A p38 MAPK-ROS axis fuels proliferation stress and DNA damage during CRISPR-Cas9 gene editing in hematopoietic stem and progenitor cells

Cell Reports Medicine, Год журнала: 2024, Номер 5(11), С. 101823 - 101823

Опубликована: Ноя. 1, 2024

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 CRISPR-Cas9-induced double-strand breaks, enhancing reconstitution capacity edited HSPCs. However, this results in lower HDR efficiency, rendering ex necessary yet detrimental. Mechanistically, triggers multi-step process initiated p38 mitogen-activated protein kinase (MAPK) phosphorylation, which generates mitogenic reactive oxygen species (ROS), promoting fast cell-cycle progression subsequent proliferation-induced damage. Thus, inhibition before delays G1/S transition expands transcriptionally defined HSCs, ultimately endowing cells with superior multi-lineage differentiation, persistence throughout serial transplantation, enhanced polyclonal repertoire, better-preserved genome integrity. Our data identify proliferative stress as driver HSPC dysfunction fundamental implications designing more effective safer correction strategies

Язык: Английский

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Design principles of gene circuits for longevity

Trends in Cell Biology, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

HighlightsSystems-level approaches complement static insights by revealing how gene regulatory networks (GRNs) dynamically regulate cellular aging and promote longevity.Observing the dynamics of heme biosynthesis nucleolar silencing in budding yeast reveals distinct modes, synthetic biology can significantly extend lifespan.Negative feedback loops aging-related processes such as proteostasis, energy metabolism, DNA damage response pathways maintain homeostasis counteract deterioration.Synthetic offers potential interventions to reinforce circuits, thereby mitigating age-related diseases promoting healthy aging.AbstractAging is a dynamic process that driven disruption homeostatic (GRNs). Traditional studies often focus on individual genes, but understanding their interplay key unraveling mechanisms aging. This review explores circuits influence longevity highlights role maintaining balance. The SIR2–HAP circuit serves model explore mutual inhibition between influences trajectories engineering stable fixed points or oscillations within these lifespan. Feedback crucial for are also reviewed, we highlight destabilization accelerates By leveraging systems biology, strategies proposed may stabilize single cells, enhancing resilience damage.

Язык: Английский

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Engineered stem cells by emerging biomedical stratagems

Science Bulletin, Год журнала: 2023, Номер 69(2), С. 248 - 279

Опубликована: Дек. 4, 2023

Язык: Английский

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Alginate-polylysine-alginate (APA) microencapsulated transgenic human amniotic epithelial cells ameliorate fibrosis in hypertrophic scars

Inflammation Research, Год журнала: 2025, Номер 74(1)

Опубликована: Янв. 25, 2025

Язык: Английский

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Editorial to the Special Issue “Retinopathies: A Challenge for Early Diagnosis, Innovative Treatments, and Reliable Follow-Up”

Medicina, Год журнала: 2025, Номер 61(4), С. 662 - 662

Опубликована: Апрель 3, 2025

The Special Issue “Retinopathies: A Challenge for Early Diagnosis, Innovative Treatments, and Reliable Follow-Up” brings together a diverse yet interconnected collection of research papers that collectively address the multifaceted challenges retinal diseases [...]

Язык: Английский

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The View from a Milestone in Gene Therapy

New England Journal of Medicine, Год журнала: 2025, Номер 392(17), С. 1745 - 1746

Опубликована: Май 1, 2025

Язык: Английский

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Stem cell heterogeneity, plasticity, and regulation

Life Sciences, Год журнала: 2023, Номер 334, С. 122240 - 122240

Опубликована: Ноя. 2, 2023

Язык: Английский

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Tissue‐Penetrating Ultrasound‐Triggered Hydrogel for Promoting Microvascular Network Reconstruction

Advanced Science, Год журнала: 2024, Номер 11(23)

Опубликована: Апрель 10, 2024

Abstract The microvascular network plays an important role in providing nutrients to the injured tissue and exchanging various metabolites. However, how achieve efficient penetration of is bottleneck restricting reconstruction network. Herein, hydrogel precursor solution can efficiently penetrate damaged area, ultrasound triggers release thrombin from liposomes hydrolyze fibrinogen, forming a fibrin solid situ with calcium ions transglutaminase as catalysts, effectively solving impedance tissues ultimately significantly promoting formation networks within tissues. First, fibrinogen complex permeated into tissue. Second, triggered thrombin, activates transglutaminase, hydrolyzes fibrinogen. Third, monomers are catalyzed form hydrogels area. In vitro studies have shown that penetrated artificial bone 15 s after ultrasonic triggering, formed continuous triggering for 30 s. Overall, this innovative strategy solved problem resistance ultrasound‐triggered tissues, finally regeneration.

Язык: Английский

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Mobilization-based engraftment of haematopoietic stem cells: a new perspective for chemotherapy-free gene therapy and transplantation

British Medical Bulletin, Год журнала: 2023, Номер 147(1), С. 108 - 120

Опубликована: Июнь 30, 2023

In haematopoietic stem cell transplantation (HSCT), cells (HSCs) from a healthy donor replace the patient's ones. Ex vivo HSC gene therapy (HSC-GT) is form of HSCT in which HSCs, usually an autologous source, are genetically modified before infusion, to generate progeny gene-modified cells. and HSC-GT, chemotherapy administered infusion free space bone marrow (BM) niche, required for engraftment infused Here, we review alternative chemotherapy-free approaches niche voidance that could conventional regimens alleviate morbidity procedure.Literature was reviewed PubMed-listed peer-reviewed articles. No new data presented this article.Chemotherapy exerts short long-term toxicity non-haematopoietic organs. Whenever solely used allow rather than eliminating malignant cells, as case HSC-GT inborn genetic diseases, non-genotoxic sparing off-target tissues highly desirable.In principle, HSCs can be temporarily moved BM niches using mobilizing drugs or selectively cleared with targeted antibodies immunotoxins make However, translation these principles into clinically relevant settings only at beginning, whether therapeutically meaningful levels chimerism safely established remains determined.In pre-clinical models, mobilization tailored accommodate exchange Infused further endowed transient advantage.Inter-individual efficiency kinetics need carefully assessed. Investigations large animal models emerging will strengthen rationale encourage application treatment selected diseases.

Язык: Английский

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Nanotherapeutics for Macrophage Network Modulation in Tumor Microenvironments: Targets and Tools

International Journal of Nanomedicine, Год журнала: 2024, Номер Volume 19, С. 13615 - 13651

Опубликована: Дек. 1, 2024

Macrophage is an important component in the tumor immune microenvironment, which exerts significant influence on development and metastasis. Due to their dual nature of promoting suppressing inflammation, macrophages can serve as both targets for immunotherapy tools treating malignancies. However, abundant infiltration tumor-associated dominated by immunosuppressive phenotype maintains a pro-tumor engineering using nanotechnology manipulate microenvironment represent feasible approach cancer immunotherapy. Additionally, considering phagocytic specifically tumor-targeting capabilities M1 macrophages, manipulated through cellular nanotechnology, well macrophage-derived exosomes macrophage membranes, also become effective treatment. In conclusion, nanotherapeutics targeting remains immense potential macrophage-mediated treatment methods will further enhance our understanding, diagnosis, various malignants.

Язык: Английский

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