Self-organized trunk-like-structures with somites and a neural tube
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PROVIDER: PRJNA592534 | ENA |
REPOSITORIES: ENA
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Project description:The post-implantation embryo is subject to extensive growth, morphogenetic changes and lineage decisions that take place in utero and are therefore difficult to deconstruct in vivo. A robust in vitro culture system that mimics post-implantation mouse development would pave the path towards understanding the dynamics of these processes and how they are coupled. Small aggregates of mouse embryonic stem cells (mESCs) can undergo gastrulation-like events and elongation in vitro, resulting in aggregates with gene expression domains that reflect the post-occipital embryo (gastruloids1–3). However, these ordered patterns of gene expression do not correlate with embryo-like morphogenesis. Here we show that mechano-chemical manipulation of the aggregates results in Trunk-Like-Structures (TLS) with a high level of organization of the embryonic tissue layers, including the formation of a neural tube and somites. Comparative single-cell RNA-Seq (scRNA-Seq) of TLS and embryos demonstrated the molecular complexity of TLS, confirmed embryo-like gene-regulatory programs, and unveiled the presence of primordial germ cell like cells (PGCLCs). Finally, Tbx6-/- TLS formed ectopic neural tubes, recapitulating the in vivo phenotype. These results suggest that TLS are a powerful platform to study the morphogenetic changes and lineage decisions during post-implantation development in space and time.
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Project description:Integrated in vitro models of human organogenesis are needed to elucidate the multi-systemic events underlying development and disease. We report the generation of human trunk-like structures that model the co-morphogenesis, patterning, and differentiation of the human spine and spinal cord. We identified differentiation conditions for human pluripotent stem cells favoring the formation of an embryo-like extending antero-posterior (AP) axis. Single cell and spatial transcriptomics show that somitic and spinal cord differentiation trajectories organize along this axis and can self-assemble into neural tubes surrounded by somites upon extracellular matrix addition. Morphogenesis is coupled with AP patterning mechanisms which results, at later stages of organogenesis, in in vivo-like arrays of neural subtypes along a neural tube surrounded by spine and muscle progenitors contacted by neuronal projections. This integrated system of trunk development indicates that in vivo-like multi-tissue morphogenesis and topographic organization of terminal cell types can be achieved in human organoids, opening windows for the development of more complex models of organogenesis.
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Project description:Integrated in vitro models of human organogenesis are needed to elucidate the multi-systemic events underlying development and disease. We report the generation of human trunk-like structures that model the co-morphogenesis, patterning, and differentiation of the human spine and spinal cord. We identified differentiation conditions for human pluripotent stem cells favoring the formation of an embryo-like extending antero-posterior (AP) axis. Single cell and spatial transcriptomics show that somitic and spinal cord differentiation trajectories organize along this axis and can self-assemble into neural tubes surrounded by somites upon extracellular matrix addition. Morphogenesis is coupled with AP patterning mechanisms which results, at later stages of organogenesis, in in vivo-like arrays of neural subtypes along a neural tube surrounded by spine and muscle progenitors contacted by neuronal projections. This integrated system of trunk development indicates that in vivo-like multi-tissue morphogenesis and topographic organization of terminal cell types can be achieved in human organoids, opening windows for the development of more complex models of organogenesis.
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Project description:Differential Hox gene expression is central for specification of axial neuronal diversity in the spinal cord. Here, we uncover an additional function of Hox proteins in the developing spinal cord, restricted to B cluster Hox genes. We found that members of the HoxB cluster are expressed in the trunk neural tube of chicken embryo earlier than Hox from the other clusters, with poor antero-posterior axial specificity and with overlapping expression in the intermediate zone (IZ). Gain-of-function experiments of HoxB4, HoxB8 and HoxB9, respectively representative of anterior, central, and posterior HoxB genes, resulted in ectopic progenitor cells in the mantle zone. The search for HoxB8 downstream targets in the early neural tube identified the Leucine Zipper Tumor Suppressor 1 gene (Lzts1), which expression is also activated by HoxB4 and HoxB9. Gain and loss of function experiments showed that Lzts1, expressed endogenously in the IZ, controls neuronal delamination. These data collectively indicate that HoxB genes have a generic function in the developing spinal cord, controlling the expression of Lzts1 and neuronal delamination.
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Project description:Numerous models of synthetic embryos have recently been established to simulate mammalian development. Two main strategies have been developed to build mouse or human embryo-like structures (ELS): by assembling embryonic and extraembryonic stem cells or by challenging embryonic stem cells (ESCs) with a pulse of WNT agonist. However, both models did not fully recapitulate early organogenesis, particularly the emergence of brain derivatives. SUMOylation was recently identified as a general barrier to cell fate transitions. Here, we show that mouse ESCs exposed to a small-molecule inhibitor of SUMOylation alone generate adherent spheroids which, once in suspension, self-organize in gastrulating structures containing cell types spatially and functionally-related to embryonic and extraembryonic compartments. Alternatively, spheroids cultured in an optimized droplet-microfluidic device form elongated ELS characterized by a multi-axial organization of the body plan reminiscent of natural embryo morphogenesis. Single-cell transcriptomics further revealed various cell types including anterior neuronal cell types, Schwann cell precursors and somites. Mechanistically, transient SUMOylation repression gradually increases the global level of DNA methylation, which in turn represses transcription of Nanog and other pluripotency-associated genes, enhancing cellular plasticity of ESCs. Our morphogen-free protocol constitutes a new facet to study regulative mechanisms of early development by targeting reprogramming roadblocks to shape multicellular architecture.
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