Co-development of central and peripheral neurons with trunk mesendoderm in human elongating multi-lineage organized gastruloids

• Published in: Nature communications 2021-05, Vol.12 (1), p.3020-3020, Article 3020
• Main Authors: Olmsted, Zachary T., Paluh, Janet L.
• Format: Article
• Language: English
• Subjects: 13; 13/100; 14/19; 45/91; 631/136/756; 631/378/2571/2575; 631/532/2064; Biomarkers; Cell differentiation; Cell Differentiation - physiology; Central nervous system; Central Nervous System - cytology; Central Nervous System - physiology; Elongation; Endoderm; Enteric nervous system; Forkhead Transcription Factors; Gene Expression; Humanities and Social Sciences; Humans; Immunofluorescence; Innervation; Mesenchyme; Mesendoderm; Morphogenesis; multidisciplinary; Nervous system; Neural Crest; Neurodevelopment; Neurons; Organogenesis; Organoids; Peripheral nervous system; Peripheral Nervous System - cytology; Peripheral Nervous System - pathology; Phenotype; Science; Science (multidisciplinary); Self-assembly; SOXE Transcription Factors; Spinal cord; Stem cells; Three dimensional models; Transcription Factor AP-2
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23294-7

Stem cell technologies including self-assembling 3D tissue models provide access to early human neurodevelopment and fundamental insights into neuropathologies. Gastruloid models have not been used to investigate co-developing central and peripheral neuronal systems with trunk mesendoderm which we achieve here in elongating multi-lineage organized (EMLO) gastruloids. We evaluate EMLOs over a forty-day period, applying immunofluorescence of multi-lineage and functional biomarkers, including day 16 single-cell RNA-Seq, and evaluation of ectodermal and non-ectodermal neural crest cells (NCCs). We identify NCCs that differentiate to form peripheral neurons integrated with an upstream spinal cord region after day 8. This follows initial EMLO polarization events that coordinate with endoderm differentiation and primitive gut tube formation during multicellular spatial reorganization. This combined human central-peripheral nervous system model of early organogenesis highlights developmental events of mesendoderm and neuromuscular trunk regions and enables systemic studies of tissue interactions and innervation of neuromuscular, enteric and cardiac relevance. The authors generate EMLOs (elongating multi-lineage organized gastruloids): organoids that self-organize to form compartments with characteristics of the central nervous system, peripheral nervous system, mesenchyme, and gut tube.