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. 2018 Oct;17(5):e12834.
doi: 10.1111/acel.12834. Epub 2018 Aug 20.

Adult Sox2+ Stem Cell Exhaustion in Mice Results in Cellular Senescence and Premature Aging

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Free PMC article

Adult Sox2+ Stem Cell Exhaustion in Mice Results in Cellular Senescence and Premature Aging

Jéssica M Vilas et al. Aging Cell. .
Free PMC article

Abstract

Aging is characterized by a gradual functional decline of tissues with age. Adult stem and progenitor cells are responsible for tissue maintenance, repair, and regeneration, but during aging, this population of cells is decreased or its activity is reduced, compromising tissue integrity and causing pathologies that increase vulnerability, and ultimately lead to death. The causes of stem cell exhaustion during aging are not clear, and whether a reduction in stem cell function is a cause or a consequence of aging remains unresolved. Here, we took advantage of a mouse model of induced adult Sox2+ stem cell depletion to address whether accelerated stem cell depletion can promote premature aging. After a short period of partial repetitive depletion of this adult stem cell population in mice, we observed increased kyphosis and hair graying, and reduced fat mass, all of them signs of premature aging. It is interesting that cellular senescence was identified in kidney after this partial repetitive Sox2+ cell depletion. To confirm these observations, we performed a prolonged protocol of partial repetitive depletion of Sox2+ cells, forcing regeneration from the remaining Sox2+ cells, thereby causing their exhaustion. Senescence specific staining and the analysis of the expression of genetic markers clearly corroborated that adult stem cell exhaustion can lead to cellular senescence induction and premature aging.

Keywords: Sox2; adult stem cells; aging; stem cell exhaustion.

Figures

Figure 1
Figure 1
Short repetitive partial depletion of Sox2+ cells leads to defective growth and induction of senescence in mice. (a) Schematic representation of the repetitive partial depletion protocol in mice by intraperitoneal injection of GCV starting at 8 weeks, every 2 weeks, and until mice were 34 weeks. After treatment, mice were sacrificed at 36 weeks of age. (b) Body mass increase (g) in male (upper graph; n = 13) and female (lower graph; n = 11) control mice (Sox2WT; n = 8) or Sox2‐TK transgenic mice (Sox2TK; n = 16) treated with GCV along the experiment. (c) Quantification of animals (percentage, %) showing evident signs of kyphosis after GCV treatment. (d) Quantification of animals (percentage, %) showing evident signs of hair graying after GCV treatment. (e) SAbetaGal staining of kidney sections from control wild‐type (Sox2WT) and Sox2‐TK transgenic (Sox2TK) animals after GCV treatment. (f) Quantification of the number of SAbetaGal positive cells observed in stained kidney sections. (g) Chemiluminescence quantification of SAbetaGal activity using Galacton as a substrate. (h) Quantification of mRNA expression by QPCR of Ink4a, Mmp3 and Serpine1 in kidneys from control wild‐type (Sox2WT) and Sox2‐TK transgenic (Sox2TK) animals. Results are presented as mean ± SD. ***p < 0.001, **p < 0.01,*p < 0.05, n.s. nonsignificant
Figure 2
Figure 2
Prolonged repetitive partial depletion of Sox2+ cells leads to induction of senescence and premature mice. (a) Schematic representation of the prolonged repetitive partial depletion protocol in mice by intraperitoneal injection of GCV starting at 8 weeks, every 2 weeks, and until mice were 54 weeks. After treatment, mice were sacrificed at 56 weeks of age. (b) Quantification of body mass (g) in Sox2‐TK transgenic animals after GCV (n = 5) or vehicle (HBSS; n = 2) treatment. (c) Quantification of relative body mass composition (% of fat and lean mass) in Sox2‐TK transgenic animals after GCV or vehicle (HBSS) treatment. (d) SAbetaGal staining of kidney sections from Sox2‐TK transgenic animals after GCV or vehicle (HBSS) treatment. (e) Quantification of the number of SAbetaGal positive cells observed in d. (f) Chemiluminescence quantification of SAbetaGal activity using Galacton as a substrate. (g) Quantification of mRNA expression by QPCR of Ink4a, Ink4b, Il6, Mmp1, Serpine1, and Timp1 in kidneys from Sox2‐TK transgenic animals after GCV or vehicle (HBSS) treatment. Results are presented as mean ± SD. ***p < 0.001, **p < 0.01,*p < 0.05, n.s.: nonsignificant

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