ArticleCell reports. Medicine2024
A p38 MAPK-ROS axis fuels proliferation stress and DNA damage during CRISPR-Cas9 gene editing in hematopoietic stem and progenitor cells.
Article in Cell reports. Medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Adaptor-mediated rewiring of FLT3 signaling engages p38 MAPK to sustain gilteritinib resistance in acute myeloid leukemia.Leukemia · 2026Article
- In-depth characterization of stem cell potency and genotoxicity for clinical-scaleMolecular therapy. Advances · 2026Article
- Ex vivo expansion of hematopoietic stem and progenitor cells from human mobilized peripheral blood for gene therapy applications.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Inhibition of inflammation and senescence with azole compound C7 enables expansion of hematopoietic stem and progenitor cells.Stem cells translational medicine · 2026Article
- Fate Bifurcation of Cellular Senescence: Dynamic Regulation from Tumor Suppression to Recurrence Risk.Cells · 2026Review
- Zfp36l1 Inhibits DNA Damage by Regulating p21-E2F1-Rad51 Signaling During Myogenic Differentiation.International journal of molecular sciences · 2026Article
- Nanoengineered 3D culture substrate enables superior persistence and polyclonal engraftment of genetically engineered hematopoietic stem cells.Cell stem cell · 2026Article
- Molecular and phenotypic blueprint of human hematopoiesis links proliferation stress to stem cell aging.The Journal of experimental medicine · 2026Article
- Depleted uranium exposure induced ferroptosis in renal cells via the ETHE1/P38-MAPK pathway.Archives of toxicology · 2026Article
- 5G RF-EMFs Mitigate UV-Induced Genotoxic Stress Through Redox Balance and p38 Pathway Regulation in Skin Cells.Antioxidants (Basel, Switzerland) · 2026Article
- Stathmin-mediated autophagy drives the differentiation of dermal fibroblast into myofibroblast under TGFβ1 stimulation.Molecular biology reports · 2025Article
- 7,8-dihydroxyflavone attenuates NIH IIIA subtype chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) via TrkB/AKT/SIRT3 signaling activation.Translational andrology and urology · 2025Article
- Metabolic-Electrophysiological Coupling in Heart Failure: from Bidirectional Decoupling to Therapeutic Recoupling.Current heart failure reports · 2025Review
- Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells.Cell reports. Medicine · 2025Article
- Donor insertion into CX3CR1 allows epigenetic modulation of a constitutive promoter on hematopoietic stem cells and its activation upon myeloid differentiation.Nucleic acids research · 2025Article
- The future of ex vivo hematopoietic stem cell gene editing: what's next.Regenerative medicineArticle
Corrections and comments
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Authors and funding
24 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ex vivo activation is a prerequisite to reaching adequate levels of gene editing by homology-directed repair (HDR) for hematopoietic stem and progenitor cell (HSPC)-based clinical applications. Here, we show that shortening culture time mitigates the p53-mediated DNA damage response to CRISPR-Cas9-induced DNA double-strand breaks, enhancing the reconstitution capacity of edited HSPCs. However, this results in lower HDR efficiency, rendering ex vivo culture necessary yet detrimental. Mechanistically, ex vivo activation triggers a multi-step process initiated by p38 mitogen-activated protein kinase (MAPK) phosphorylation, which generates mitogenic reactive oxygen species (ROS), promoting fast cell-cycle progression and subsequent proliferation-induced DNA damage. Thus, p38 inhibition before gene editing delays G1/S transition and expands transcriptionally defined HSCs, ultimately endowing edited cells with superior multi-lineage differentiation, persistence throughout serial transplantation, enhanced polyclonal repertoire, and better-preserved genome integrity. Our data identify proliferative stress as a driver of HSPC dysfunction with fundamental implications for designing more effective and safer gene correction strategies for clinical applications.
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