2025-03-13 マサチューセッツ工科大学(MIT)
マサチューセッツ工科大学(MIT)の研究者たちは、皮膚細胞を直接ニューロン(神経細胞)に変換する新たな手法を開発しました。 従来の方法では、皮膚細胞を一度多能性幹細胞に誘導し、その後ニューロンに分化させる必要がありましたが、今回の手法では幹細胞段階を経ずに直接変換を行います。マウスの細胞を用いた実験で、この方法は高い効率性を示し、1つの皮膚細胞から10個以上のニューロンを生成することに成功しました。この技術がヒト細胞でも再現可能であれば、脊髄損傷や筋萎縮性側索硬化症(ALS)などの疾患に対する細胞療法の発展が期待されます。
研究チームは、生成した運動ニューロンをマウスの脳に移植し、宿主組織と統合されることを確認しました。この成果は、将来的な細胞置換療法の可能性を示唆しています。
<関連情報>
- https://news.mit.edu/2025/mit-engineers-turn-skin-cells-into-neurons-for-cell-therapy-0313
- https://www.cell.com/cell-systems/abstract/S2405-4712(25)00038-9
- https://www.cell.com/cell-systems/abstract/S2405-4712(25)00039-0
増殖履歴と転写因子レベルが運動ニューロンへの直接転換を促す Proliferation history and transcription factor levels drive direct conversion to motor neurons
Nathan B. Wang ∙ Brittany A. Lende-Dorn ∙ Adam M. Beitz∙ … ∙ Honour O. Adewumi ∙ Timothy M. O’Shea ∙ Kate E. Galloway
Cell Systems Published:March 13, 2025
DOI:https://doi.org/10.1016/j.cels.2025.101205
Graphical abstract
Highlights
- Proliferation history offers a principal axis to distinguish TF effect on fate
- Levels of individual TFs differentially influence the rate of conversion
- Proliferation history shapes the cell’s response to levels of pioneer TF, Ngn2
- Driving early hyperproliferation increases direct conversion of adult human fibroblasts
Summary
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.
コンパクトな転写因子カセットが、直接転換によって機能的で移植可能な運動ニューロンを生成する Compact transcription factor cassettes generate functional, engraftable motor neurons by direct conversion
Nathan B. Wang∙ Honour O. Adewumi∙ Brittany A. Lende-Dorn∙ Adam M. Beitz∙ Timothy M. O’Shea∙ Kate E. Galloway
Cell Systems Published:March 13, 2025
DOI:https://doi.org/10.1016/j.cels.2025.101206
Graphical abstract
Highlights
- Compact, conversion cassettes are compatible with diverse delivery vectors
- Cocktail and conversion culture conditions influence the cell states of iMNs
- Optimized conversion cocktail supports neurotrophin-free conversion to iMN-like cells
- iMNs display electrical activity and graft in vivo within the central nervous system
Summary
Direct conversion generates patient-specific, disease-relevant cell types, such as neurons, that are rare, limited, or difficult to isolate from common and easily accessible cells, such as skin cells. However, low rates of direct conversion and complex protocols limit scalability and, thus, the potential of cell-fate conversion for biomedical applications. Here, we optimize the conversion protocol by examining process parameters, including transcript design; delivery via adeno-associated virus (AAV), retrovirus, and lentivirus; cell seeding density; and the impact of media conditions. Thus, we report a compact, portable conversion process that boosts proliferation and increases direct conversion of mouse fibroblasts to induced motor neurons (iMNs) to achieve high conversion rates of above 1,000%, corresponding to more than ten motor neurons yielded per cell seeded, which we achieve through expansion. Our optimized, direct conversion process generates functional motor neurons at scales relevant for cell therapies (>107 cells) that graft with the mouse central nervous system. High-efficiency, compact, direct conversion systems will support scaling to patient-specific, neural cell therapies.
