Molecular and cellular determinants of healthy receptive and aged endometrium
Kuupäev
2024-11-08
Autorid
Ajakirja pealkiri
Ajakirja ISSN
Köite pealkiri
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Abstrakt
Viljatus puudutab hinnanguliselt 15% kõigist paaridest, avaldades olulist mõju nende elukvaliteedile. Maailmas, kus inimkond vananeb ja lapsesaamise iga on pidevas tõusutrendis, on vanusega seotud viljatus oluline meditsiiniline probleem. Kehavälise viljastamise (IVF) kiire areng koos sugurakkude ja embrüote külmutamise tehnoloogiatega on võimaldanud laste saamist kuni 50-te eluaastateni. Selleks, et hinnata hormoonasendusravi edukust ja valida optimaalne päev embrüo siirdamiseks, kasutatakse endomeetriumi vastuvõtlikkuse ehk retseptiivsuse testimist ultraheli, histoloogiliste ja molekulaarsete markerite abil. Varasemad uuringud on näidanud et molekulaarsete retseptiivsuse testide kliiniline tulemuslikkus kõigub suurtes piirides. Lisaks on üle 40-aastaste naiste seas IVF edukus madalam isegi kasutades nooremate naiste doonormunarakke või siirdamiseelset embrüote geneetilist testimist.
Käesoleva töö eesmärkideks oli: 1) uurida, kuidas endomeetriumi rakuline koostis muutub menstruaaltsükli jooksul ja kuidas see mõjutab endomeetriumi koe geeniekspressiooni profiili; 2) leida endomeetriumi markereid naise verest ja uurida vanuse mõju koe geeniekspressioonile, ning 3) hinnata vanuse mõju endomeetriumi geeniekspressioonile.
Koe geeniekspressiooni profiili uudne bioinformaatiline analüüs (dekonvolutsioon) tuvastas rakulisi muutusi luteaalfaasi endomeetriumis ja võimaldas kohandada endomeetriumi testimiseks kasutatavate RNA markerite profiili. Kuigi vereproovist ei leitud potentsiaalseid miRNA markereid, tuvastasime endomeetriumist retseptiivsuse seisukohast olulised uued endomeetriumi regulatoorsed RNA molekulid. Vanemate naiste endomeetriumi geeniekspressioon näitas rakuvananemise markeri p16 kõrgemat ekspressiooni epiteelis, ning dekonvolutsioon näitas haruldase epiteeli rakupopulatsiooni (ripsrakud) oluliselt kõrgemat proportsiooni, mis võib olla tingitud hormoonitundlikkuse langusest.
Kokkuvõtvalt annavad käesoleva töö tulemused mõista, et endomeetriumi testimiseks kasutatavad transkriptoomitestid peavad võtma arvesse rakulise koosluse muutusi, ning vanemate naiste viljatusravi edukust saab parandada ning muuta ohutumaks kasutades vananeva endomeetriumi molekulaarseid ja rakulisi markereid.
Infertility affects 15% of all couples, having a significant impact on their quality of life. In the modern world of aging mankind, where the maternal age is constantly increasing, age-related infertility is an important medical problem. The development of in vitro fertilisation (IVF) together with rapid development of gamete and embryo freezing technologies has made it possible to have children even in the 50s. To assess the response to hormone therapy and predict the optimal day for embryo transfer, receptivity testing of uterine lining (endometrium) using ultrasonic, histological and molecular markers, is applied. Previous studies have conflicting results on the clinical efficacy of transcriptomic endometrial receptivity tests. In addition, IVF success rate is lower among women over 40, even with the use of donor oocytes from younger women or following pre-implantation genetic testing of embryos. The aims of this work were to 1) test how the cellular composition of endometrium changes during the menstrual cycle and affects the gene expression profile of the whole endometrial tissue sample; 2) identify the endometrial markers from the woman's blood and investigate the effect of advanced age on the endometrial gene expression, and 3) assess the effect of woman’s age on the gene expression profile of endometrial tissue. A novel deconvolution analysis of the tissue unravelled cellular changes in the mid-secretory phase and allowed us to tailor the gene expression profile of transcriptomic endometrial test. While no miRNA markers were found in the blood sample, we identified new endometrial regulating RNA molecules associated with endometrial receptivity. Deconvolution of the gene expression profile of the endometrium of advanced maternal age women revealed a higher proportion of a rare epithelial cell population, the multiciliated cells, and the higher expression of cell senescence marker p16 in the endometrial epithelium in the advanced age group, which may be related to the chronic changes in endometrium concurrent with woman’s age. In conclusion, the results of this work point that transcriptomic tests for endometrial testing must account for the cellular composition in the endometrium during transition to the receptive state, and the success of infertility treatment in older women could be substantially improved and made safer using the molecular and cellular markers of the aging endometrium.
Infertility affects 15% of all couples, having a significant impact on their quality of life. In the modern world of aging mankind, where the maternal age is constantly increasing, age-related infertility is an important medical problem. The development of in vitro fertilisation (IVF) together with rapid development of gamete and embryo freezing technologies has made it possible to have children even in the 50s. To assess the response to hormone therapy and predict the optimal day for embryo transfer, receptivity testing of uterine lining (endometrium) using ultrasonic, histological and molecular markers, is applied. Previous studies have conflicting results on the clinical efficacy of transcriptomic endometrial receptivity tests. In addition, IVF success rate is lower among women over 40, even with the use of donor oocytes from younger women or following pre-implantation genetic testing of embryos. The aims of this work were to 1) test how the cellular composition of endometrium changes during the menstrual cycle and affects the gene expression profile of the whole endometrial tissue sample; 2) identify the endometrial markers from the woman's blood and investigate the effect of advanced age on the endometrial gene expression, and 3) assess the effect of woman’s age on the gene expression profile of endometrial tissue. A novel deconvolution analysis of the tissue unravelled cellular changes in the mid-secretory phase and allowed us to tailor the gene expression profile of transcriptomic endometrial test. While no miRNA markers were found in the blood sample, we identified new endometrial regulating RNA molecules associated with endometrial receptivity. Deconvolution of the gene expression profile of the endometrium of advanced maternal age women revealed a higher proportion of a rare epithelial cell population, the multiciliated cells, and the higher expression of cell senescence marker p16 in the endometrial epithelium in the advanced age group, which may be related to the chronic changes in endometrium concurrent with woman’s age. In conclusion, the results of this work point that transcriptomic tests for endometrial testing must account for the cellular composition in the endometrium during transition to the receptive state, and the success of infertility treatment in older women could be substantially improved and made safer using the molecular and cellular markers of the aging endometrium.
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