TY - JOUR
T1 - A versatile polypharmacology platform promotes cytoprotection and viability of human pluripotent and differentiated cells
AU - Chen, Yu
AU - Tristan, Carlos A.
AU - Chen, Lu
AU - Jovanovic, Vukasin M.
AU - Malley, Claire
AU - Chu, Pei Hsuan
AU - Ryu, Seungmi
AU - Deng, Tao
AU - Ormanoglu, Pinar
AU - Tao, Dingyin
AU - Fang, Yuhong
AU - Slamecka, Jaroslav
AU - Hong, Hyenjong
AU - LeClair, Christopher A.
AU - Michael, Sam
AU - Austin, Christopher P.
AU - Simeonov, Anton
AU - Singeç, Ilyas
N1 - Publisher Copyright:
© 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - Human pluripotent stem cells (hPSCs) are capable of extensive self-renewal yet remain highly sensitive to environmental perturbations in vitro, posing challenges to their therapeutic use. There is an urgent need to advance strategies that ensure safe and robust long-term growth and functional differentiation of these cells. Here, we deployed high-throughput screening strategies to identify a small-molecule cocktail that improves viability of hPSCs and their differentiated progeny. The combination of chroman 1, emricasan, polyamines, and trans-ISRIB (CEPT) enhanced cell survival of genetically stable hPSCs by simultaneously blocking several stress mechanisms that otherwise compromise cell structure and function. CEPT provided strong improvements for several key applications in stem-cell research, including routine cell passaging, cryopreservation of pluripotent and differentiated cells, embryoid body (EB) and organoid formation, single-cell cloning, and genome editing. Thus, CEPT represents a unique poly-pharmacological strategy for comprehensive cytoprotection, providing a rationale for efficient and safe utilization of hPSCs.
AB - Human pluripotent stem cells (hPSCs) are capable of extensive self-renewal yet remain highly sensitive to environmental perturbations in vitro, posing challenges to their therapeutic use. There is an urgent need to advance strategies that ensure safe and robust long-term growth and functional differentiation of these cells. Here, we deployed high-throughput screening strategies to identify a small-molecule cocktail that improves viability of hPSCs and their differentiated progeny. The combination of chroman 1, emricasan, polyamines, and trans-ISRIB (CEPT) enhanced cell survival of genetically stable hPSCs by simultaneously blocking several stress mechanisms that otherwise compromise cell structure and function. CEPT provided strong improvements for several key applications in stem-cell research, including routine cell passaging, cryopreservation of pluripotent and differentiated cells, embryoid body (EB) and organoid formation, single-cell cloning, and genome editing. Thus, CEPT represents a unique poly-pharmacological strategy for comprehensive cytoprotection, providing a rationale for efficient and safe utilization of hPSCs.
UR - http://www.scopus.com/inward/record.url?scp=85105154010&partnerID=8YFLogxK
U2 - 10.1038/s41592-021-01126-2
DO - 10.1038/s41592-021-01126-2
M3 - Article
C2 - 33941937
AN - SCOPUS:85105154010
SN - 1548-7091
VL - 18
SP - 528
EP - 541
JO - Nature Methods
JF - Nature Methods
IS - 5
ER -