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Article

Induced Pluripotent Stem Cell-Derived Fibroblasts Efficiently Engage Senescence Pathways but Show Increased Sensitivity to Stress Inducers

by
Marie-Lyn Goyer
1,2,
Cynthia Desaulniers-Langevin
1,2,
Anthony Sonn
1,2,
Georgio Mansour Nehmo
1,2,
Véronique Lisi
1,
Basma Benabdallah
1,
Noël J.-M. Raynal
1,2 and
Christian Beauséjour
1,2,*
1
Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
2
Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, QC H3T 1J4, Canada
*
Author to whom correspondence should be addressed.
Cells 2024, 13(10), 849; https://doi.org/10.3390/cells13100849
Submission received: 24 April 2024 / Revised: 10 May 2024 / Accepted: 13 May 2024 / Published: 16 May 2024
(This article belongs to the Special Issue Reprogrammed Cells in Disease Modeling and Drug Discovery II)
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Abstract

The risk of aberrant growth of induced pluripotent stem cell (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. Herein, we evaluate the integrity of cellular senescence pathways and DNA double-strand break (DSB) repair in Sendai virus reprogrammed iPSC-derived human fibroblasts (i-HF) compared to their parental skin fibroblasts (HF). Using transcriptomics analysis and 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 the 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 iPSC-derived fibroblast; transformation; senescence; SASP; DNA repair

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MDPI and ACS Style

Goyer, M.-L.; Desaulniers-Langevin, C.; Sonn, A.; Mansour Nehmo, G.; Lisi, V.; Benabdallah, B.; Raynal, N.J.-M.; Beauséjour, C. Induced Pluripotent Stem Cell-Derived Fibroblasts Efficiently Engage Senescence Pathways but Show Increased Sensitivity to Stress Inducers. Cells 2024, 13, 849. https://doi.org/10.3390/cells13100849

AMA Style

Goyer M-L, Desaulniers-Langevin C, Sonn A, Mansour Nehmo G, Lisi V, Benabdallah B, Raynal NJ-M, Beauséjour C. Induced Pluripotent Stem Cell-Derived Fibroblasts Efficiently Engage Senescence Pathways but Show Increased Sensitivity to Stress Inducers. Cells. 2024; 13(10):849. https://doi.org/10.3390/cells13100849

Chicago/Turabian Style

Goyer, Marie-Lyn, Cynthia Desaulniers-Langevin, Anthony Sonn, Georgio Mansour Nehmo, Véronique Lisi, Basma Benabdallah, Noël J.-M. Raynal, and Christian Beauséjour. 2024. "Induced Pluripotent Stem Cell-Derived Fibroblasts Efficiently Engage Senescence Pathways but Show Increased Sensitivity to Stress Inducers" Cells 13, no. 10: 849. https://doi.org/10.3390/cells13100849

APA Style

Goyer, M.-L., Desaulniers-Langevin, C., Sonn, A., Mansour Nehmo, G., Lisi, V., Benabdallah, B., Raynal, N. J.-M., & Beauséjour, C. (2024). Induced Pluripotent Stem Cell-Derived Fibroblasts Efficiently Engage Senescence Pathways but Show Increased Sensitivity to Stress Inducers. Cells, 13(10), 849. https://doi.org/10.3390/cells13100849

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