Non-enzymatic role of SOD1 in intestinal stem cell growth
Intestinal homeostasis is maintained by the intestinal stem cells (ISCs). Superoxide dismutase 1 (SOD1) has been known for nearly half a century for its canonical role as an antioxidant enzyme. Scientists established intestinal organoids from tamoxifen-inducible intestinal epithelial cell-specific Sod1 knockout mice in this study. They found that loss of Sod1 suppressed the proliferation and survival of cells and Lgr5 gene expression.
The mouse intestinal organoid is a useful ex vivo model for studying ISCs. Organoids can be generated from dissociated crypts or single Lgr5+ cells in vitro and passaged for more than eight months without genetic alterations. In this work, researchers used the organoid model to study the function of SOD1 in ISCs and their enzymatic activity. SOD1 is a ROS-scavenging enzyme, but there have been conflicting reports on the impact of Sod1 loss on intracellular ROS levels. This study found notable increases in WNT signaling and Paneth cell number after Sod1 deletion in organoids.
This increase occurred before the reduction of Lgr5 gene expression. All these data indicate that redundant WNT signaling plays a vital role in sod1 loss-induced organoid growth defects. Epithelial Sod1 deficiency in vivo inhibited the survival of crypt stem cells but not the proliferation and crypt-villus architecture. Stromal/mesenchymal cells are absent in organoids but present in the small intestine. These stromal cells provide essential niche factors for ISCs in vitro. Also, this study indicated that the Supplementation of EREG, but not AREG and EGF, in vitro could rescue the growth of Sod1 deficient organoids.
https://www.nature.com/articles/s41419-022-05267-w
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