Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), REBIRTH-Research Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.
Stem Cell Discovery, Novo Nordisk A/S, Måløv, Denmark.
Nat Biotechnol. 2021 Jun;39(6):737-746. doi: 10.1038/s41587-021-00815-9. Epub 2021 Feb 8.
Organoid models of early tissue development have been produced for the intestine, brain, kidney and other organs, but similar approaches for the heart have been lacking. Here we generate complex, highly structured, three-dimensional heart-forming organoids (HFOs) by embedding human pluripotent stem cell aggregates in Matrigel followed by directed cardiac differentiation via biphasic WNT pathway modulation with small molecules. HFOs are composed of a myocardial layer lined by endocardial-like cells and surrounded by septum-transversum-like anlagen; they further contain spatially and molecularly distinct anterior versus posterior foregut endoderm tissues and a vascular network. The architecture of HFOs closely resembles aspects of early native heart anlagen before heart tube formation, which is known to require an interplay with foregut endoderm development. We apply HFOs to study genetic defects in vitro by demonstrating that NKX2.5-knockout HFOs show a phenotype reminiscent of cardiac malformations previously observed in transgenic mice.
已经为肠道、大脑、肾脏和其他器官生成了早期组织发育的类器官模型,但心脏的类似方法还很缺乏。在这里,我们通过在 Matrigel 中嵌入人类多能干细胞聚集体,然后通过小分子的双相 WNT 通路调节进行定向心脏分化,生成复杂的、高度结构化的三维心脏形成类器官 (HFO)。HFO 由心肌层组成,由心内膜样细胞排列,并被隔膜-横隔样原基包围;它们进一步包含空间和分子上不同的前肠内胚层组织和血管网络。HFO 的结构与心脏管形成前早期天然心脏原基的某些方面非常相似,已知这需要与前肠内胚层发育相互作用。我们通过证明 NKX2.5 敲除 HFO 显示出类似于先前在转基因小鼠中观察到的心脏畸形的表型,将 HFO 应用于体外研究遗传缺陷。