Dietary restriction delays but cannot heal irradiation-induced hair graying by preserving hair follicle stem cells in quiescence
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA656422 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12427681.fastq.gz | Fastqsanger.gz | |||
| SRR12427682.fastq.gz | Fastqsanger.gz | |||
| SRR12427683.fastq.gz | Fastqsanger.gz | |||
| SRR12427684.fastq.gz | Fastqsanger.gz | |||
| SRR12427685.fastq.gz | Fastqsanger.gz |
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Project description:DNA damage represents one of the cell intrinsic causes of stem cell aging, which leads to differentiation induced removal of damaged stem cells in skin and blood. Dietary restriction (DR) retards aging across various species including several strains of laboratory mice. Whether, DR has the potential to ameliorate DNA damage driven stem cell exhaustion remains incompletely understood. Here, we show that DR strongly extends the time to hair graying in response to γ–irradiation (IR) induced DNA damage of C57BL/6J mice. The study shows that DR prolongs quiescence of hair follicle stem cells (HFSCs) by silencing gene regulatory networks and metabolic switches that control proliferation and tissue regeneration. DR-mediated prolongation of HSFC quiescence blocks hair growth and prevents the depletion of HFSCs and ckit+ melanoblasts in response to IR. However, prolongation of HSFCs quiescence also leads to a suppression of DNA repair pathways and cannot prevent melanoblast loss and hair graying in the long run, when hair cycling is re- initiated even after extended periods of time. Together, these results support a model indicating that nutrient deprivation can delay but not heal DNA damage driven extinction of HFSCs and melanoblasts by stalling HSFCs in a prolonged state of quiescence coupled with inhibition of DNA repair. Disconnecting these two types of responses to DR could have the potential to delay stem cell aging.
2024-02-21 | GSE156014 | GEO
Project description:The incidence of diseases, including cancer, increases with age. While age-associated diseases with stem cell exhaustion are potentially antagonistic to cancer development1, the relationship between those is still largely unknown. Here, we report that melanocyte stem cells (McSCs) and their niche coordinately govern the antagonism between poliosis (hair graying) and melanoma. We found that McSCs undergo senescence-associated differentiation (seno-differentiation) in response to DNA double strand breaks (DSBs) such as by ionizing radiation (IR) and ageing upon their activation for self-renewal, leading to their depletion and resultant hair graying at the cost of cancer protection. RNA-seq and functional analysis of the skin exposed to different types of genotoxic stress revealed that activation of the p53-p21 axis and TBK1 pathway by DSBs within McSCs causes their depletion. Comparative analysis of the young vs. aged stem cell niche identified the KIT ligand (KITL/SCF) as a master niche factor for McSC self-renewal. Strikingly, co-exposure of the irradiated skin to carcinogens rescued hair graying by augmenting the secretory phenotype of niche cells to repress McSC seno-differentiation through the dual activation of KIT signaling and arachidonic acid pathway in McSCs. Collectively, our data provide concrete evidence for the phenotypic trade-off between ageing and cancer based on the niche.
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Project description:The exposome, an individual’s lifelong environmental exposure, profoundly impacts health. Somatic tissues undergo functional decline with age, exhibiting characteristic ageing phenotypes including hair graying and cancer. However, the specific genotoxins, signals and cellular mechanisms underlying each phenotype remain largely unknown. Here, we report that melanocyte stem cells (McSCs) and their niche coordinately determine individual stem cell fate through antagonistic, stress-responsive pathways, depending on the type of genotoxic damage incurred. McSC fate-tracking in mice revealed that McSCs undergo cellular senescence-associated differentiation (seno-differentiation) in response to DNA double-strand breaks (DSBs), resulting in their selective depletion and hair graying, and effectively protecting against melanoma. Conversely, carcinogens can suppress McSC seno-differentiation, even in DSB-harboring cells, by activating arachidonic acid metabolism and the niche-derived KIT ligand, thereby promoting McSC self-renewal. Collectively, the fate of individual stem cell clones - expansion versus exhaustion - cumulatively and antagonistically governs ageing phenotypes through interaction with the niche.
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Project description:The exposome, an individual’s lifelong environmental exposure, profoundly impacts health. Somatic tissues undergo functional decline with age, exhibiting characteristic ageing phenotypes including hair graying and cancer. However, the specific genotoxins, signals and cellular mechanisms underlying each phenotype remain largely unknown. Here, we report that melanocyte stem cells (McSCs) and their niche coordinately determine individual stem cell fate through antagonistic, stress-responsive pathways, depending on the type of genotoxic damage incurred. McSC fate-tracking in mice revealed that McSCs undergo cellular senescence-associated differentiation (seno-differentiation) in response to DNA double-strand breaks (DSBs), resulting in their selective depletion and hair graying, and effectively protecting against melanoma. Conversely, carcinogens can suppress McSC seno-differentiation, even in DSB-harboring cells, by activating arachidonic acid metabolism and the niche-derived KIT ligand, thereby promoting McSC self-renewal. Collectively, the fate of individual stem cell clones - expansion versus exhaustion - cumulatively and antagonistically governs ageing phenotypes through interaction with the niche.
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Project description:The exposome, an individual’s lifelong environmental exposure, profoundly impacts health. Somatic tissues undergo functional decline with age, exhibiting characteristic ageing phenotypes including hair graying and cancer. However, the specific genotoxins, signals and cellular mechanisms underlying each phenotype remain largely unknown. Here, we report that melanocyte stem cells (McSCs) and their niche coordinately determine individual stem cell fate through antagonistic, stress-responsive pathways, depending on the type of genotoxic damage incurred. McSC fate-tracking in mice revealed that McSCs undergo cellular senescence-associated differentiation (seno-differentiation) in response to DNA double-strand breaks (DSBs), resulting in their selective depletion and hair graying, and effectively protecting against melanoma. Conversely, carcinogens can suppress McSC seno-differentiation, even in DSB-harboring cells, by activating arachidonic acid metabolism and the niche-derived KIT ligand, thereby promoting McSC self-renewal. Collectively, the fate of individual stem cell clones - expansion versus exhaustion - cumulatively and antagonistically governs ageing phenotypes through interaction with the niche.
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Project description:The exposome, an individual’s lifelong environmental exposure, profoundly impacts health. Somatic tissues undergo functional decline with age, exhibiting characteristic ageing phenotypes including hair graying and cancer. However, the specific genotoxins, signals and cellular mechanisms underlying each phenotype remain largely unknown. Here, we report that melanocyte stem cells (McSCs) and their niche coordinately determine individual stem cell fate through antagonistic, stress-responsive pathways, depending on the type of genotoxic damage incurred. McSC fate-tracking in mice revealed that McSCs undergo cellular senescence-associated differentiation (seno-differentiation) in response to DNA double-strand breaks (DSBs), resulting in their selective depletion and hair graying, and effectively protecting against melanoma. Conversely, carcinogens can suppress McSC seno-differentiation, even in DSB-harboring cells, by activating arachidonic acid metabolism and the niche-derived KIT ligand, thereby promoting McSC self-renewal. Collectively, the fate of individual stem cell clones - expansion versus exhaustion - cumulatively and antagonistically governs ageing phenotypes through interaction with the niche.
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Project description:Hair follicle stem cell progeny heal blisters while pausing skin development
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Project description:Injury in adult tissue generally reactivates developmental programs to foster regeneration, but it is not known whether this paradigm applies to growing tissue. Here, by employing blisters, we show that epidermal wounds heal at the expense of skin development. The regenerated epidermis suppresses the expression of tissue morphogenesis genes accompanied by delayed hair follicle (HF) growth. Lineage tracing experiments, cell proliferation dynamics, and mathematical modeling reveal that the progeny of HF junctional zone stem cells, which undergo a morphological transformation, repair the blisters while not promoting HF development. In contrast, the contribution of interfollicular stem cell progeny to blister healing is small. These findings demonstrate that tissue development can be sacrificed for the sake of wound regeneration and suggest that tissue repair does not coincide with the reactivation of developmental programs in all regenerative contexts. Our study elucidates the key cellular mechanism of wound healing in skin blistering diseases.
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Project description:A better understanding of human melanocyte and melanocyte stem cell (McSC) biology is essential for treating melanocyte-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate the SASH1 function in melanocyte lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical exams, human cell assays, yeast two-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. We identified SASH1 as a novel regulator in McSC maintenance and discovered that TNKS2 is crucial for SASH1’s role in vitro. Additionally, the S519N variant is located in one of multiple tankyrase binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder showcases accelerated aging in human McSC, linking both gain and loss of pigmentation to McSC dysfunction in the same individuals. The findings offer new insights into the roles of SASH1 and TNKS2 in McSC maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with skin disorders should include an assessment and history of hair pigmentation loss.
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Project description:Antagonistic stem cell fate under stress governs decisions between hair graying and melanoma
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