critical ovarian microenvironment directly influencing the oocyte. Using a cytokine an-tibody array, we identified a unique fibroinflammatory cytokine signature in follicular fluid across an aging series of women (27.7–44.8 years). This signature (IL‐3, IL‐7, IL‐15, TGFβ1, TGFβ3 and MIP‐1) increased with chronologic age, was inversely correlated to anti‐Müllerian hormone (AMH) levels, and was independent of body mass index (BMI). We focused on one specific protein, TGFβ3, for further validation. By investigating this cytokine in human cumulus cells and ovarian tissue, we found that the age‐dependent increase in TGFβ3 expression was unique to the ovarian stroma but not other ovarian sub‐compartments. This study broadens our understanding of inflammaging in the female reproductive system and provides a defined fibroinflammatory aging signature in fol-licular fluid and molecular targets in the ovary with potential clinical utility.
AB - The female reproductive system ages before any other organ system in the body. This phenomenon can have tangible clinical implications leading to infertility, miscarriages, birth defects and systemic deterioration due to estrogen loss. “Fibroinflammation” is a hallmark of aging tissues; there is an increase in inflammatory cytokines and fibrotic tissue in the aging ovarian stroma. We systematically evaluated immunomodulatory factors in human follicular fluid, which, like the stroma, is a critical ovarian microenvironment directly influencing the oocyte. Using a cytokine an-tibody array, we identified a unique fibroinflammatory cytokine signature in follicular fluid across an aging series of women (27.7–44.8 years). This signature (IL‐3, IL‐7, IL‐15, TGFβ1, TGFβ3 and MIP‐1) increased with chronologic age, was inversely correlated to anti‐Müllerian hormone (AMH) levels, and was independent of body mass index (BMI). We focused on one specific protein, TGFβ3, for further validation. By investigating this cytokine in human cumulus cells and ovarian tissue, we found that the age‐dependent increase in TGFβ3 expression was unique to the ovarian stroma but not other ovarian sub‐compartments. This study broadens our understanding of inflammaging in the female reproductive system and provides a defined fibroinflammatory aging signature in fol-licular fluid and molecular targets in the ovary with potential clinical utility.
KW - Cytokine
KW - Fibrosis
KW - Human
KW - Inflammation
KW - Ovary
KW - TGFβ3
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U2 - 10.3390/ijms22094902
DO - 10.3390/ijms22094902
M3 - Article
C2 - 34063149
AN - SCOPUS:85105191384
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 9
M1 - 4902
ER -