Abstract
The pituitary gland contains SOX2-expressing stem cells. However, their functional significance remains largely unmapped. We investigated their importance by depleting SOX2+ cells through diphtheria toxin (DT)-mediated ablation. DT treatment of adult Sox2CreERT2/+;R26iDTR/+ mice (after tamoxifen-induced expression of DT receptor in SOX2+ cells) resulted in 80% obliteration of SOX2+ cells in the endocrine pituitary, coinciding with reduced pituisphere-forming activity. Counterintuitively for a stem cell population, the SOX2+ cell compartment did not repopulate. Considering the more active phenotype of the stem cells during early-postnatal pituitary maturation, SOX2+ cell ablation was also performed in 4- and 1-week-old animals. Ablation grade diminished with decreasing age and was accompanied by a proliferative reaction of the SOX2+ cells, suggesting a rescue attempt. Despite this activation, SOX2+ cells did also not recover. Finally, the major SOX2+ cell depletion in adult mice did not affect the homeostatic maintenance of pituitary hormonal cell populations, nor the corticotrope remodelling response to adrenalectomy challenge. Taken together, our study shows that pituitary SOX2+ fail to regenerate after major depletion which does not affect adult endocrine cell homeostasis and remodelling. Thus, pituitary SOX2+ cells may constitute a copious stem cell reserve or may have other critical role(s) still to be clearly defined.
Highlights
The pituitary gland plays a pivotal role in the endocrine system and governs essential physiological processes like growth, metabolism, puberty, reproduction and stress response
Our study shows that SRY-related HMG box transcription factor 2 (SOX2)+ cells of the adult pituitary do not restore their own cell compartment after major depletion, which does not affect the maintenance of the different hormonal cell populations during homeostasis, nor the endocrine cell remodelling as triggered by adrenalectomy
Multipotent differentiation capacity of the remaining sphere-inducing cells toward hormonal cells was still functional as tested for distinct hormonal cell lineages (i.e. adrenocorticotropic hormone (ACTH)+, growth hormone (GH)+, PRL+ and αGSU+ cells, the latter encompassing the thyroid-stimulating hormone (TSH)+ thyrotropes and the luteinizing hormone (LH)+/follicle-stimulating hormone (FSH)+ gonadotropes; Fig. 1d)
Summary
The pituitary gland plays a pivotal role in the endocrine system and governs essential physiological processes like growth, metabolism, puberty, reproduction and stress response. Stem cells have been identified, displaying as central characteristic the expression of the stemness regulator SRY-related HMG box transcription factor 2 (SOX2)[2,3,4,5]. Despite their identification about 10 years ago, the functional role of the stem cells in the postnatal gland is far from clear. Following pituitary damage as inflicted by transgenic endocrine cell ablation, the SOX2+ stem cell compartment becomes activated; acute expansion of the SOX2+ cell population and co-expression of the ablated hormone supports their involvement in the regenerative response that is unfolding upon injury[6,7,8]. Our study shows that SOX2+ cells of the adult pituitary do not restore their own cell compartment after major depletion, which does not affect the maintenance of the different hormonal cell populations during homeostasis, nor the endocrine cell remodelling as triggered by adrenalectomy
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