Ma Yana, Qian Jingjing, Xu Xin, Wei Cheng, Wang Minyuan, Zhang Peipei, Chen Sijia, Zhang Lingyan, Zhang Yanling, Wang Yanpeng, Xu Wenzhi, Liu Mengying, Lin Xiaona
Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China.
Front Bioeng Biotechnol. 2024 Dec 11;12:1449955. doi: 10.3389/fbioe.2024.1449955. eCollection 2024.
Extensive trauma frequently disrupts endometrial regeneration by diminishing endometrial stem cells/progenitor cells, affecting female fertility. While bone marrow mesenchymal stem cell (BMSC) transplantation has been suggested as an approach to address endometrial injury, it comes with certain limitations. Recent advancements in endometrial epithelial organoids (EEOs) have displayed encouraging potential for endometrial regeneration. Therefore, this study aims to explore whether EEOs surpass BMSCs in their ability to repair injured endometrium and to examine whether the restoration process involves the integration of EEOs into the endometrial tissue of the recipient.
We developed rat EEOs (rEEOs) mimicking the features of the rat endometrium. Subsequently, we created a rat model of endometrial injury to compare the effects of rEEOs and rat BMSCs (rBMSCs) on endometrial regeneration and reproductive recovery. Bulk RNA-sequencing analysis was conducted to further investigate the capacity of rEEOs for endometrial regeneration and to identify discrepancies between rEEOs and rBMSCs. Additionally, to track the fate of the transplanted cells , we transplanted green fluorescent protein (GFP) -labelled rEEOs or red fluorescent protein (RFP) -labelled rBMSCs.
In a rat model of endometrial injury, we observed that fertility recovery in rats transplanted with rEEOs was more comparable to that of normal rats than in those treated with rBMSC. rEEOs possess a high concentration of endometrial epithelial stem/progenitor cells and secrete vascular endothelial growth factor (VEGF)-A to promote endometrial neovascularization. Significantly, we observed that cells from GFP-labelled rEEOs could integrate and differentiate into functional glands within the injured endometrium of recipient rats.
EEOs offer a transformative approach to address the challenges of endometrial trauma. Their remarkable regenerative potential holds promise for the restoration of damaged endometrium. As we venture into the future, the concept of utilizing patient-specific EEOs for transplantation emerges as a tantalizing prospect. However, the EEOs in our experiments were mainly cultured in Matrigel, which has barriers to clinical translation as a biomaterial, a new biomaterial to be explored. Secondly, our experiments have been successful only in rat models, and more efforts need to be made before clinical translation.
广泛性创伤常因减少子宫内膜干细胞/祖细胞而破坏子宫内膜再生，影响女性生育能力。虽然骨髓间充质干细胞（BMSC）移植已被提议作为解决子宫内膜损伤的一种方法，但它存在一定局限性。子宫内膜上皮类器官（EEO）的最新进展显示出在子宫内膜再生方面令人鼓舞的潜力。因此，本研究旨在探讨EEO在修复受损子宫内膜的能力上是否优于BMSC，并研究修复过程是否涉及EEO整合到受体的子宫内膜组织中。
我们构建了模拟大鼠子宫内膜特征的大鼠EEO（rEEO）。随后，我们建立了大鼠子宫内膜损伤模型，以比较rEEO和大鼠BMSC（rBMSC）对子宫内膜再生和生殖恢复的影响。进行了批量RNA测序分析，以进一步研究rEEO促进子宫内膜再生的能力，并确定rEEO和rBMSC之间的差异。此外，为了追踪移植细胞的命运，我们移植了绿色荧光蛋白（GFP）标记的rEEO或红色荧光蛋白（RFP）标记的rBMSC。
在大鼠子宫内膜损伤模型中，我们观察到，与接受rBMSC治疗的大鼠相比，接受rEEO移植的大鼠生育能力恢复情况更接近正常大鼠。rEEO含有高浓度的子宫内膜上皮干细胞/祖细胞，并分泌血管内皮生长因子（VEGF）-A以促进子宫内膜新生血管形成。值得注意的是，我们观察到来自GFP标记的rEEO的细胞能够整合并分化为受体大鼠受损子宫内膜内的功能性腺体。
EEO为应对子宫内膜创伤挑战提供了一种变革性方法。它们卓越的再生潜力为受损子宫内膜的修复带来了希望。随着我们迈向未来，利用患者特异性EEO进行移植的概念成为一个诱人的前景。然而，我们实验中的EEO主要在基质胶中培养，作为一种生物材料，基质胶存在临床转化障碍，需要探索新的生物材料。其次，我们的实验仅在大鼠模型中取得成功，在进行临床转化之前还需要做出更多努力。
