van Voorden A Jantine, Boussata Souad, Keijser Remco, Vermij Marloes, Wagner Muriel K, Ganzevoort Wessel, Afink Gijs B
Reproductive Biology Laboratory, Amsterdam University Medical Center Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Amsterdam Reproduction and Development Research Institute, 1105 AZ Amsterdam, The Netherlands.
Int J Mol Sci. 2024 Dec 31;26(1):271. doi: 10.3390/ijms26010271.
Placentation disorders, including severe preeclampsia and fetal growth restriction, have their origins in early pregnancy, whereas symptoms typically present later on. To investigate the pathogenesis of these diseases, there is a need for a reliable in vitro model system of early placenta development with known pregnancy outcomes. Therefore, we optimized the generation of human induced trophoblast stem cells (iTSCs) from term umbilical cord, enabling non-invasive collection of patient-derived material immediately after birth. Using a direct reprogramming approach previously described for dermal fibroblasts, we investigated the effects of three supplements (A-485, BMP4, and EPZ-6438) to assess their potential to enhance iTSC induction. The generated iTSCs fulfilled the criteria for bona fide first-trimester trophoblasts and exhibited key functional capacities, including long-term self-renewal, differentiation into hormone-producing syncytiotrophoblasts and invasive extravillous trophoblasts, and the formation of organoids. Furthermore, transcriptomic analysis revealed high similarity between the generated iTSCs and trophoblast stem cells derived from first-trimester placental tissue. The supplements did not improve the generation of iTSCs. In conclusion, we successfully generated bona fide iTSCs from term umbilical cord using a direct reprogramming approach, providing a robust and clinically relevant model to study early placentation mechanisms in patient-derived trophoblasts.
胎盘形成障碍，包括重度子痫前期和胎儿生长受限，起源于妊娠早期，而症状通常在后期出现。为了研究这些疾病的发病机制，需要一个具有已知妊娠结局的可靠的早期胎盘发育体外模型系统。因此，我们优化了从足月脐带中生成人诱导滋养层干细胞（iTSC）的方法，能够在出生后立即非侵入性地收集患者来源的材料。使用先前针对真皮成纤维细胞描述的直接重编程方法，我们研究了三种补充剂（A-485、BMP4和EPZ-6438）的作用，以评估它们增强iTSC诱导的潜力。所生成的iTSC符合真正的孕早期滋养层细胞的标准，并表现出关键的功能能力，包括长期自我更新、分化为产生激素的合体滋养层细胞和侵袭性绒毛外滋养层细胞，以及类器官的形成。此外，转录组分析显示所生成的iTSC与来自孕早期胎盘组织的滋养层干细胞高度相似。这些补充剂并没有改善iTSC的生成。总之，我们使用直接重编程方法成功地从足月脐带中生成了真正的iTSC，为研究患者来源的滋养层细胞中的早期胎盘形成机制提供了一个强大且与临床相关的模型。
