Advanced maternal age causes premature placental senescence and malformation via dysregulated alpha-Klotho expression in trophoblasts

作者全名："Chen, Zhi; Xiong, Liling; Jin, Huili; Yu, Jiaxiao; Li, Xin; Fu, Huijia; Wen, Li; Qi, Hongbo; Tong, Chao; Saffery, Richard; Kilby, Mark D.; Baker, Philip N."

作者地址："[Chen, Zhi; Xiong, Liling; Jin, Huili; Yu, Jiaxiao; Li, Xin; Fu, Huijia; Wen, Li; Qi, Hongbo; Tong, Chao] Chongqing Med Univ, Affiliated Hosp 1, Dept Obstet, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Chen, Zhi; Xiong, Liling; Jin, Huili; Yu, Jiaxiao; Li, Xin; Fu, Huijia; Wen, Li; Qi, Hongbo; Tong, Chao] Chongqing Med Univ, State Key Lab Maternal & Fetal Med Chongqing Muni, Chongqing, Peoples R China; [Chen, Zhi; Xiong, Liling; Jin, Huili; Yu, Jiaxiao; Li, Xin; Fu, Huijia; Wen, Li; Qi, Hongbo; Tong, Chao; Saffery, Richard; Baker, Philip N.] Chongqing Med Univ, Chinese Minist Educ, Int Collaborat Lab Reprod & Dev, Chongqing, Peoples R China; [Saffery, Richard] Royal Childrens Hosp, Murdoch Childrens Res Inst, Canc Dis & Dev Epigenet, Melbourne, Vic, Australia; [Kilby, Mark D.] Univ Birmingham, Inst Metab & Syst Res, Ctr Womens & Newborn Hlth, Birmingham, W Midlands, England; [Baker, Philip N.] Univ Leicester, Coll Life Sci, Leicester, Leics, England"

通信作者："Qi, HB; Tong, C (corresponding author), Chongqing Med Univ, Affiliated Hosp 1, Dept Obstet, 1 Youyi Rd, Chongqing 400016, Peoples R China."

来源：AGING CELL

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000659010300001

JCR分区：Q1

影响因子：7.8

年份：2021

卷号：20

期号：7

开始页：　

结束页：　

文献类型：Article

关键词：advanced maternal age; placenta; senescence; trophoblast; alpha-klotho

摘要："Advanced maternal age (AMA) pregnancy is associated with higher risks of adverse perinatal outcomes, which may result from premature senescence of the placenta. alpha-Klotho is a well-known antiaging protein; however, its expression and effect on the placenta in AMA pregnancies have not yet been fully elucidated. The expression patterns of alpha-Klotho in mouse and human placentas from AMA pregnancies were determined by Western blotting and immunohistochemistry (IHC) staining. alpha-Klotho expression in JAR cells was manipulated to investigate its role in trophoblastic senescence, and transwell assays were performed to assess trophoblast invasion. The downstream genes regulated by alpha-Klotho in JAR cells were first screened by mRNA sequencing in alpha-Klotho-knockdown and control JAR cells and then validated. alpha-Klotho-deficient mice were generated by injecting klotho-interfering adenovirus (Ad-Klotho) via the tail vein on GD8.5. Ablation of alpha-Klotho resulted in not only a senescent phenotype and loss of invasiveness in JAR cells but also a reduction in the transcription of cell adhesion molecule (CAM) genes. Overexpression of alpha-Klotho significantly improved invasion but did not alter the expression of senescence biomarkers. alpha-Klotho-deficient mice exhibited placental malformation and, consequently, lower placental and fetal weights. In conclusion, AMA results in reduced alpha-Klotho expression in placental trophoblasts, therefore leading to premature senescence and loss of invasion (possibly through the downregulation of CAMs), both of which ultimately result in placental malformation and adverse perinatal outcomes."

基金机构："National Key R&D Program of China [2018YFC1004103]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81871189, 81520108013, 82071675, 82001580]; Chongqing Science and Technology CommissionNatural Science Foundation Project of CQ CSTC [cstc2017jcyjBX0045]"

基金资助正文："This work was supported by The National Key R&D Program of China (2018YFC1004103), the National Natural Science Foundation of China (81871189, 81520108013, 82071675 and 82001580), and the Chongqing Science and Technology Commission (cstc2017jcyjBX0045)."