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Human ovarian tissue in-vitro culture: primordial follicle activation as a new strategy for female fertility preservation

Abstract

Cryopreservation and transplantation of ovarian tissue is the only fertility preservation option used for prepubertal girls and women who don’t have a chance for embryo or oocyte vitrification. For women with aggressive cancer, hormone-responsive malignancies, autoimmune diseases, etc. ovary transplantation cannot be performed so an alternative technology called in-vitro follicle activation is thinkable. In this method, dormant primordial follicles are activated from the resting primordial pool by in-vitro culture and enter their growth phase. Different in-vitro culture media and supplements in addition to various culturing methods have been conducted for activating these dormant follicles. Furthermore, several signaling pathways such as Hippo, phosphatidylinositol-3-kinase, and mTOR influence follicle activation. Therefore, the addition of different activators of these signaling pathways can beneficially regulate this culture system. This review summarizes the findings on different aspects of human ovarian tissue culture strategies for in-vitro follicular activation, their medium, and different factors involved in this activation. Afterward, signaling pathways important for follicle activation and their clinical applications towards improving activation in culture are also reviewed.

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Abbreviations

α-MEM:

Alpha minimal essential medium

Akt1:

Protein kinase B

AMH:

Anti-Müllerian hormone

bFGF:

Basic fibroblast growth factor

BMP:

Bone morphogenetic protein

CCN:

Connective tissue growth factor (CTGF), Cystein rich protein (Cyr61), and Nephroblastoma overexpressed genes

DOR:

Diminished ovarian reserve

E2:

Estradiol

EBSS:

Earle’s balanced salt solution

ECM:

Extracellular matrix

FGF:

Fibroblast growth factor

FSH:

Follicle stimulating hormone

GDF9:

Growth differentiation factor 9

HSA:

Human serum albumin

hUC-MSC:

Human umbilical cord mesenchymal stem cells

ITS:

Insulin-transferin-selenium

IVA:

In-vitro activation

IVF:

In-vitro fertilization

LATSI1/2:

Large tumor suppressor kinases 1 and 2

mTOR:

Mammalian target of rapamycin

MST1/2:

Mammalian Ste-20 like kinases 1 and 2

PDK1:

3-Phosphoinositide dependent kinase-1

PEG:

Polyethylene glycol

PI3K:

Phosphatidylinositol 3 kinase

POI:

Premature ovarian insufficiency

PTEN:

Protein phosphatase with TENsin homolog

rpS6:

Ribosomal protein S6

S1p:

Sphingosine-1-phosphate

Smad:

Caenorhabditis elegans SMA (“small” worm phenotype) and Drosophila MAD (“Mothers Against Decapentaplegic”)

TAZ:

Transcriptional coactivator PDZ-binding motif

Tsc:

Tumor suppressor tuberous sclerosis complex

YAP:

Yes associated protein

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ZG: Performed the literature search and manuscript writing; NK-R: Manuscript writing and image illustration; BE: Idea for the article and manuscript revision.

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Correspondence to Bita Ebrahimi.

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This is a review study and Ethics Committee of Royan Institute confirmed that no ethical approval is required.

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Ghezelayagh, Z., Khoshdel-Rad, N. & Ebrahimi, B. Human ovarian tissue in-vitro culture: primordial follicle activation as a new strategy for female fertility preservation. Cytotechnology 74, 1–15 (2022). https://doi.org/10.1007/s10616-021-00510-2

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  • DOI: https://doi.org/10.1007/s10616-021-00510-2

Keywords

  • Fertility preservation
  • Hippo signaling
  • Human ovary
  • mTOR signaling
  • PI3K pathway
  • Primordial follicle activation