Synthetic hydrogel supports the function and regeneration of artificial ovarian tissue in mice.

Amanda S Perez,Hong Zhou,Ariella Shikanov,Jiwon Kim,Jake Claflin,Anu David

doi:10.1038/npjregenmed.2016.10

Abstract

Many prepubertal girls and young women suffer from premature ovarian insufficiency induced by chemotherapy given for treatment of cancer and autoimmune diseases. Autotransplantation of cryopreserved ovarian tissue could restore the lost ovarian endocrine function and fertility. Unfortunately, tissue ischemia, inconsistent graft quality and the risk of reintroducing malignant cells may stand in the way of the clinical translation of this approach. To address these risks and limitations, we engineered an artificial ovarian tissue from immature follicles using a synthetic hydrogel, poly(ethylene glycol) vinyl sulfone (PEG-VS), as a supportive matrix. Enzymatically isolated follicles from 6–7-day-old mice ovaries were encapsulated in 7% PEG-VS hydrogels modified with 0.5 mmol/l RGD and crosslinked with a trifunctional matrix metalloproteinase-sensitive peptide. PEG hydrogels with the encapsulated follicles were orthotopically implanted into ovariectomised mice to investigate whether PEG hydrogel supports folliculogenesis and steroidogenesis in vivo. After 30 days, grafts revealed multiple fully developed antral follicles and corpora lutea, which corresponded with regular ovulation cycles and follicle-stimulating hormone (FSH) levels. The elevated levels of FSH, caused by bilateral ovariectomy, were reversed by the implanted follicles and maintained at physiological levels for 60 days. Importantly, primordial and primary follicles still represented 60% of the follicular pool, demonstrating selective recruitment of primordial follicles into the growing pool. Functioning blood vessels in the grafts 30 and 60 days after implantation proved the capability of PEG hydrogels to undergo graft remodelling and revascularisation. Our results demonstrate that PEG hydrogels with encapsulated immature ovarian follicles successfully functioned as an artificial ovarian tissue for 60 days in vivo.

Highlights

The number of cancer survivors has been growing owing to advancements in anticancer treatments, and the long-term survival rates improved 480% in most childhood malignancies.[1,2] Yet, cytotoxic chemotherapy, radiotherapy and bone marrow transplantation treatments often cause infertility and premature ovarian failure.[3,4] Clinically approved fertility preservation options exist only for adult patients who can produce a fully mature egg.[5]If the anticancer treatment can be delayed, these patients can undergo hormonal stimulation to stimulate follicle development and recover mature oocytes.[6]
Histological analysis of PEG hydrogels explanted 14, 30 and 60 days after transplantation was performed to evaluate the development of the implanted follicles
As primordial follicles were recruited into the growing pool, a 51.4% decrease of primordial follicles occurred over 60 days in vivo

Summary

Introduction

The number of cancer survivors has been growing owing to advancements in anticancer treatments, and the long-term survival rates improved 480% in most childhood malignancies.[1,2] Yet, cytotoxic chemotherapy, radiotherapy and bone marrow transplantation treatments often cause infertility and premature ovarian failure.[3,4] Clinically approved fertility preservation options exist only for adult patients who can produce a fully mature egg.[5]If the anticancer treatment can be delayed, these patients can undergo hormonal stimulation to stimulate follicle development and recover mature oocytes.[6]. The number of cancer survivors has been growing owing to advancements in anticancer treatments, and the long-term survival rates improved 480% in most childhood malignancies.[1,2] Yet, cytotoxic chemotherapy, radiotherapy and bone marrow transplantation treatments often cause infertility and premature ovarian failure.[3,4] Clinically approved fertility preservation options exist only for adult patients who can produce a fully mature egg.[5]. The option of egg preservation is not applicable to patients who require immediate treatment or prepubescent girls, whose dormant ovaries cannot produce mature eggs.[6] the cytotoxic chemotherapy affects the ability of the prepubescent girls to undergo complete and physiological puberty.[7] This eventually leads to a variety of long-term clinical complications, such as delayed growth of bones, impaired cognitive development, cardiovascular and metabolic complications.[8]

Methods

Results

Conclusion