Encapsulation of Mesenchymal Stem Cells in 3D Ovarian Cell Constructs Promotes Stable and Long-Term Hormone Secretion with Improved Physiological Outcomes in a Syngeneic Rat Model

Loss of ovarian function (e.g., due to menopause) leads to profound physiological effects in women including changes in sexual function and osteoporosis. Hormone therapies are a known solution, but their use has significantly decreased due to concerns over cardiovascular disease and certain cancers. We recently reported a tissue-engineering strategy for cell hormone therapy (cHT) in which granulosa cells and theca cells are encapsulated to mimic native ovarian follicles. cHT improved physiological outcomes and safety compared to pharmacological hormone therapies in a rat ovariectomy model. However, cHT did not achieve estrogen levels as high as ovary-intact animals. In this report, we examined if hormone secretion from cHT constructs is impacted by incorporation of bone marrow-derived mesenchymal stem cells (BMSC) since these cells contain regulatory factors such as aromatase necessary for estrogen production. Incorporation of BMSCs led to enhanced estrogen secretion in vitro. Moreover, cHT constructs with BMSCs achieved estrogen secretion levels significantly greater than constructs without BMSCs in ovariectomized rats from 70 to 90 days after implantation, while also regulating pituitary hormones. cHT constructs with BMSC ameliorated estrogen deficiency-induced uterine atrophy without hyperplasia. The results indicate that inclusion of BMSC in cHT strategies can improve performance.