DataSheet_1_Interleukin-6 is dispensable in pituitary normal development and homeostasis but needed for pituitary stem cell activation following local injury.docx

Recently, we discovered that the cytokine interleukin-6 (IL-6) acts as a pituitary stem cell-activating factor, both when administered in vivo and when added to stem cell organoid cultures in vitro. Moreover, its expression, predominantly localized in the gland’s stem and mesenchymal cells, promptly increases following damage in the adult pituitary, leading to stem-cell proliferative activation. Given these findings that IL-6 is involved in pituitary stem cell regulation, we addressed the question whether the cytokine has an impact on the pituitary phenotype during active phases of the gland’s remodeling, in particular embryonic development and neonatal maturation, as well as during homeostasis at adulthood and aging, all unknown today. Using the IL-6 knock-out (KO) mouse model, we show that IL-6 is dispensable for pituitary embryonic and neonatal endocrine cell development, as well as for hormonal cell homeostasis in adult and aging glands. The findings match the absence of effects on the stem cell compartment at these stages. However, using this IL-6 KO model, we found that IL-6 is needed for the acute stem-cell proliferative activation reaction upon pituitary injury. Intriguingly, regeneration still occurs which may be due to compensatory behavior by other cytokines which are upregulated in the damaged IL-6 KO pituitary, although at lower but prolonged levels, which might lead to a delayed (and less forceful) stem cell response. Taken together, our study revealed that IL-6 is dispensable for normal pituitary development and homeostasis but plays a key role in the prompt stem cell activation upon local damage, although its presence is not essentially needed for the final regenerative realization.

近期，我们研究发现，细胞因子白细胞介素-6（IL-6）作为一种垂体干细胞激活因子，无论是体内给药还是体外添加至干细胞类器官培养中，均能发挥作用。此外，其表达主要局限于腺体的干细胞和间充质细胞，在成年垂体受损后迅速增加，从而引发干细胞增殖活化。鉴于这些发现表明IL-6参与垂体干细胞的调控，我们针对这一问题进行了探讨，即该细胞因子是否会对垂体在活跃重塑阶段（尤其是胚胎发育和新生儿成熟期）以及成年和衰老期的稳态维持产生影响，这些影响目前尚属未知。利用IL-6敲除（KO）小鼠模型，我们证实IL-6对于垂体胚胎和新生儿内分泌细胞发育，以及成年和衰老腺体中激素细胞的稳态维持并非必需。这些发现与干细胞区室在此阶段未受影响的现象相吻合。然而，使用该IL-6 KO模型，我们发现IL-6对于垂体损伤后急性干细胞增殖活化反应是必需的。令人感兴趣的是，再生仍会发生，这可能是由于受损的IL-6 KO垂体中其他细胞因子（其表达上调）的补偿性作用，尽管其水平较低且持续时间较长，这可能导致干细胞反应的延迟（且力度较弱）。综合以上研究，我们揭示IL-6对于正常的垂体发育和稳态维持并非必需，但在局部损伤后迅速激活干细胞的过程中发挥着关键作用，尽管其存在并非再生实现的必要条件。