ELF5-controlled transcriptional networks define stem cell potency and differentiation in the trophoblast compartment

干细胞是具有自我繁殖能力(‘自我更新’)以及形成各种终末分化的身体细胞类型的细胞。出于这个原因，干细胞在生物医学研究和再生医学中引起了极大的兴趣。我们对仅对胎盘组织有贡献的干细胞(即所谓的滋养层干细胞)特别感兴趣。这些干细胞对于研究妊娠早期的发育过程具有巨大的价值，因为在怀孕初期，人类无法获得生物材料。从长远来看，它们也可能被证明对治疗妊娠障碍很有价值，其中许多妊娠障碍是基于胎盘功能缺陷的，即为成长中的婴儿调节所有营养和氧气供应的器官。一个关键的问题是，这种特殊类型的干细胞的扩增和分化是如何调控的，以确保形成功能齐全的胎盘。残存的滋养层干细胞极有可能在母亲的子宫中形成侵袭性肿瘤，这一事实进一步加强了这个问题的重要性。我们已经确定，这种机制可能是由一个特定的分子自我控制的，该分子调节胎盘基因的活性，即转录因子ELF5。本项目研究ELF5如何促进滋养层干细胞自我更新以及分化为特定胎盘细胞类型的分子基础。在促进特定干细胞群体的扩张和触发它们的终末分化之间的这种分子‘开关’功能对于健康的怀孕(对母亲和婴儿来说)是至关重要的。它还可能被证明可以翻译到存在这种分子的其他细胞和器官系统中，这些系统特别容易受到增殖和分化之间的不平衡的影响，例如易患癌症的乳房。因此，了解ELF5的功能机制可能会为分子途径建立一个范例，确保正常生殖以及成年和衰老过程中的健康。

Lay summary (4000 chrs) Stem cells are cells that have the potential to reproduce themselves ('self-renew') as well as to form various terminally differentiated cell types of the body. For this reason stem cells are of high interest for biomedical research and regenerative medicine. We are particularly interested in stem cells that contribute exclusively to tissues of the placenta (so-called trophoblast stem cells). These stem cells are of enormous value to study developmental processes at the earliest stages of pregnancy where biological material is not available from humans. In the longer term they may also prove to be valuable for the treatment of pregnancy disorders many of which are based on a defective function of the placenta, i.e. the organ that mediates all nutrition and oxygen supply to the growing baby. A key question is how the expansion and then differentiation of this particular stem cell type is regulated to ensure the formation of a fully functional placenta. The importance of this question is further reinforced by the fact that residual trophoblast stem cells pose a tremendous risk of aggressive tumour formation in the uterus of the mother. We have identified that this mechanism may be self-controlled by a specific molecule that regulates the activity of placental genes, the transcription factor ELF5. This project investigates the molecular basis how ELF5 promotes both, trophoblast stem cell self-renewal as well as differentiation into specific placental cell types. This molecular 'switch' function between promoting the expansion of a specific stem cell population followed by triggering their terminal differentiation is of fundamental importance for a healthy pregnancy (for both mother and baby). It may also prove to be translatable into other cell and organ systems where this molecule is present and that are particularly susceptible to an imbalance between proliferation and differentiation, such as the breast with its susceptibility to develop cancer. Hence understanding the mechanism of ELF5 function may establish a paradigm for molecular pathways that ensure normal reproduction as well as health throughout adult life and ageing.