Next-generation disease modeling with direct conversion: a new path to old neurons

Area of Science:

• Stem Cell Biology
• Neuroscience
• Disease Modeling

Background:

• Induced pluripotent stem cells (iPSCs) are valuable for modeling developmental and monogenetic disorders.
• The rejuvenated identity of iPSCs limits their utility in modeling age-associated diseases.
• Cellular aging hallmarks are crucial for understanding and modeling age-related conditions.

Purpose of the Study:

• To review the state-of-the-art in direct fibroblast-to-induced neuron (iN) conversion.
• To elucidate the epigenetic, transcriptomic, and metabolic changes during fibroblast conversion to iNs.
• To discuss the unique advantages of iNs for modeling age-related and epigenetic diseases.

Main Methods:

• Review of current literature on direct cell-type conversion techniques.
• Analysis of epigenetic, transcriptomic, and metabolic profiles of converting fibroblasts.
• Comparison of induced neurons (iNs) with other reprogramming-based neuronal models.

Main Results:

• Direct iN conversion circumvents cellular rejuvenation, preserving age-related characteristics.
• Key molecular and metabolic shifts occur during the fibroblast-to-iN transition.
• iNs offer a distinct model system compared to iPSC-derived neurons for specific disease types.

Conclusions:

• Direct iN conversion is a promising strategy for modeling diseases with strong age-related and epigenetic components.
• iNs complement iPSC-based models, expanding the scope of disease modeling capabilities.
• Further characterization of in vitro-generated neurons is essential for refining disease modeling applications.