TY - JOUR
KW - Purkinje neuron
KW - morphogens
KW - multiplexed screen
KW - organoids
KW - single-cell RNA-seq
KW - transplantation
AU - Neal D. Amin
AU - Kevin W. Kelley
AU - Konstantin Kaganovsky
AU - Massimo Onesto
AU - Jin Hao
AU - Yuki Miura
AU - James P. McQueen
AU - Noah Reis
AU - Genta Narazaki
AU - Tommy Li
AU - Shravanti Kulkarni
AU - Sergey Pavlov
AU - Sergiu P. Pașca
AB - Morphogens choreograph the generation of remarkable cellular diversity in the developing nervous system. Differentiation of stem cells in vitro often relies upon the combinatorial modulation of these signaling pathways. However, the lack of a systematic approach to understand morphogen-directed differentiation has precluded the generation of many neural cell populations, and the general principles of regional specification and maturation remain incomplete. Here, we developed an arrayed screen of 14 morphogen modulators in human neural organoids cultured for over 70 days. Deconvolution of single-cell-multiplexed RNA sequencing data revealed design principles of brain region specification. We tuned neural subtype diversity to generate a tachykinin 3 (TAC3)-expressing striatal interneuron type within assembloids. To circumvent limitations of in vitro neuronal maturation, we used a neonatal rat transplantation strategy that enabled human Purkinje neurons to develop their hallmark complex dendritic branching. This comprehensive platform yields insights into the factors influencing stem cell-derived neural diversification and maturation.
BT - Cell Stem Cell
DA - 2024-12-05
DO - 10.1016/j.stem.2024.10.016
IS - 12
N2 - Morphogens choreograph the generation of remarkable cellular diversity in the developing nervous system. Differentiation of stem cells in vitro often relies upon the combinatorial modulation of these signaling pathways. However, the lack of a systematic approach to understand morphogen-directed differentiation has precluded the generation of many neural cell populations, and the general principles of regional specification and maturation remain incomplete. Here, we developed an arrayed screen of 14 morphogen modulators in human neural organoids cultured for over 70 days. Deconvolution of single-cell-multiplexed RNA sequencing data revealed design principles of brain region specification. We tuned neural subtype diversity to generate a tachykinin 3 (TAC3)-expressing striatal interneuron type within assembloids. To circumvent limitations of in vitro neuronal maturation, we used a neonatal rat transplantation strategy that enabled human Purkinje neurons to develop their hallmark complex dendritic branching. This comprehensive platform yields insights into the factors influencing stem cell-derived neural diversification and maturation.
PY - 2024
SP - 1831
EP - 1846.e9
T2 - Cell Stem Cell
TI - Generating human neural diversity with a multiplexed morphogen screen in organoids
UR - https://www.sciencedirect.com/science/article/pii/S1934590924003783
VL - 31
Y2 - 2024-12-06
SN - 1934-5909
ER -