bims-instec 2022-03-06 papers

Cell Mol Gastroenterol Hepatol. 2022 Feb 23. pii: S2352-345X(22)00038-8. [Epub ahead of print]

Glucagon-like peptide-2 stimulates S-phase entry of intestinal Lgr5+ stem cells.

Maegan E Chen, Setareh Malekian Naeini, Arjuna Srikrishnaraj, Daniel J Drucker, Zivit Fesler, Patricia L Brubaker.

BACKGROUND AIMS: Leucine-rich repeat-containing G-protein coupled receptor-5 (Lgr5)+/olfactomedin-4 (Olfm4)+ intestinal stem cells (ISCs) in the crypt-base are crucial for homeostatic maintenance of the epithelium. The gut hormone, glucagon-like peptide-21-33 (GLP-2), stimulates intestinal proliferation and growth; however, the actions of GLP-2 on the Lgr5+ ISCs remain unclear. The aim of this study was to determine whether and how GLP-2 regulates Lgr5+ ISC cell cycle dynamics and number.
METHODS: Lgr5-eGFP-IRES-creERT2 mice were acutely administered human Gly2-GLP-2, or the GLP-2 receptor antagonist, GLP-23-33. Intestinal epithelial-insulin-like growth factor-1 receptor knockout and control mice were treated chronically with hGly2-GLP-2. Cell cycle parameters were determined by EdU, BrdU, Ki67 and phosphohistone-3 labeling and cell cycle gene expression.
RESULTS: Acute hGly2-GLP-2 treatment increased the proportion of eGFP+EdU+/OLFM4+EdU+ cells by 11-22% (p<0.05), without affecting other cell cycle markers. hGly2-GLP-2 treatment also increased the ratio of eGFP+ cells in early-to-late S-phase by 97% (p<0.001), and increased the proportion of eGFP+ cells entering S-phase by 218% (p<0.001). hGly2-GLP-2 treatment induced jejunal expression of genes involved in cell cycle regulation (p<0.05), and increased expression of Mcm3 in the Lgr5-expressing cells by 122% (p<0.05). Conversely. GLP-23-33 reduced the proportion of eGFP+EdU+ cells by 27% (p<0.05), as well as the expression of jejunal cell cycle genes (p<0.05). Finally, chronic hGly2-GLP-2 treatment increased the number of OLFM4+ cells/crypt (p<0.05), in an intestinal epithelial insulin-like growth factor-1 receptor-dependent manner.
CONCLUSIONS: These findings expand the actions of GLP-2 to encompass acute stimulation of Lgr5+ ISC S-phase entry through the GLP-2R, and chronic induction of Lgr5+ ISC expansion through downstream intestinal insulin-like growth factor-1 signaling.

Keywords: Cell cycle; GLP-2; Lgr5; Olfm4; S-phase; intestine; proliferation

DOI: https://doi.org/10.1016/j.jcmgh.2022.02.011

Cell Rep. 2022 Mar 01. pii: S2211-1247(22)00165-6. [Epub ahead of print]38(9): 110438

BMP gradient along the intestinal villus axis controls zonated enterocyte and goblet cell states.

Joep Beumer, Jens Puschhof, Fjodor Yousef Yengej, Lianzheng Zhao, Adriana Martinez-Silgado, Marloes Blotenburg, Harry Begthel, Charelle Boot, Alexander van Oudenaarden, Ye-Guang Chen, Hans Clevers.

Intestinal epithelial cells derive from stem cells at the crypt base and travel along the crypt-villus axis to die at the villus tip. The two dominant villus epithelial cell types, absorptive enterocytes and mucous-secreting goblet cells, are mature when they exit crypts. Murine enterocytes switch functional cell states during migration along the villus. Here, we ask whether this zonation is driven by the bone morphogenetic protein (BMP) gradient, which increases toward the villus. Using human intestinal organoids, we show that BMP signaling controls the expression of zonated genes in enterocytes. We find that goblet cells display similar zonation involving antimicrobial genes. Using an inducible Bmpr1a knockout mouse model, we confirm that BMP controls these zonated genes in vivo. Our findings imply that local manipulation of BMP signal strength may be used to reset the enterocyte "rheostat" of carbohydrate versus lipid uptake and to control the antimicrobial response through goblet cells.

Keywords: BMP signaling; CRISPR-Cas9; enterocytes; intestinal differentiation; organoids; single-cell RNA sequencing

DOI: https://doi.org/10.1016/j.celrep.2022.110438

Nat Rev Mol Cell Biol. 2022 Feb 28.

Metabolic regulation of somatic stem cells in vivo.

Corbin E Meacham, Andrew W DeVilbiss, Sean J Morrison.

Metabolism has been studied mainly in cultured cells or at the level of whole tissues or whole organisms in vivo. Consequently, our understanding of metabolic heterogeneity among cells within tissues is limited, particularly when it comes to rare cells with biologically distinct properties, such as stem cells. Stem cell function, tissue regeneration and cancer suppression are all metabolically regulated, although it is not yet clear whether there are metabolic mechanisms unique to stem cells that regulate their activity and function. Recent work has, however, provided evidence that stem cells do have a metabolic signature that is distinct from that of restricted progenitors and that metabolic changes influence tissue homeostasis and regeneration. Stem cell maintenance throughout life in many tissues depends upon minimizing anabolic pathway activation and cell division. Consequently, stem cell activation by tissue injury is associated with changes in mitochondrial function, lysosome activity and lipid metabolism, potentially at the cost of eroding self-renewal potential. Stem cell metabolism is also regulated by the environment: stem cells metabolically interact with other cells in their niches and are able to sense and adapt to dietary changes. The accelerating understanding of stem cell metabolism is revealing new aspects of tissue homeostasis with the potential to promote tissue regeneration and cancer suppression.

DOI: https://doi.org/10.1038/s41580-022-00462-1