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Offspring production of ovarian organoids derived from spermatogonial stem cells by defined factors with chromatin reorganization
Journal of Advanced Research ( IF 10.7 ) Pub Date : 2021-03-17 , DOI: 10.1016/j.jare.2021.03.006
Huacheng Luo 1 , Xiaoyong Li 1 , Geng G Tian 1 , Dali Li 2 , Changliang Hou 1 , Xinbao Ding 1 , Lin Hou 1 , Qifeng Lyu 3 , Yunze Yang 1 , Austin J Cooney 4 , Wenhai Xie 1 , Ji Xiong 1 , Hu Wang 1 , Xiaodong Zhao 5 , Ji Wu 1, 6
Affiliation  

Introduction

Fate determination of germline stem cells remains poorly understood at the chromatin structure level.

Objectives

Our research hopes to develop successful offspring production of ovarian organoids derived from spermatogonial stem cells (SSCs) by defined factors.

Methods

The offspring production from oocytes transdifferentiated from mouse SSCs with tracking of transplanted SSCs in vivo, single cell whole exome sequencing, and in 3D cell culture reconstitution of the process of oogenesis derived from SSCs. The defined factors were screened with ovarian organoids. We uncovered extensive chromatin reorganization during SSC conversion into induced germline stem cells (iGSCs) using high throughput chromosome conformation.

Results

We demonstrate successful production of offspring from oocytes transdifferentiated from mouse spermatogonial stem cells (SSCs). Furthermore, we demonstrate direct induction of germline stem cells (iGSCs) differentiated into functional oocytes by transduction of H19, Stella, and Zfp57 and inactivation of Plzf in SSCs after screening with ovarian organoids. We uncovered extensive chromatin reorganization during SSC conversion into iGSCs, which was highly similar to female germline stem cells. We observed that although topologically associating domains were stable during SSC conversion, chromatin interactions changed in a striking manner, altering 35% of inactive and active chromosomal compartments throughout the genome.

Conclusion

We demonstrate successful offspring production of ovarian organoids derived from SSCs by defined factors with chromatin reorganization. These findings have important implications in various areas including mammalian gametogenesis, genetic and epigenetic reprogramming, biotechnology, and medicine.



中文翻译:

通过染色质重组的特定因素产生源自精原干细胞的卵巢类器官的后代

介绍

在染色质结构水平上,生殖系干细胞的命运测定仍然知之甚少。

目标

我们的研究希望通过确定的因素开发成功的后代生产源自精原干细胞 (SSC) 的卵巢类器官。

方法

从小鼠 SSC 转分化的卵母细胞产生的后代,在体内跟踪移植的 SSC、单细胞全外显子组测序,以及在 3D 细胞培养中重建源自 SSC 的卵子发生过程。用卵巢类器官筛选确定的因素。我们使用高通量染色体构象在 SSC 转化为诱导生殖系干细胞 (iGSC) 期间发现了广泛的染色质重组。

结果

我们证明了从小鼠精原干细胞 (SSC) 转分化的卵母细胞成功生产后代。此外,我们展示了在用卵巢类器官筛选后,通过转导H19StellaZfp57以及在 SSC 中失活Plzf直接诱导生殖系干细胞 (iGSC) 分化成功能性卵母细胞。我们在 SSC 转化为 iGSC 期间发现了广泛的染色质重组,这与雌性生殖系干细胞高度相似。我们观察到,虽然拓扑关联结构域在 SSC 转换过程中是稳定的,但染色质相互作用发生了惊人的变化,改变了整个基因组中 35% 的非活性和活性染色体区室。

结论

我们通过染色质重组的特定因素证明了从 SSC 衍生的卵巢类器官的成功后代生产。这些发现在包括哺乳动物配子发生、遗传和表观遗传重编程、生物技术和医学在内的各个领域具有重要意义。

更新日期:2021-03-17
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