Chemogenetic tuning reveals optimal MAPK signaling for cell-fate programming
Brittany A Lende-Dorn1, Jane C Atkinson1, Yunbeen Bae1
1Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA.
Cell Reports
|September 6, 2025
Summary
Optimizing mitogen-activated protein kinase (MAPK) signaling levels is crucial for efficient cell-fate reprogramming. Too little signaling hinders conversion, while too much induces senescence, highlighting a therapeutic "Goldilocks" zone.
Area of Science:
- Cellular reprogramming
- Signal transduction pathways
- Developmental biology
Background:
- Cell state transitions are governed by complex interactions between signaling pathways and gene regulatory networks.
- Transcription factors initiate cell fate changes, but require a receptive cellular environment.
- The precise role of signaling pathway intensity in establishing cell receptivity is not well understood.
Purpose of the Study:
- To investigate how varying levels of the oncogene HRASG12V impact the direct conversion of fibroblasts into induced motor neurons.
- To define the relationship between mitogen-activated protein kinase (MAPK) signaling strength and the efficiency of cell-fate programming.
- To identify optimal signaling conditions for therapeutic cell reprogramming.
Main Methods:
- Utilized a direct conversion model system.
- Manipulated levels of the HRASG12V oncogene to modulate MAPK signaling.
- Employed chemogenetic techniques to precisely control MAPK activity.
- Assessed conversion rates and cellular responses, including senescence and Ngn2 activity.
Main Results:
- Direct conversion rates exhibited a biphasic response to increasing HRASG12V levels.
- An optimal, intermediate level of MAPK signaling ('Goldilocks' zone) maximized conversion efficiency.
- Elevated HRASG12V levels led to cellular senescence, inhibiting reprogramming.
- MAPK signaling influenced conversion not only through proliferation but also by modulating the activity of the transcription factor Ngn2.
Conclusions:
- Cell-fate reprogramming efficiency is sensitive to the precise intensity of signaling pathways, demonstrating a non-monotonic dose-response.
- Therapeutic interventions for cell reprogramming require careful tuning within a defined signaling landscape.
- Understanding the interplay between genetic factors and signaling levels is critical for optimizing regenerative medicine strategies.
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