Context-dependent responses of Drosophila intestinal stem cells to intracellular reactive oxygen species

Abstract

Reactive oxygen species (ROS) contribute to cellular redox environment and serve as signaling molecules. Excessive ROS can lead to oxidative stress that are involved in a broad spectrum of physiological and pathological conditions. Stem cells have unique ROS regulation while cancer cells frequently show a constitutive oxidative stress that is associated with the invasive phenotype. Antioxidants have been proposed to forestall tumor progression while targeted oxidants have been used to destroy tumor cells. However, the delicate beneficial range of ROS levels for stem cells and tumor cells under distinct contexts remains elusive. Here, we used Drosophila midgut intestinal stem cell (ISCs) as an in vivo model system to tackle this question. The ROS levels of ISCs remained low in comparison to that of differentiated cells and increased with ageing, which was accompanied by elevated proliferation of ISCs in aged Drosophila. Neither upregulation nor downregulation of ROS levels significantly affected ISCs, implicating an intrinsic homeostatic range of ROS in ISCs. Interestingly, we observed similar moderately elevated ROS levels in both tumor-like ISCs induced by Notch (N) depletion and extracellular matrix (ECM)-deprived ISCs induced by β-integrin (mys) depletion. Elevated ROS levels further promoted the proliferation of tumor-like ISCs while reduced ROS levels suppressed the hyperproliferation phenotype; on the other hand, further increased ROS facilitated the survival of ECM-deprived ISCs while reduced ROS exacerbated the loss of ECM-deprived ISCs. However, N- and mys-depleted ISCs, which resembled metastatic tumor cells, harbored even higher ROS levels and were subjected to more severe cell loss, which could be partially prevented by ectopic supply of antioxidant enzymes, implicating a delicate pro-surviving and proliferating range of ROS levels for ISCs. Taken together, our results revealed stem cells can differentially respond to distinct ROS levels under various conditions and suggested that the antioxidant-based intervention of stem cells and tumors should be formulated with caution according to the specific situations.

Keywords

• Reactive oxygen species
• Drosophila
• Intestinal stem cell
• Tumor
• Notch
• Integrin