bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2021‒11‒07
four papers selected by
Maria-Virginia Giolito

  1. Cell Stem Cell. 2021 Oct 25. pii: S1934-5909(21)00416-1. [Epub ahead of print]
      The high turnover and regenerative capacity of the adult intestine relies on resident stem cells located at the bottom of the crypt. The enteric nervous system consists of an abundant network of enteric glial cells (EGCs) and neurons. Despite the close proximity of EGCs to stem cells, their in vivo role as a stem cell niche is still unclear. By analyzing the mouse and human intestinal mucosa transcriptomes at the single-cell level, we defined the regulation of EGC heterogeneity in homeostasis and chronic inflammatory bowel disease. Ablation of EGC subpopulations revealed that the repair potential of intestinal stem cells (ISCs) is regulated by a specific subset of glial fibrillary acidic protein (GFAP)+ EGCs. Mechanistically, injury induces expansion of GFAP+ EGCs, which express several WNT ligands to promote LGR5+ ISC self-renewal. Our work reveals the dynamically regulated heterogeneity of EGCs as a key part of the intestinal stem cell niche in regeneration and disease.
    Keywords:  Enteric glial cells; Inflammatory Bowel Disease; Intestinal stem cells; Regeneration; Stem cell niches; WNT signaling
  2. Proc Natl Acad Sci U S A. 2021 Nov 09. pii: e2112814118. [Epub ahead of print]118(45):
      Intestinal epithelial damage is associated with most digestive diseases and results in detrimental effects on nutrient absorption and production of hormones and antimicrobial defense molecules. Thus, understanding epithelial repair and regeneration following damage is essential in developing therapeutics that assist in rapid healing and restoration of normal intestinal function. Here we used a well-characterized enteric virus (rotavirus) that damages the epithelium at the villus tip but does not directly damage the intestinal stem cell, to explore the regenerative transcriptional response of the intestinal epithelium at the single-cell level. We found that there are specific Lgr5 + cell subsets that exhibit increased cycling frequency associated with significant expansion of the epithelial crypt. This was accompanied by an increase in the number of immature enterocytes. Unexpectedly, we found rotavirus infects tuft cells. Transcriptional profiling indicates tuft cells respond to viral infection through interferon-related pathways. Together these data provide insights as to how the intestinal epithelium responds to insults by providing evidence of stimulation of a repair program driven by stem cells with involvement of tuft cells that results in the production of immature enterocytes that repair the damaged epithelium.
    Keywords:  damage; interferon; rotavirus; single-cell RNA-sequencing; tuft cell
  3. Cancer Res. 2021 Nov 04. pii: canres.1261.2021. [Epub ahead of print]
      Colorectal cancer (CRC) is among the leading causes of cancer-associated deaths worldwide. Treatment failure and tumor recurrence due to survival of therapy-resistant cancer stem/initiating cells represent major clinical issues to overcome. In this study, we identified lysine methyltransferase 9 (KMT9), an obligate heterodimer composed of KMT9α and KMT9β that monomethylates histone H4 at lysine 12 (H4K12me1), as an important regulator in colorectal tumorigenesis. KMT9α and KMT9β were overexpressed in CRC and colocalized with H4K12me1 at promoters of target genes involved in the regulation of proliferation. Ablation of KMT9α drastically reduced colorectal tumorigenesis in mice and prevented the growth of murine as well as human patient-derived tumor organoids. Moreover, loss of KMT9α impaired the maintenance and function of CRC stem/initiating cells and induced apoptosis specifically in this cellular compartment. Together, these data suggest that KMT9 is an important regulator of colorectal carcinogenesis, identifying KMT9 as a promising therapeutic target for the treatment of CRC.
  4. Mol Biol Rep. 2021 Nov 02.
      BACKGROUND: To adapt to daily changes in the external environment, organisms have developed circadian rhythm systems with a period of approximately 24 h. Many studies have reported that both circadian rhythms and exosomes play important roles in the development and metastasis of tumors. However, whether circadian clock genes can affect the progression of tumors by regulating exosomes remains unclear.METHODS AND RESULTS: In this study, we isolated exosomes from the supernatant of human colorectal cancer (CRC) cells, including SW480, SW620, and HCT116 cells, by differential centrifugation and characterized exosomes by transmission electron microscopy, nanoparticle tracking analysis, and Western blot analysis. Then, we found that exosomes derived from SW480, SW620 and HCT116 cells could promote the migration of HCT116 and human umbilical vein endothelial cells. Exosomes derived from SW620 cells showed increased stimulating effects when we increased the expression of BMAL1, a core circadian protein. In contrast, exosomes derived from SW480 and HCT116 cells showed decreased stimulating effects when we knocked down the expression of BMAL1. Furthermore, we discovered that BMAL1 promotes the release of exosomes by HCT116 and SW620 cells. In addition, by luciferase assay, we confirmed that BMAL1 transcriptionally regulates the expression of Rab27a, a key molecule related to the secretion of exosomes.
    CONCLUSIONS: Our data reveal a new mechanism by which BMAL1 induces CRC metastasis by stimulating exosome secretion. This finding may help further clarify the role of circadian rhythm in the progression of CRC.
    Keywords:  BMAL1; Circadian rhythm; Colorectal cancer; Exosome; Tumor metastasis