title: Restoring Ovarian Endocrine Function with Encapsulated Ovarian Allograft in Immune Competent Mice.
abstract: Premature ovarian insufficiency (POI) is a major complication of cytotoxic treatments due to extreme ovarian sensitivity to chemotherapy and radiation. In pediatric cancer patients modern therapy has improved the long-term survival to over 80% in the United States. However, these cancer survivors face long-term health problems related to treatment toxicity. In female cancer survivors POI leads to sterility, along with the consequences of estrogen deficiency such as premature osteopenia, muscle wasting, accelerated cardiovascular diseases and a vast array of other health and developmental problems. These long-lasting effects are particularly significant for young girls reaching puberty. As such, restoring ovarian endocrine function is paramount in this population. In the present study, we evaluated the feasibility of restoring ovarian endocrine function in ovariectomized mice by transplanting syngeneic and allogeneic ovarian tissue encapsulated in alginate capsules or TheraCyte®. Histological analysis of the implants retrieved after 7 and 30 days' post implantation showed follicular development up to the secondary and antral stages in both syngeneic and allogeneic implants. Implantation of syngeneic and allogeneic ovarian grafts encapsulated in TheraCyte devices restored ovarian endocrine function, which was confirmed by decreased serum FSH levels from 60 to 70 ng/mL in ovariectomized mice to 30-40 ng/mL 30 days after implantation. Absence of allo-MHC-specific IgG and IgM antibodies in the sera of implanted mice with allogeneic ovarian tissue encapsulated in TheraCyte indicate that the implants did not evoke an allo-immune response, while the allogeneic controls were rejected 21 days after implantation. Our results show that TheraCyte effectively isolates the graft from immune recognition but also supports follicular growth.
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: David
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: James Ronald
authors.initials: JR
authors.lastname: Day
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Alexa Leigh
authors.initials: AL
authors.lastname: Cichon
authors.affiliation: Department of Surgery Transplantation Biology, Medical Science Research Building I, 1150 West Medical Center Drive, A520B, Ann Arbor, MI, 48109, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Lefferts
authors.affiliation: Department of Surgery Transplantation Biology, Medical Science Research Building I, 1150 West Medical Center Drive, A520B, Ann Arbor, MI, 48109, USA.|Department of Microbiology and Immunology, Medical Science Research Building I, 1150 West Medical Center Drive, A520B, Ann Arbor, MI, 48109, USA.
authors.forename: Marilia
authors.initials: M
authors.lastname: Cascalho
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA. shikanov@umich.edu.|Department of Macromolecular Sciences and Engineering, University of Michigan, Ann Arbor, MI, 48109, USA. shikanov@umich.edu.
authors.forename: Ariella
authors.initials: A
authors.lastname: Shikanov
mesh_terms: D000464:Alginates / Q000627:therapeutic use*; D064591:Allografts; D000818:Animals; D005260:Female; D020723:Glucuronic Acid / Q000627:therapeutic use; D006603:Hexuronic Acids / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D010053:Ovary / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D016649:Primary Ovarian Insufficiency / Q000276:immunology / Q000378:metabolism / Q000601:surgery; D014185:Transplantation, Isogeneic
chemical_list: D000464:Alginates; D006603:Hexuronic Acids; D020723:Glucuronic Acid
keywords: Alginate; Endocrine function; Follicular growth; Ovariectomy; TheraCyte®