【AI详解】Establishment and differentiation of long-term trophoblast organoid cultures from the human placenta.

文献信息

一句话小结

本研究开发了一种新的三维类器官培养系统，能够从第一孕期人类胎盘中分离并长期培养滋养层细胞，成功重现了胎盘的结构和功能特征。该系统为研究妊娠障碍及胎盘发育提供了重要的实验模型，有助于深入理解滋养层细胞与母体环境的相互作用。

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滋养层细胞 · 类器官培养 · 胎盘发育

摘要

人类胎盘对于成功的生殖至关重要。不同物种的胎盘在解剖结构和发育上存在很大差异，这意味着动物模型提供的关于人类胎盘发育和功能的信息有限。直到最近，从人类胎盘中分离出能够在体外增殖的滋养层细胞几乎是不可能的，这限制了我们对妊娠障碍的理解。生成一个能够重现人类胎盘独特特征的体外模型一直是一个挑战。第一个能够长期培养并分化为合胞胎滋养层细胞（SCT）和外绒毛滋养层细胞（EVT）的体外人类滋养层细胞模型是一个二维（2D）人类滋养层干细胞培养系统。在此，我们描述了一种从第一孕期人类胎盘中分离滋养层细胞的协议，这些细胞可以在三维（3D）类器官培养系统中长期生长。滋养层类器官可以在2-3周内建立，每7-10天传代一次，并可培养超过一年。这些人类滋养层类器官的结构组织与绒毛胎盘相似，具有一层细胞滋养层（VCT），该层细胞可分化为叠加的SCT。改变培养基的成分会导致滋养层类器官分化为HLA-G+的EVT细胞，这些细胞会迅速迁移并侵入其所培养的Matrigel液滴中。我们之前的研究确认滋养层类器官与体内胎盘在转录组及产生胎盘激素的能力方面具有相似性。该类器官培养系统提供了一个实验模型，用于研究人类胎盘的发育和功能，以及滋养层细胞与局部和全身母体环境的相互作用。

英文摘要

The human placenta is essential for successful reproduction. There is great variation in the anatomy and development of the placenta in different species, meaning that animal models provide limited information about human placental development and function. Until recently, it has been impossible to isolate trophoblast cells from the human placenta that proliferate in vitro. This has limited our ability to understand pregnancy disorders. Generating an in vitro model that recapitulates the unique features of the human placenta has been challenging. The first in vitro model system of human trophoblast that could be cultured long term and differentiated to syncytiotrophoblast (SCT) and extravillous trophoblast (EVT) was a two-dimensional (2D) culture system of human trophoblast stem cells. Here, we describe a protocol to isolate trophoblast from first-trimester human placentas that can be grown long term in a three-dimensional (3D) organoid culture system. Trophoblast organoids can be established within 2-3 weeks, passaged every 7-10 d, and cultured for over a year. The structural organization of these human trophoblast organoids closely resembles the villous placenta with a layer of cytotrophoblast (VCT) that differentiates into superimposed SCT. Altering the composition of the medium leads to differentiation of the trophoblast organoids into HLA-G+ EVT cells which rapidly migrate and invade through the Matrigel droplet in which they are cultured. Our previous research confirmed that there is similarity between the trophoblast organoids and in vivo placentas in their transcriptomes and ability to produce placental hormones. This organoid culture system provides an experimental model to investigate human placental development and function as well as interactions of trophoblast cells with the local and systemic maternal environment.

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主要研究问题

1. 在建立人类胎盘滋养层器官培养时，如何确保培养基成分的最佳组合以促进滋养层细胞的分化？
2. 三维器官培养系统与传统的二维培养系统相比，在滋养层细胞的生长和分化方面有哪些优势？
3. 如何评估滋养层器官的结构和功能是否与体内胎盘相似？
4. 在研究妊娠疾病时，滋养层器官培养系统能够提供哪些具体的实验数据或见解？
5. 滋养层细胞与母体环境的相互作用在胎盘发育中扮演了怎样的角色？

核心洞察

1. 研究背景和目的

人类胎盘在成功生育中扮演着至关重要的角色，但不同物种胎盘的解剖和发育差异使得动物模型在研究人类胎盘发育和功能时存在局限性。以往由于缺乏有效的方法来体外分离和培养人类胎盘的滋养层细胞，阻碍了对妊娠疾病的深入理解。因此，本研究旨在建立一种能够长期培养和分化人类胎盘滋养层细胞的三维（3D）类器官模型，以便更好地研究人类胎盘的发育和功能。

2. 主要方法和发现

研究团队开发了一个协议，可以从早孕阶段的人类胎盘中分离滋养层细胞，并在三维类器官培养系统中进行长期培养。所建立的滋养层类器官可以在2-3周内形成，每7-10天传代一次，并可以培养超过一年。观察发现，这些类器官的结构组织与绒毛胎盘相似，表现出细胞外滋养层（VCT）向超层滋养层（SCT）的分化特征。此外，通过改变培养基的成分，类器官可分化为HLA-G阳性的外绒毛滋养层（EVT）细胞，这些细胞能够快速迁移并侵入培养的基质凝胶（Matrigel）中。研究中还证实了滋养层类器官在转录组和孕激素产生能力上与体内胎盘的相似性。

3. 核心结论

该研究成功建立了一个能够长期培养和分化人类滋养层细胞的三维类器官系统，提供了一个有效的实验模型来探讨人类胎盘的发育与功能。滋养层类器官不仅能够模拟胎盘的结构，还能够在生理上反映胎盘的某些关键特性，为研究孕期相关疾病提供了新的工具。

4. 研究意义和影响

这项研究的意义在于，它为理解人类胎盘的生物学提供了新的实验平台，克服了以往研究中的局限性。通过这种新的3D类器官模型，研究人员可以更深入地探讨滋养层细胞与母体环境的相互作用，进而为妊娠相关疾病的研究和治疗提供科学依据。这一突破不仅对基础生物学研究有重要贡献，也可能推动临床研究和新疗法的发展，具有广泛的社会和医学影响。

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引用本文的文献

1. Trophoblast organoids as a model for maternal-fetal interactions during human placentation. - Margherita Y Turco;Lucy Gardner;Richard G Kay;Russell S Hamilton;Malwina Prater;Michael S Hollinshead;Alasdair McWhinnie;Laura Esposito;Ridma Fernando;Helen Skelton;Frank Reimann;Fiona M Gribble;Andrew Sharkey;Steven G E Marsh;Stephen O’Rahilly;Myriam Hemberger;Graham J Burton;Ashley Moffett - Nature (2018)
2. Perinatal Derivatives: Where Do We Stand? A Roadmap of the Human Placenta and Consensus for Tissue and Cell Nomenclature. - Antonietta Rosa Silini;Roberta Di Pietro;Ingrid Lang-Olip;Francesco Alviano;Asmita Banerjee;Mariangela Basile;Veronika Borutinskaite;Günther Eissner;Alexandra Gellhaus;Bernd Giebel;Yong-Can Huang;Aleksandar Janev;Mateja Erdani Kreft;Nadja Kupper;Ana Clara Abadía-Molina;Enrique G Olivares;Assunta Pandolfi;Andrea Papait;Michela Pozzobon;Carmen Ruiz-Ruiz;Olga Soritau;Sergiu Susman;Dariusz Szukiewicz;Adelheid Weidinger;Susanne Wolbank;Berthold Huppertz;Ornella Parolini - Frontiers in bioengineering and biotechnology (2020)
3. Generation of Trophoblast-Like Cells From Hypomethylated Porcine Adult Dermal Fibroblasts. - Sharon Arcuri;Georgia Pennarossa;Fulvio Gandolfi;Tiziana A L Brevini - Frontiers in veterinary science (2021)
4. The Role of the 3Rs for Understanding and Modeling the Human Placenta. - Joana Costa;Ruth Mackay;Sophie-Christine de Aguiar Greca;Alessandro Corti;Elisabete Silva;Emmanouil Karteris;Arti Ahluwalia - Journal of clinical medicine (2021)
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6. Functional Analysis of p21Cip1/ and Its Family Members in Trophoblastic Cells of the Placenta and Its Roles in Preeclampsia. - Nina-Naomi Kreis;Alexandra Friemel;Lukas Jennewein;Samira Catharina Hoock;Anna Elisabeth Hentrich;Thorsten Nowak;Frank Louwen;Juping Yuan - Cells (2021)
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10. Modeling Innate Antiviral Immunity in Physiological Context. - Monty E Goldstein;Margaret A Scull - Journal of molecular biology (2022)

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