人类早期胚胎发育体外模型研究进展

Advances in the development of human embryo models

人类早期胚胎发育阶段对于胎儿的健康出生至关重要。然而,由于伦理和技术的限制,人类早期胚胎发育的具体调控机制仍未完全解密。除了人类胚胎体外培养技术以外,以干细胞为基础模拟人类真实胚胎结构的体外模型被构建出来,被称为“类胚胎/胚胎模型”。通常人类胚胎模型可大致分为两类:非整合型和整合型胚胎模型。整合型胚胎模型通常包含胚内和胚外细胞类型并具有发育成完整胎儿的潜力,而非整合型胚胎模型则不包含任何相关的胚外组织。本文系统总结了人类体外非整合型和整合型胚胎模型的最新研究进展,探讨了有关国际干细胞研究的伦理政策,并简要阐述了人类胚胎模型潜在的应用前景和未来机遇。以期为研究人类早期胚胎发育过程中不同细胞谱系的特化轨迹,以及早期胚胎发育缺陷等重大疾病的临床药物筛选和再生医学提供新的研究思路。

Human early embryonic development is critical for a healthy fetus birth.However,the specific molecular regulatory mechanisms of lineage development,cell fate decisions and embryonic patterning are still shrouded in mystery.Our knowledge about early human embryogenesis has been greatly improved with the recent progress in in vitro culture conditions for human blastocysts and the advancements in omics technology.However,ethical and technological challenges continue to pose obstacles in these studies.With the rapid development of human pluripotent stem cells,they can be coaxed to form embryo-like structures that mimic early human embryonic development in vitro,termed“embryo models”.Interest in human embryonic development has been reinvigorated with the continuing advances in this area.Human embryo models can be divided into two categories"non-integrated embryo models"and“integrated embryo models”according to the different cellular components they possessed.Integrated embryo models represent the embryo-like structures containing both embryonic and extra-embryonic cell types,including blastoids,human extra-embryoids(hEEs),E-assembloids,stem-cell-derived synthetic whole embryo models(SEMs),peri gastruloids,bilaminiods and heX-embryoids.While non-integrated embryo models sometimes lack the extra embryonic tissues,including embryoid bodies(EBs),gastruloids,micro-patterned colonies,post-implantation amniotic sac embryoids(PASE).Besides,non-human primate cynomolgus monkey models have greatly expanded our knowledge towards human developmental biology.In this review,we summarized recent human stem cell-based non integrated and integrated embryo models,and pointed out the technical challenges remained with proposed future directions.These findings lay an important foundation for understanding early human embryonic development,promoting research into human stem cells and their application,as well as preventing and treating early pregnancy loss or congenital diseases.On the other hand,embryo-like structures derived from human stem cell-based integrated embryo models,although do not fully,almost recapitulate the key events and structural organization of the in vivo counterparts,thus eliciting a serious compact on traditional ethical and practical concerns.In the future,non-integrated human embryo models and non-human primate models,which pose fewer ethical challenges,may provide a straightforward way to study the human early embryonic development.