Goyer, M.; Deslauniers-Langevin, C.; Sonn, A.; Mansour-Nehmo, G.; Lisi, V.; Benabdallah, B.; Beauséjour, C. Induced Pluripotent Stem Cell-Derived Fibroblasts Efficiently Engage Senescence Pathways But Show Increased Sensitivity to Stress Inducers. Preprints2024, 2024041775. https://doi.org/10.20944/preprints202404.1775.v1
APA Style
Goyer, M., Deslauniers-Langevin, C., Sonn, A., Mansour-Nehmo, G., Lisi, V., Benabdallah, B., & Beauséjour, C. (2024). Induced Pluripotent Stem Cell-Derived Fibroblasts Efficiently Engage Senescence Pathways But Show Increased Sensitivity to Stress Inducers. Preprints. https://doi.org/10.20944/preprints202404.1775.v1
Chicago/Turabian Style
Goyer, M., Basma Benabdallah and Christian Beauséjour. 2024 "Induced Pluripotent Stem Cell-Derived Fibroblasts Efficiently Engage Senescence Pathways But Show Increased Sensitivity to Stress Inducers" Preprints. https://doi.org/10.20944/preprints202404.1775.v1
Abstract
The risk of malignant transformation of induced pluripotent stem cells (iPSC)-derived cells in response to DNA damage is a potential concern as the tumor suppressor genes TP53 and CDKN2A are transiently inactivated during reprogramming. Here, we evaluated the integrity of cellular senescence pathways and DNA double-strand break (DSB) repair in iPSC-derived human fibroblasts (i-HF) compared to their parental skin fibroblasts (HF). Using a variety of functional assays, we show that the capacity of i-HF to enter senescence and repair DSB is not compromised after damage induced by ionizing radiation (IR) or overexpression of H-RASV12. Still, i-HF lines are transcriptionally different from their parental lines, showing enhanced metabolic activity and higher expression of p53-related effector genes. As a result, i-HF lines generally exhibit increased sensitivity to various stresses, have an elevated senescence-associated secretory phenotype (SASP) and cannot be immortalized unless p53 expression is knocked down. In conclusion, while our results suggest that i-HF are not at a greater risk of transformation, their overall hyperactivation of senescence pathways may impede their function as a cell therapy product.
Keywords
iPSC-derived fibroblast; transformation; senescence; SASP; DNA repair
Subject
Biology and Life Sciences, Other
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
