Proliferation history and transcription factor levels drive direct conversion to motor neurons
Name
Proliferation history and transcription factor levels drive direct conversion to motor neurons.pdf
Description
Accepted version
Size
3.73 MB
Format
Adobe PDF
Checksum (MD5)
441d727d10817282f7e9dfc02b57dea5
Author(s)
Wang, Nathan B
Lende-Dorn, Brittany A
Beitz, Adam M
Han, Patrick
Adewumi, Honour O
O’Shea, Timothy M
Galloway, Kate E
Date Issued
April 16, 2025
Journal
Cell Systems
Publisher
Elsevier BV
Citation
Wang N, Lende-Dorn B, Beitz A ...Proliferation history and transcription factor levels drive direct conversion to motor neurons. Cell Systems, 2025; 16.
Version
Author's final manuscript
Abstract
The sparse and stochastic nature of conversion has obscured our understanding of how transcription factors (TFs) drive cells to new identities. To overcome this limit, we develop a tailored, high-efficiency conversion system that increases the direct conversion of fibroblasts to motor neurons 100-fold. By tailoring the cocktail to a minimal set of transcripts, we reduce extrinsic variation, allowing us to examine how proliferation and TFs synergistically drive conversion. We show that cell state-as set by proliferation history-defines how cells interpret the levels of TFs. Controlling for proliferation history and titrating each TF, we find that conversion correlates with levels of the pioneer TF Ngn2. By isolating cells by both their proliferation history and Ngn2 levels, we demonstrate that levels of Ngn2 expression alone are insufficient to predict conversion rates. Rather, proliferation history and TF levels combine to drive direct conversion. Finally, increasing the proliferation rate of adult human fibroblasts generates morphologically mature induced human motor neurons at high rates.
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Creative Commons Attribution-NonCommercial-NoDerivatives
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DOI of Published Version
https://doi.org/10.1016/j.cels.2025.101205
