Sabina Kanton

All Publications

• Human assembloids. Development (Cambridge, England) Kanton, S., Pasca, S. P. 2022; 149 (20)

  Abstract

  Deconstructing and then reconstructing developmental processes ex vivo is crucial to understanding how organs assemble and how physiology can be disrupted in disease. Human 3D stem cell-derived systems, such as organoids, have facilitated this pursuit; however, they often do not capture inter-tissue or inter-lineage cellular interactions that give rise to emergent tissue properties during development. Assembloids are self-organizing 3D cellular systems that result from the integration of multiple organoids or the combination of organoids with missing cell types or primary tissue explants. Here, we outline the concept and types of assembloids and present their applications for studying the nervous system and other tissues. We describe tools that are used to probe and manipulate assembloids and delineate current challenges and the potential for this new approach to interrogate development and disease.

  View details for DOI 10.1242/dev.201120

  View details for PubMedID 36317797

• Comparison of induced neurons reveals slower structural and functional maturation in humans than in apes ELIFE Schoernig, M., Ju, X., Fast, L., Ebert, S., Weigert, A., Kanton, S., Schaffer, T., Kasri, N., Treutlein, B., Peter, B., Hevers, W., Taverna, E. 2021; 10

  Abstract

  We generated induced excitatory neurons (iNeurons, iNs) from chimpanzee, bonobo, and human stem cells by expressing the transcription factor neurogenin-2 (NGN2). Single-cell RNA sequencing showed that genes involved in dendrite and synapse development are expressed earlier during iNs maturation in the chimpanzee and bonobo than the human cells. In accordance, during the first 2 weeks of differentiation, chimpanzee and bonobo iNs showed repetitive action potentials and more spontaneous excitatory activity than human iNs, and extended neurites of higher total length. However, the axons of human iNs were slightly longer at 5 weeks of differentiation. The timing of the establishment of neuronal polarity did not differ between the species. Chimpanzee, bonobo, and human neurites eventually reached the same level of structural complexity. Thus, human iNs develop slower than chimpanzee and bonobo iNs, and this difference in timing likely depends on functions downstream of NGN2.

  View details for DOI 10.7554/eLife.59323

  View details for Web of Science ID 000618603100001

  View details for PubMedID 33470930

  View details for PubMedCentralID PMC7870144

• Organoid single-cell genomic atlas uncovers human-specific features of brain development. Nature Kanton, S., Boyle, M. J., He, Z., Santel, M., Weigert, A., Sanchís-Calleja, F., Guijarro, P., Sidow, L., Fleck, J. S., Han, D., Qian, Z., Heide, M., Huttner, W. B., Khaitovich, P., Pääbo, S., Treutlein, B., Camp, J. G. 2019; 574 (7778): 418-422

  Abstract

  The human brain has undergone substantial change since humans diverged from chimpanzees and the other great apes1,2. However, the genetic and developmental programs that underlie this divergence are not fully understood. Here we have analysed stem cell-derived cerebral organoids using single-cell transcriptomics and accessible chromatin profiling to investigate gene-regulatory changes that are specific to humans. We first analysed cell composition and reconstructed differentiation trajectories over the entire course of human cerebral organoid development from pluripotency, through neuroectoderm and neuroepithelial stages, followed by divergence into neuronal fates within the dorsal and ventral forebrain, midbrain and hindbrain regions. Brain-region composition varied in organoids from different iPSC lines, but regional gene-expression patterns remained largely reproducible across individuals. We analysed chimpanzee and macaque cerebral organoids and found that human neuronal development occurs at a slower pace relative to the other two primates. Using pseudotemporal alignment of differentiation paths, we found that human-specific gene expression resolved to distinct cell states along progenitor-to-neuron lineages in the cortex. Chromatin accessibility was dynamic during cortex development, and we identified divergence in accessibility between human and chimpanzee that correlated with human-specific gene expression and genetic change. Finally, we mapped human-specific expression in adult prefrontal cortex using single-nucleus RNA sequencing analysis and identified developmental differences that persist into adulthood, as well as cell-state-specific changes that occur exclusively in the adult brain. Our data provide a temporal cell atlas of great ape forebrain development, and illuminate dynamic gene-regulatory features that are unique to humans.

  View details for DOI 10.1038/s41586-019-1654-9

  View details for PubMedID 31619793

  View details for PubMedCentralID 5647789

• Multilineage communication regulates human liver bud development from pluripotency. Nature Camp, J. G., Sekine, K., Gerber, T., Loeffler-Wirth, H., Binder, H., Gac, M., Kanton, S., Kageyama, J., Damm, G., Seehofer, D., Belicova, L., Bickle, M., Barsacchi, R., Okuda, R., Yoshizawa, E., Kimura, M., Ayabe, H., Taniguchi, H., Takebe, T., Treutlein, B. 2017; 546 (7659): 533-538

  Abstract

  Conventional two-dimensional differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. Three-dimensional organoids generate complex organ-like tissues; however, it is unclear how heterotypic interactions affect lineage identity. Here we use single-cell RNA sequencing to reconstruct hepatocyte-like lineage progression from pluripotency in two-dimensional culture. We then derive three-dimensional liver bud organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during liver bud development. We find that liver bud hepatoblasts diverge from the two-dimensional lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark three-dimensional liver buds against fetal and adult human liver single-cell RNA sequencing data, and find a striking correspondence between the three-dimensional liver bud and fetal liver cells. We use a receptor-ligand pairing analysis and a high-throughput inhibitor assay to interrogate signalling in liver buds, and show that vascular endothelial growth factor (VEGF) crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.

  View details for DOI 10.1038/nature22796

  View details for PubMedID 28614297