Future Pluripotency
Research for
iPS Cell Therapy and
Disease Modeling:
CiRA and Gladstone
March 2025
_edited.jpg)
James Douglas Boyd
Founder, CEO, Editor-in-Chief
.png)
Discipline
Biomedicine
Institutions
▣ Center for iPS Cell Research and Application (iPS細胞研究所), or CiRA (サイラ), Kyoto University (京都大学)
▣ Gladstone Institutes, University of California San Francisco
Participants
▣ YAMANAKA Shinya (玉川 安騎男): President, CiRA Foundation; Director Emeritus, CIRA; Senior Investigator, Gladstone
▣ Steven FINKBEINER: Director, Gladstone Center for Systems and Therapeutics; Director, Taube/Koret Center for Neurodegenerative Disease Research; Director, Hellman Family Foundation Alzheimer’s Disease Research Program
▣ Benoît BRUNEAU: Director, Gladstone Institute of Cardiovascular Disease
▣ Bruce CONKLIN: Senior Investigator, Gladstone Institutes; Deputy Director, Innovative Genomics Institute (IGI)
▣ TOMODA Kiichiro (友田 紀一郎): Associate Professor, CiRA; Research Investigator, Gladstone
Topics
Reprogramming efficiency enhancement, cocktail choice, episomal plasmids, reproducible differentiation, GMP-grade production, the Waddington landscape, transdifferentiation, translation-initiation factors, CiRA/Gladstone, etc.
Reprogramming Efficiency, Researcher Needs, and Industrial Constraints
▣ Despite the large number of publications on cocktail design and programming efficiency improvements, low-efficiency reprogramming and modest colony yields are described to be adequate, in many cases, for researcher purposes.
▣ Beyond reprogramming enhancement studies, researcher cocktail choice is restricted to biotech company kits. GMP-grade standardization is the ultimate bottleneck constraining reprogramming cocktail choice. Yamanaka-sensei shares his assessment that transcription factor (TF) choice in reprogramming cocktails won't change absent a demonstration of radical improvement.
▣ Yamanaka-sensei's overall assessment of reprogramming enhancement research is that it has delivered only mild improvements.
▣ Professor Bruneau regards the first decade of reprogramming research as being valuable in establishing basic efficiency improvements and developing GMP-grade production.
Translation-Motivated Reprogramming Innovations
▣ Example of innovation: Use of p53 inhibition for improving the efficiency of episomal plasmid reprogramming, which was preferred to lentiviral vectors as an integration-free method.
▣ Example of innovation: Professor Finkbeiner identifies epigenetic marker retention via transdifferentiation as a translational motivation for the use of transdifferentiated cells (e.g., for disease-modeling of neurodegenerative disorders). However, Professor Finkbeiner and Tomoda-sensei agree that the low expansion capacity of transdifferentiated cells is a comparative weakness relative to iPS cells.
Differentiation Precision as a Frontier in Reprogramming Research
▣ Tomoda-sensei shares that epigenetic control is sought for improving the precision with which iPSCs respond to differentiation cues.
▣ Professor Conklin shares that, within the Waddington landscape, identification of pluripotency states from which differentiation can be reproducibly executed is sought. Such states may not be naive pluripotency states; there is some concern regarding the sensitivity of cell fate trajectories beginning from naive pluripotency states.
▣ Post-transcriptional reprogramming enhancement is a topic of current research. Some companies are adding micro-RNAs to cocktails. Yamanaka-sensei's Gladstone lab is investigating post-transcriptional regulation on pluripotency and differentiation precision, with particular attention paid to the eukaryotic translation initiation factors gamma (elf4G) family.
Executive Summary