Non-autonomous induction of epithelial lineage infidelity and hyperplasia by DNA damage

ABSTRACTSeveral epithelial tissues contain stem cell reserves to replenish cells lost during normal homeostasis or upon injury. However, how epithelial tissues respond to distinct types of damage, and how stem cell plasticity and proliferation are regulated in these contexts, remain poorly understood. Here, we reveal that genotoxic agents, but not mechanical damage, induce hyperplasia and lineage infidelity in three related epithelial tissues: the mammary gland, interfollicular epidermis and hair follicle. Furthermore, DNA damage also promotes stromal proliferation. In the mammary gland, we find that DNA damage activates multipotency within the myoepithelial population and hyper-proliferation of their luminal progeny, resulting in tissue disorganization. Additionally, in epidermal and hair follicle epithelia, DNA damage induces basal cell hyperplasia with the formation of abnormal, multi-layered K14+/K10+ cells. This behavior does not involve apoptosis or immunity, and is epithelial cell non-autonomous; stromal fibroblasts are both necessary and sufficient to induce the epithelial response. Thus, genotoxic agents that are used chemotherapeutically to promote cancer cell death can have the opposite effect on wild-type epithelial tissue, paradoxically promoting hyperplasia and inducing both stemness and lineage infidelity.

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PBX1 Attenuates Hair Follicle-Derived Mesenchymal Stem Cell Senescence and Apoptosis by Alleviating Reactive Oxygen Species-Mediated DNA Damage Instead of Enhancing DNA Damage Repair

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.739868 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuan Wang ◽

Yutong Sui ◽

Aobo Lian ◽

Xing Han ◽

Feilin Liu ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Stem Cells ◽

Dna Damage ◽

Dna Repair ◽

Stem Cell ◽

Hair Follicle ◽

Cellular Senescence ◽

Cell Senescence ◽

Oxygen Species ◽

Age Related

Tissues and organs undergo structural deterioration and functional decline during aging. DNA damage is considered a major cause of stem cell senescence. Although stem cells develop sophisticated DNA repair systems, when the intrinsic and extrinsic insults exceed the DNA repair capacity, cellular senescence, and age-related diseases inevitably occur. Therefore, the prevention and alleviation of DNA damage is an alternative to DNA repair in attenuating stem cell senescence and preventing age-related diseases. Pre-B-cell leukaemia homeobox 1 (PBX1) participates in maintaining the pluripotency of human embryonic and haematopoietic stem cells. Our recent studies showed that PBX1 promotes hair follicle-derived mesenchymal stem cell (HF-MSC) proliferation, decreases cellular senescence and apoptosis, and enhances induced pluripotent stem cell generation. Whether PBX1 attenuates HF-MSC senescence and apoptosis by alleviating DNA damage or by enhancing DNA repair remains unknown. In this study, we aimed to determine the effects of PBX1 on the intrinsic ROS or extrinsic H2O2-induced cellular senescence of HF-MSCs. To this end, we generated HF-MSCs overexpressing either PBX1, or poly (ADP-ribose) polymerase 1, or both. Our results showed that PBX1 overexpression attenuates HF-MSC senescence and apoptosis by alleviating reactive oxygen species (ROS)-mediated DNA damage instead of enhancing DNA repair. This is the first study to report that PBX1 attenuates stem cell senescence and apoptosis by alleviating DNA damage. It provides new insight into the mechanism of stem cell senescence and lays the foundation for the development of strategies for age-related disease prevention and treatment, and in particular, hair follicle repair and regeneration.

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The 1996 Veylien Henderson Award of the Society of Toxicology of Canada. Current concepts: neutrophils and the activation of carcinogens in the breast and other organs

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y98-083 ◽

1998 ◽

Vol 76 (7-8) ◽

pp. 693-700 ◽

Cited By ~ 10

Author(s):

P David Josephy ◽

Brenda L Coomber

Keyword(s):

Mammary Gland ◽

Epithelial Cells ◽

Chemical Carcinogenesis ◽

Reactive Species ◽

Epithelial Tissue ◽

Chemical Carcinogens ◽

Tissue Inflammation ◽

Epithelial Tissues

Many chemical carcinogens target epithelial tissues, but the biological and biochemical bases of carcinogen specificity remain largely unknown. Focusing on the mammary gland, we discuss the concept that neutrophils metabolize carcinogens to reactive species that damage adjacent epithelial cells. This mechanism may help to explain why epithelial cells are sensitive targets for chemical carcinogenesis, despite their limited bioactivation capacity.Key words: carcinogenesis, neutrophil, bioactivation, peroxidase, epithelial tissue, inflammation.

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The effect of bromocriptine on mammary-gland ultrastructure of hyperprolactinemic rats

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100111136 ◽

1984 ◽

Vol 42 ◽

pp. 204-205

Author(s):

I.C. Murray

Keyword(s):

Mammary Gland ◽

Dopamine Agonist ◽

Alveolar Epithelium ◽

Mammary Glands ◽

Female Rats ◽

Control Group ◽

Cell Hyperplasia ◽

Once Daily ◽

Long Evans

In women, hyperprolactinemia is often due to a prolactin (PRL)-secreting adenoma or PRL cell hyperplasia. RRL excess stimulates the mammary glands and causes proliferation of the alveolar epithelium. Bromocriptine, a dopamine agonist, inhibits PRL secretion and is given to women to treat nonpuerperal galactorrhea. Old female rats have been reported to have PRL cell hyperplasia or adenoma leading to PRL hypersecretion and breast stimulation. Herein, we describe the effect of bromocriptine and consequently the reduction in serum PRL levels on the ultrastructure of rat mammary glands.Female Long-Evans rats, 23 months of age, were divided into control and bromocriptine-treated groups. The control animals were injected subcutaneously once daily with a 10% ethanol vehicle and were later divided into a normoprolactinemic control group with serum PRL levels under 30 ng/ml and a hyperprolactinemic control group with serum PRL levels above 30 ng/ml.

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