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Human heart-forming organoids recapitulate early heart and foregut development.

ABSTRACT: 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.

SUBMITTER: Drakhlis L

PROVIDER: S-EPMC8192303 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Human heart-forming organoids recapitulate early heart and foregut development.

Drakhlis Lika L Biswanath Santoshi S Farr Clara-Milena CM Lupanow Victoria V Teske Jana J Ritzenhoff Katharina K Franke Annika A Manstein Felix F Bolesani Emiliano E Kempf Henning H Liebscher Simone S Schenke-Layland Katja K Hegermann Jan J Nolte Lena L Meyer Heiko H de la Roche Jeanne J Thiemann Stefan S Wahl-Schott Christian C Martin Ulrich U Zweigerdt Robert R

Nature biotechnology 20210208 6

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 cel ...[more]

PMID: 33558697

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Project description:Hematopoietic stem cells (HSCs) derive from the hemogenic endothelium of the dorsal aorta, which develops in spatial and functional proximity to the heart anlagen in the human embryo. Despite the biomedical importance of HSCs, their in vitro induction and niche-like stabilization in a proper developmental context is challenging and poorly established. The underlying reasons include the poorly understood signals controlling HSC formation and the lack of unequivocal markers specifying their stages of differentiation and maturation. Our recently established human pluripotent stem cell (hPSC)-derived heart-forming organoids (HFOs) represent complex, well-patterned multi-tissue structures recapitulating key aspects of heart, foregut and vasculature development. Modulating HFO development by the stage-dependent supplementation of hemato-endothelial factors, we here report the generation of blood-generating-HFOs (BG-HFOs). While maintaining their well-patterned heart anlagen, BG-HFOs comprise a dense, mesenchyme-embedded endothelial layer giving rise to hematopoietic cells thereby resembling – in vitro - aspects of the intra-embryonic region giving rise to definitive hematopoiesis in vivo. Single cell-RNA sequencing of BG-HFOs revealed a gene expression signature of hematopoietic progenitor cells (HPCs) as well as patterns resembling hematopoietic derivatives such as erythroid, megakaryocytic and myeloid cells. Notably, BG-HFO-derived CD34pos CD43pos and CD34neg CD43pos cells display erythroid and myeloid potential in colony forming unit (CFU) assays, while CD34pos CD43neg HPCs retain lymphoid potential, observed via generation of T-cell progenitors in artificial thymic organoid (ATO)-based assays. This suggests presence of different multipotent HPCs in BG-HFOs and a potential transient downregulation of CD43 in lymphoid-restricted HPCs. Together, BG-HFOs represent the first human model of cardiac, endothelial and multipotent-hematopoietic cell co-development. The study promotes research on the multi-tissue interactions of hematopoiesis in vitro, overcoming limitations of such studies in the human embryo.

Dataset Information

Human heart-forming organoids recapitulate early heart and foregut development.

Publications

Human heart-forming organoids recapitulate early heart and foregut development.

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