Summary Use of single-cell transcriptomics to measure how well medium spiny projection neurons, derived from human pluripotent stem cells, recapitulate human striatal development in vivo.
Background Stem cell engineering and grafting of striatal medium spiny projection neurons (MSNs) is a promising strategy to understand the molecular mechanisms underlying Huntington Disease (HD) and for future cell-replacement strategies. However, optimal recapitulation of MSN development requires a deep knowledge of how MSNs form during early fetal striatal development. In our recent work (Bocchi et al., Science 2021) we were able to map the developmental landscape of individual cell states transitioning from early progenitors of the LGE to MSNs and then classify how subtype-specific heterogeneity progresses through the expression of specific combinations of gene regulatory networks, transcription factors and cardinal genes including uniquely human specific lincRNAs identified de novo.
Aims and Methods Here we aim to measure the fidelity of MSNs derived from human pluripotent stem cells with our recently developed protocol, by comparing the transcriptome of each cell generated in vitro to the in vivo counterpart.
Results By comparing our in vivo MSN cell-atlas to our new in vitro derived MSN cell-atlas, we show that our protocol is able to mimic cell-fate acquisition steps seen in vivo, in terms of gene and cell type composition. Furthermore, we show that we are able to produce, for the first time, both D1 and D2-MSNs after 25 days of differentiation. Thus, stem cells under these new culture conditions recapitulate key stages of in vivo striatal development.
Conclusions Overall, we expect that our in vivo and in vitro single-cell datasets will act as benchmarks to quantify and refine current stem cell engineering protocols and to achieve a deeper understanding of the HD pathophysiology to accelerate the development of effective therapies.
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