David Anu, Day James Ronald, Cichon Alexa Leigh, Lefferts Adam, Cascalho Marilia, Shikanov Ariella
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
Ann Biomed Eng. 2017 Jul;45(7):1685-1696. doi: 10.1007/s10439-016-1780-6. Epub 2016 Dec 27.
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.
卵巢早衰（POI）是细胞毒性治疗的主要并发症，因为卵巢对化疗和放疗极为敏感。在美国，现代疗法已将儿科癌症患者的长期生存率提高到80%以上。然而，这些癌症幸存者面临与治疗毒性相关的长期健康问题。在女性癌症幸存者中，POI会导致不育，以及雌激素缺乏的后果，如过早出现骨质减少、肌肉萎缩、心血管疾病加速以及一系列其他健康和发育问题。这些长期影响对进入青春期的年轻女孩尤为显著。因此，恢复该人群的卵巢内分泌功能至关重要。在本研究中，我们评估了通过移植包裹在藻酸盐胶囊或TheraCyte中的同基因和异基因卵巢组织来恢复去卵巢小鼠卵巢内分泌功能的可行性。植入后7天和30天取出的植入物的组织学分析显示，同基因和异基因植入物中的卵泡均发育至次级卵泡和窦状卵泡阶段。植入包裹在TheraCyte装置中的同基因和异基因卵巢移植物可恢复卵巢内分泌功能，这通过去卵巢小鼠血清促卵泡生成素（FSH）水平从60至70 ng/mL降至植入后30天的30 - 40 ng/mL得到证实。植入包裹在TheraCyte中的异基因卵巢组织的小鼠血清中不存在同种异体主要组织相容性复合体（allo - MHC）特异性IgG和IgM抗体，这表明植入物未引发同种异体免疫反应，而异基因对照组在植入后21天被排斥。我们的结果表明，TheraCyte能有效将移植物与免疫识别隔离开来，同时也支持卵泡生长。
