Adult Sox2+ stem cell exhaustion in mice results in cellular senescence and premature aging.

Jéssica M Vilas,Alba Ferreirós,Sabela Da Silva‐Álvarez,Manuel Collado,Tomás García‐Caballero,María Gómez,Sagrario Ortega,Manuel Serrano,Miguel González‐Barcia,Patricia González,Carmen Carneiro,Anxo Vidal

doi:10.1111/acel.12834

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.

Highlights

Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS),Universidade de Santiago de Compostela,Santiago de Compostela,Spain
The echoMRI, we observed a clear reduction of fat mass (Figure 2c) in percentage of animals showing gray hair was significantly higher in GCV‐treated mice compared to HBSS control mice, in agreement the Sox2‐thymidine kinase (TK) group treated with GCV compared to the Sox2‐WT
Quantification of SAbetaGal positive cells in various sections hair after 15 days, compared to Sox2‐WT treated mice (Figure S3), from kidneys extracted from different animals revealed a massive pointing to a functional defect in Sox2‐TK mice after treatment

Summary

Introduction

Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS),Universidade de Santiago de Compostela,Santiago de Compostela,Spain. We decided to test the stem cell exhaustion hypothesis of aging by subjecting transgenic mice to a protocol of partial repetitive depletion of adult Sox2+ cells. (e) SAbetaGal staining of kidney sections from control wild‐type (Sox2WT) and Sox2‐TK transgenic (Sox2TK) animals after GCV treatment.

Results

Conclusion