Abstract
Premature ovarian insufficiency (POI) is a significant complication of cytotoxic treatments due to extreme ovarian sensitivity to chemotherapy and radiation. POI is particularly devastating for young girls reaching puberty, because it irreversibly affects their physical and cognitive development. Changes occurring during puberty determine their height, bone health, insulin responsiveness, lipid metabolism, cardiovascular health and cognition. The only available treatment for POI during puberty is hormone replacement therapy (HRT), which delivers non-physiological levels of estrogen, lacks other ovarian hormones and pulsatility, and is not responsive to feedback regulation. Here we report that ovarian allografts encapsulated in a hydrogel-based capsule and implanted in ovariectomized mice restore ovarian endocrine function in immune competent mice. Ovarian tissue from BALB/c mice was encapsulated in poly(ethylene-glycol) (PEG) hydrogels, with a proteolytically degradable core and a non-degradable shell. The dual capsules were implanted subcutaneously in immune competent ovariectomized C57BL/6 mice for a period of 60 days. As expected, non-encapsulated ovarian allografts implanted in a control group sensitized the recipients as confirmed with donor-specific IgG in the serum, which increased 26-fold in the 3 weeks following transplantation (p = 0.02) and infiltration of the graft with CD8 T cells consistent with allo-immunity. In contrast, encapsulation in the Dual PEG capsules prevented sensitization to the allograft in all the recipients with no evidence of lymphocytic infiltration. In summary, the approach of hydrogel-based immunoisolation presents a minimally invasive and robust cell-therapy to restore hormonal balance in ovarian insufficiency. This report is the first to demonstrate the application of a tunable PEG-based hydrogel as an immunoisolator of allogeneic ovarian tissue to restore endocrine function in ovariectomized mice and prevent cell-mediated immune rejection in immune competent mice.
Highlights
Premature ovarian insufficiency (POI) is a significant complication of cytotoxic treatments due to extreme ovarian sensitivity to chemotherapy and radiation
Www.nature.com/scientificreports health, insulin responsiveness, lipid metabolism, cardiovascular health and cognition[9,10,11]. These changes are initiated before puberty and orchestrated by the pulsatile secretion of gonadotropin releasing hormone (GnRH) and growth hormone (GH) from the hypothalamus, which in turn regulate the release of gonadotropins, luteinizing (LH) and follicle-stimulating (FSH) hormones from the pituitary
To mitigate the limitations of hormone replacement therapy (HRT) and to avoid the risk of cancer recurrence associated with autotransplantation of ovarian tissue from subjects with hematologic cancers, we have developed a novel strategy to restore ovarian endocrine function
Summary
Premature ovarian insufficiency (POI) is a significant complication of cytotoxic treatments due to extreme ovarian sensitivity to chemotherapy and radiation. The only available treatment for POI during puberty is hormone replacement therapy (HRT), which delivers non-physiological levels of estrogen, lacks other ovarian hormones and pulsatility, and is not responsive to feedback regulation. Changes occurring during puberty promote the physical and psychologic development into adulthood determining height, bone www.nature.com/scientificreports health, insulin responsiveness, lipid metabolism, cardiovascular health and cognition[9,10,11]. These changes are initiated before puberty and orchestrated by the pulsatile secretion of gonadotropin releasing hormone (GnRH) and growth hormone (GH) from the hypothalamus, which in turn regulate the release of gonadotropins, luteinizing (LH) and follicle-stimulating (FSH) hormones from the pituitary. In patients with hematological malignancies, this procedure cannot be performed because of the risk of introducing malignant cells present in the ovarian tissue, nor would it be helpful for patients who did not cryopreserve their tissue before the anti-cancer treatments, which by far is the most common case[31,32,33,34]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
