Sox2+ Adult Stem and Progenitor Cells Are Important for Tissue Regeneration and Survival of Mice

Abstract

Summary The transcription factor Sox2 maintains the pluripotency of early embryonic cells and regulates the formation of several epithelia during fetal development. Whether Sox2 continues to play a role in adult tissues remains largely unknown. We here show that Sox2 marks adult cells in several epithelial tissues where its expression has not previously been characterized, including the stomach, cervix, anus, testes, lens and multiple glands. Genetic lineage tracing and transplantation experiments demonstrate that Sox2-expressing cells continuously give rise to mature cell types within these tissues, documenting their self-renewal and differentiation potentials. Consistent with these findings, ablation of Sox2+ cells in mice results in a disruption of epithelial tissue homeostasis and lethality. Developmental fate mapping reveals that Sox2+ adult stem cells originate from fetal Sox2+ tissue progenitors. Thus, our results identify Sox2 expression in numerous adult ectodermal and endodermal stem cell compartments, which are critical for normal tissue regeneration and survival.

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

“…Apart from its role during early development, Sox2 is also expressed in progenitors at later stages of the mouse embryo (Graham et al, 2003; Doetzlhofer et al, 2006; Klassen et al, 2004; Aubert et al, 2003), and its expression persists in the adult organism in tissue stem cells of stratified and glandular epithelia of ectodermal and endodermal origin, as well as in sensory cells (Merkel and taste bud cells) and spermatogonial stem cells, where it has been proved to be a critical factor sustaining the homeostasis of these tissues (Arnold et al, 2011). Recently also, it has been shown that Sox2 expression diminishes with aging in several tissues in mice and humans (Carrasco‐Garcia et al, 2018).…”

“…In an interesting manner, however, partial depletion of Sox2+ cells causes a reversible disruption of tissue integrity, and restoration of normal tissue homeostasis rescues morbidity. This recovery originates from the action of residual Sox2+ cells capable of reorganizing and regenerating the affected tissues (Arnold et al, 2011). …”

“…We took advantage of transgenic Sox2‐TK mice, in which herpes simplex virus type‐1 (HSV1) thymidine kinase (TK) gene was inserted into the Sox2 allele (Arnold et al, 2011). A similar mouse model previously generated in the laboratory of Konrad Hochedlinger was successfully used to prove that adult Sox2+ cells are stem and progenitor cells in a number of tissues (Arnold et al, 2011).…”

“…A similar mouse model previously generated in the laboratory of Konrad Hochedlinger was successfully used to prove that adult Sox2+ cells are stem and progenitor cells in a number of tissues (Arnold et al, 2011). Once we obtained these mice, we decided to confront Sox2‐WT mice versus Sox2‐TK mice, both treated with GCV.…”

“…We also confirmed the reduction in the number of Sox2+ cells, and the effects produced by the partial depletion in tissues previously described as dependent on the activity of stem and progenitor Sox2+ cells. We inspected the testis (Arnold et al, 2011), esophagus and trachea (Zhang et al, 2017) and found that GCV‐treated mice were showing atrophic seminiferous tubules (Figure S2), a feature previously described for these transgenic mice after acute depletion of Sox2+ cells (Arnold et al, 2011) and a frequent event during aging (Gosden, Richardson, Brown, & Davidson, 1982), and a decreased epithelial cellularity in esophagus and trachea that corresponded with a reduced number of Sox2+ cells (Figure S2). …”