Intestinal Stem Cell Proliferation and Tissue Homeostasis
Enterocytes secrete various ligands to promote the proliferation of intestinal stem cells (ISCs) in response to injury, ensuring rapid tissue repair. However, ISCs must return to basal self-renewal rates to avoid overgrowth after tissue repair. Currently, the mechanisms that prevent hyperplasia following injury remain largely unknown.
Our published findings indicate that the bone morphogenetic protein (BMP) signaling pathway is activated in response to injury to suppress ISC proliferation. These findings also provide evidence for how co-regulation of antagonistic signals mediates tissue homeostasis and how disconnect between these signals can lead to abnormal tissue homeostasis (Guo et al., J Cell Biol 2013). Indeed, loss-of-function mutations in the BMP receptor type 1A and mothers against decapentaplegic homolog 4 (SMAD4s) have been found in human gastrointestinal polyposis syndromes, underscoring the importance of the effect of BMP-signaling on proliferation. The BMP-signaling pathway functions in the ISCs to antagonize ISC proliferation following injury. However, the transcriptional downstream targets of BMP signaling remain unknown.
We are currently testing phosphatase and tensin homolog (PTEN) and Wnt signaling as candidate downstream targets of BMP signaling, as they have been established as targets of BMP signaling in the mammalian intestine. In parallel we have performed RNA-seq analysis between wild type and BMP mutant intestines to identify novel evolutionarily conserved downstream targets of BMP-signaling and are currently analyzing the results in both fly and mouse tissues. Given the similarities between Drosophila and mammalian intestinal homeostasis, identifying the mechanism by which BMP-signaling regulates ISC proliferation in our model system will presumably have broad clinical implications for the diagnosis and treatment of colon cancer.