Limits...
A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres.

Flores I, Blasco MA - PLoS ONE (2009)

Bottom Line: Telomere maintenance is essential to ensure proper size and function of organs with a high turnover.In particular, a dwarf phenotype as well as phenotypes associated to premature loss of tissue regeneration, including the skin (hair loss, hair graying, decreased wound healing), are found in mice deficient for telomerase, the enzyme responsible for maintaining telomere length.Together, these findings indicate the existence of a p53-dependent senescence response acting on stem/progenitor cells with dysfunctional telomeres that is actively limiting their contribution to tissue regeneration, thereby impinging on tissue fitness.

View Article: PubMed Central - PubMed

Affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.

ABSTRACT
Telomere maintenance is essential to ensure proper size and function of organs with a high turnover. In particular, a dwarf phenotype as well as phenotypes associated to premature loss of tissue regeneration, including the skin (hair loss, hair graying, decreased wound healing), are found in mice deficient for telomerase, the enzyme responsible for maintaining telomere length. Coincidental with the appearance of these phenotypes, p53 is found activated in several tissues from these mice, where is thought to trigger cellular senescence and/or apoptotic responses. Here, we show that p53 abrogation rescues both the small size phenotype and restitutes the functionality of epidermal stem cells (ESC) of telomerase-deficient mice with dysfunctional telomeres. In particular, p53 ablation restores hair growth, skin renewal and wound healing responses upon mitogenic induction, as well as rescues ESCmobilization defects in vivo and defective ESC clonogenic activity in vitro. This recovery of ESC functions is accompanied by a downregulation of senescence markers and an increased proliferation in the skin and kidney of telomerase-deficient mice with critically short telomeres without changes in apoptosis rates. Together, these findings indicate the existence of a p53-dependent senescence response acting on stem/progenitor cells with dysfunctional telomeres that is actively limiting their contribution to tissue regeneration, thereby impinging on tissue fitness.

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p53 deletion rescues epidermal and hair growth responses in late-generation telomerase-deficient mice.(A) Wound healing of wild-type, G3 Terc−/− and G3 Terc−/−p53−/− skin. (B) Percentage of initial wound area left at the indicated days after the punch was created. Three wounds were created per mouse, and the total number of wounds per genotype is indicated in the graph (n). (C) Statistical analysis showing that the healing rate is significantly different between genotypes is also shown (p-values). Bottom: Representative images of wounds 4 days after the first wound was made (1, 2 and 3 in the figure correspond to the first, second and third wound at 4, 2 and 0 days, respectively, after the first wound was created). (D) Representative tail-skin sections from wild-type, G3 Terc−/− and G3 Terc−/−p53−/− littermates before and after TPA-treatment. Continuous black double-point arrows mark inter-follicular (IFE) thickness. Black dashes double-point arrows mark hair follicle (HF) length. (E) Quantification of the HF length (bottom) and IFE thickness (top). Histomorphometry was performed in three mice of each genotype (n), quantifying 30 hair follicles (HF) per group. Note the increased HF length and epidermis thickness in TPA-treated wild-type and G3 Terc−/−p53−/− mice, compared with a defective response in TPA-treated G3 Terc−/− animals. Scale bar, 50 µm.
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pone-0004934-g001: p53 deletion rescues epidermal and hair growth responses in late-generation telomerase-deficient mice.(A) Wound healing of wild-type, G3 Terc−/− and G3 Terc−/−p53−/− skin. (B) Percentage of initial wound area left at the indicated days after the punch was created. Three wounds were created per mouse, and the total number of wounds per genotype is indicated in the graph (n). (C) Statistical analysis showing that the healing rate is significantly different between genotypes is also shown (p-values). Bottom: Representative images of wounds 4 days after the first wound was made (1, 2 and 3 in the figure correspond to the first, second and third wound at 4, 2 and 0 days, respectively, after the first wound was created). (D) Representative tail-skin sections from wild-type, G3 Terc−/− and G3 Terc−/−p53−/− littermates before and after TPA-treatment. Continuous black double-point arrows mark inter-follicular (IFE) thickness. Black dashes double-point arrows mark hair follicle (HF) length. (E) Quantification of the HF length (bottom) and IFE thickness (top). Histomorphometry was performed in three mice of each genotype (n), quantifying 30 hair follicles (HF) per group. Note the increased HF length and epidermis thickness in TPA-treated wild-type and G3 Terc−/−p53−/− mice, compared with a defective response in TPA-treated G3 Terc−/− animals. Scale bar, 50 µm.

Mentions: The skin is one of the tissues where the pro-aging effects of short telomeres are more clearly visible in the context of telomerase-deficient mice [27]. In particular third generation (G3) Terc−/− mice show a delay in wound closure and a stunted hair growth response after mitogen induction [9], [27]. These skin defects are further aggravated at old ages leading to severe premature alopecia and hair graying in late generation Terc−/− [27]. Here, we set to address whether p53 activation in response to short telomeres contributes to defective skin and hair regeneration by limiting ESC functionality. To this end, we generated increasing generations of mice doubly deficient for Terc and p53 reaching third generation (G3) Terc−/−p53−/− mice, as well as the corresponding G3 Terc−/−p53+/+ littermate controls (see Methods for breeding strategies). First, we assessed the role of p53 in the impaired wound healing response associated to critically short telomeres [27] To this end, three consecutive punch biopsies were performed on dorsal skin of age-matched (2-months old) G3 Terc−/−p53−/− and G3 Terc−/−p53+/+ littermates, as well as wild-type controls (Methods). The rate of wound healing was monitored as the percentage of the initial wound area left open at different times after the wound was made (Methods). One wound was created 2 days after the other and the animals were killed 6 days after the last wound was made. As previously reported for middle-age telomerase-deficient mice, young G3 Terc−/−p53+/+ mice exhibited a delay in wound closure (Fig. 1a–c), with average wound areas at day 3 of 26% and 67% for wild type mice and G3 Terc−/−p53+/+ mice, respectively (p = 0.013) and 6% and 43% for wild type mice and G3 Terc−/−p53+/+ mice, respectively at day 6 (p<0.001; Fig. 1a–c). Interestingly, we observed a partial recovery to normal wound healing rates in the case of G3 Terc−/−p53−/−. At day 3, only 46% of the initial wound area persists, which is further decreased to 17% three days later (Fig. 1a–c). Taken together, these results indicate that the skin of G3 Terc−/−p53−/− mice presents a faster wound-healing rate than that of the corresponding G3 Terc−/−p53+/+ littermates, supporting an inhibitory effect of p53 in the wound healing process in mice with short telomeres.


A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres.

Flores I, Blasco MA - PLoS ONE (2009)

p53 deletion rescues epidermal and hair growth responses in late-generation telomerase-deficient mice.(A) Wound healing of wild-type, G3 Terc−/− and G3 Terc−/−p53−/− skin. (B) Percentage of initial wound area left at the indicated days after the punch was created. Three wounds were created per mouse, and the total number of wounds per genotype is indicated in the graph (n). (C) Statistical analysis showing that the healing rate is significantly different between genotypes is also shown (p-values). Bottom: Representative images of wounds 4 days after the first wound was made (1, 2 and 3 in the figure correspond to the first, second and third wound at 4, 2 and 0 days, respectively, after the first wound was created). (D) Representative tail-skin sections from wild-type, G3 Terc−/− and G3 Terc−/−p53−/− littermates before and after TPA-treatment. Continuous black double-point arrows mark inter-follicular (IFE) thickness. Black dashes double-point arrows mark hair follicle (HF) length. (E) Quantification of the HF length (bottom) and IFE thickness (top). Histomorphometry was performed in three mice of each genotype (n), quantifying 30 hair follicles (HF) per group. Note the increased HF length and epidermis thickness in TPA-treated wild-type and G3 Terc−/−p53−/− mice, compared with a defective response in TPA-treated G3 Terc−/− animals. Scale bar, 50 µm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2654505&req=5

pone-0004934-g001: p53 deletion rescues epidermal and hair growth responses in late-generation telomerase-deficient mice.(A) Wound healing of wild-type, G3 Terc−/− and G3 Terc−/−p53−/− skin. (B) Percentage of initial wound area left at the indicated days after the punch was created. Three wounds were created per mouse, and the total number of wounds per genotype is indicated in the graph (n). (C) Statistical analysis showing that the healing rate is significantly different between genotypes is also shown (p-values). Bottom: Representative images of wounds 4 days after the first wound was made (1, 2 and 3 in the figure correspond to the first, second and third wound at 4, 2 and 0 days, respectively, after the first wound was created). (D) Representative tail-skin sections from wild-type, G3 Terc−/− and G3 Terc−/−p53−/− littermates before and after TPA-treatment. Continuous black double-point arrows mark inter-follicular (IFE) thickness. Black dashes double-point arrows mark hair follicle (HF) length. (E) Quantification of the HF length (bottom) and IFE thickness (top). Histomorphometry was performed in three mice of each genotype (n), quantifying 30 hair follicles (HF) per group. Note the increased HF length and epidermis thickness in TPA-treated wild-type and G3 Terc−/−p53−/− mice, compared with a defective response in TPA-treated G3 Terc−/− animals. Scale bar, 50 µm.
Mentions: The skin is one of the tissues where the pro-aging effects of short telomeres are more clearly visible in the context of telomerase-deficient mice [27]. In particular third generation (G3) Terc−/− mice show a delay in wound closure and a stunted hair growth response after mitogen induction [9], [27]. These skin defects are further aggravated at old ages leading to severe premature alopecia and hair graying in late generation Terc−/− [27]. Here, we set to address whether p53 activation in response to short telomeres contributes to defective skin and hair regeneration by limiting ESC functionality. To this end, we generated increasing generations of mice doubly deficient for Terc and p53 reaching third generation (G3) Terc−/−p53−/− mice, as well as the corresponding G3 Terc−/−p53+/+ littermate controls (see Methods for breeding strategies). First, we assessed the role of p53 in the impaired wound healing response associated to critically short telomeres [27] To this end, three consecutive punch biopsies were performed on dorsal skin of age-matched (2-months old) G3 Terc−/−p53−/− and G3 Terc−/−p53+/+ littermates, as well as wild-type controls (Methods). The rate of wound healing was monitored as the percentage of the initial wound area left open at different times after the wound was made (Methods). One wound was created 2 days after the other and the animals were killed 6 days after the last wound was made. As previously reported for middle-age telomerase-deficient mice, young G3 Terc−/−p53+/+ mice exhibited a delay in wound closure (Fig. 1a–c), with average wound areas at day 3 of 26% and 67% for wild type mice and G3 Terc−/−p53+/+ mice, respectively (p = 0.013) and 6% and 43% for wild type mice and G3 Terc−/−p53+/+ mice, respectively at day 6 (p<0.001; Fig. 1a–c). Interestingly, we observed a partial recovery to normal wound healing rates in the case of G3 Terc−/−p53−/−. At day 3, only 46% of the initial wound area persists, which is further decreased to 17% three days later (Fig. 1a–c). Taken together, these results indicate that the skin of G3 Terc−/−p53−/− mice presents a faster wound-healing rate than that of the corresponding G3 Terc−/−p53+/+ littermates, supporting an inhibitory effect of p53 in the wound healing process in mice with short telomeres.

Bottom Line: Telomere maintenance is essential to ensure proper size and function of organs with a high turnover.In particular, a dwarf phenotype as well as phenotypes associated to premature loss of tissue regeneration, including the skin (hair loss, hair graying, decreased wound healing), are found in mice deficient for telomerase, the enzyme responsible for maintaining telomere length.Together, these findings indicate the existence of a p53-dependent senescence response acting on stem/progenitor cells with dysfunctional telomeres that is actively limiting their contribution to tissue regeneration, thereby impinging on tissue fitness.

View Article: PubMed Central - PubMed

Affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.

ABSTRACT
Telomere maintenance is essential to ensure proper size and function of organs with a high turnover. In particular, a dwarf phenotype as well as phenotypes associated to premature loss of tissue regeneration, including the skin (hair loss, hair graying, decreased wound healing), are found in mice deficient for telomerase, the enzyme responsible for maintaining telomere length. Coincidental with the appearance of these phenotypes, p53 is found activated in several tissues from these mice, where is thought to trigger cellular senescence and/or apoptotic responses. Here, we show that p53 abrogation rescues both the small size phenotype and restitutes the functionality of epidermal stem cells (ESC) of telomerase-deficient mice with dysfunctional telomeres. In particular, p53 ablation restores hair growth, skin renewal and wound healing responses upon mitogenic induction, as well as rescues ESCmobilization defects in vivo and defective ESC clonogenic activity in vitro. This recovery of ESC functions is accompanied by a downregulation of senescence markers and an increased proliferation in the skin and kidney of telomerase-deficient mice with critically short telomeres without changes in apoptosis rates. Together, these findings indicate the existence of a p53-dependent senescence response acting on stem/progenitor cells with dysfunctional telomeres that is actively limiting their contribution to tissue regeneration, thereby impinging on tissue fitness.

Show MeSH
Related in: MedlinePlus