Researchers characterized intestinal goblet cells (GCs) expression diversity and defined how a specific GC subtype, localized in the intercrypt surface epithelium, functionally contributed to the formation of the mucus barrier.
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sized%20by%20goblet%20cells%20%28GCs%29%5Cu2014specialized%20secretory%20cells%20classically%20viewed%20as%20a%20homogeneous%20cell%20type.%20Studies%20identifying%20divergent%20functional%20features%20in%20GC%20subpopulations%2C%20including%20differential%20mucus%20biosynthesis%20rates%20and%20responses%20to%20bacteria%2C%20suggest%20that%20GC%20populations%20may%20in%20fact%20be%20heterogeneous.%5CnRATIONALEIn%20the%20present%20study%2C%20we%20characterized%20intestinal%20GC%20expression%20diversity%20and%20defined%20how%20a%20specific%20GC%20subtype%2C%20localized%20in%20the%20intercrypt%20surface%20epithelium%2C%20functionally%20contributes%20to%20the%20formation%20of%20the%20mucus%20barrier.%5CnRESULTSUsing%20mCherry-MUC2%20transgenic%20mice%20to%20sort%20and%20isolate%20GCs%2C%20we%20generated%20transcriptomic%20and%20proteomic%20profiles%20to%20characterize%20the%20GC%20expression%20landscape%20in%20both%20the%20small%20intestine%20and%20the%20colon.%20Single-cell%20transcriptomic%20analysis%20revealed%20several%20distinct%20GC%20clusters%20in%20each%20tissue%20region%2C%20which%20segregated%20into%20two%20separate%20trajectories.%20One%20trajectory%20had%20enriched%20expression%20of%20known%20GC-specific%20genes%20%28e.g.%2C%20Clca1%20and%20Fcgbp%29%20and%20was%20designated%20as%20canonical%20GCs.%20Conversely%2C%20the%20other%20trajectory%20was%20enriched%20for%20the%20expression%20of%20genes%20typically%20associated%20with%20enterocytes%20%28e.g.%2C%20Dmbt1%20and%20Gsdmc4%29%2C%20so%20we%20designated%20this%20trajectory%20as%20noncanonical.In%20the%20colon%2C%20the%20most%20differentiated%20GCs%20are%20the%20high%5Cu2013mucus%20turnover%20cells%20localized%20to%20the%20surface%20epithelium%20between%20crypts%2C%20which%20were%20designated%20as%20intercrypt%20GCs%20%28icGCs%29.%20These%20cells%20had%20expression%20profiles%20that%20were%20distinct%20from%20those%20of%20crypt-resident%20GCs%2C%20so%20we%20investigated%20their%20role%20in%20forming%20the%20mucus%20barrier.%20We%20exploited%20the%20lectin-binding%20features%20of%20mucus%20to%20resolve%20the%20three-dimensional%20organization%20of%20mucus%20in%20live%20tissue%20explants.%20Results%20demonstrated%20that%20icGCs%20secreted%20distinct%20mucus%20that%20filled%20the%20spatial%20regions%20between%20mucus%20plumes%20secreted%20from%20crypt%20openings.%20The%20intercrypt%20mucus%20was%20impenetrable%20to%20bacteria-sized%20beads%3B%20however%2C%20it%20was%20more%20penetrable%20to%20smaller%20molecules%20compared%20with%20crypt%20plume%20mucus.%20Penetrable%20surface%20mucus%20may%20be%20important%20for%20the%20absorption%20of%20ions%20and%20other%20compounds%2C%20whereas%20denser%20mucus%20within%20the%20crypt%20compartment%20contributes%20to%20the%20shielding%20of%20the%20stem%20cell%20niche.Both%20mucus%20subtypes%20appear%20to%20be%20important%20for%20the%20overall%20protective%20function%20of%20mucus%2C%20because%20a%20barrier%20impenetrable%20to%20bacteria%20was%20formed%20by%20the%20mixed%2C%20net-like%20organization%20of%20intercrypt%20and%20crypt%20plume%20mucus.%20A%20mouse%20model%20with%20dysfunctional%20icGCs%20lacking%20normal%20intercrypt%20mucus%20exhibited%20an%20inadequate%20mucus%20barrier%20and%20was%20more%20susceptible%20to%20both%20chemically%20induced%20and%20spontaneous%20%28age-dependent%29%20colitis%2C%20which%20demonstrates%20the%20indispensable%20role%20of%20icGCs%20in%20maintaining%20a%20functional%20mucus%20barrier.%20Furthermore%2C%20biopsies%20from%20patients%20with%20ulcerative%20colitis%5Cu2014including%20those%20in%20remission%5Cu2014exhibited%20increased%20GC%20shedding%20and%20reduced%20icGC%20numbers.%20These%20characteristics%20were%20associated%20with%20structural%20defects%20in%20the%20mucus%20barrier%2C%20including%20gaps%20in%20the%20intercrypt%20mucus%20that%20exposed%20areas%20of%20the%20surface%20epithelium.%5CnCONCLUSIONThe%20current%20study%20identifies%20GCs%20as%20a%20heterogeneous%20population%20of%20cells%20with%20diverse%20functional%20features%20that%20indicate%20a%20dynamic%20cellular%20system.%20GCs%20at%20different%20locations%20along%20the%20crypt-surface%20axis%20contribute%20to%20a%20functional%20mucus%20barrier%20that%20protects%20the%20epithelium%20from%20microorganisms.%20The%20icGCs%20possess%20a%20specific%20role%20in%20mucus%20organization%2C%20where%20their%20malfunction%20is%20associated%20with%20colitis%20in%20both%20mice%20and%20humans.%20%3Cimg%20class%3D%5C%22fragment-image%5C%22%20aria-describedby%3D%5C%22F1-caption%5C%22%20src%3D%5C%22https%3A%5C%2F%5C%2Fscience.sciencemag.org%5C%2Fcontent%5C%2Fsci%5C%2F372%5C%2F6539%5C%2Feabb1590%5C%2FF1.medium.gif%5C%22%5C%2F%3E%20Download%20high-res%20image%20Open%20in%20new%20tab%20Download%20Powerpoint%20Diversity%20of%20GC%20expression%20and%20function.Intestinal%20GCs%20can%20be%20divided%20into%20several%20distinct%20clusters%20that%20form%20canonical%20and%20noncanonical%20trajectories%2C%20and%20gene%20expression%20profiles%20outline%20their%20topographical%20position.%20The%20specialized%20surface%20GC%20type%5Cu2014the%20icGCs%5Cu2014secrete%20mucus%20crucial%20for%20forming%20a%20protective%20barrier%20between%20bacteria%20and%20the%20epithelium.%20Depletion%20of%20icGCs%20impairs%20mucus%20function%2C%20a%20phenomenon%20observed%20in%20ulcerative%20colitis%20%28UC%29%20patients.%5CnThe%20intestinal%20mucus%20layer%2C%20an%20important%20element%20of%20epithelial%20protection%2C%20is%20produced%20by%20goblet%20cells.%20Intestinal%20goblet%20cells%20are%20assumed%20to%20be%20a%20homogeneous%20cell%20type.%20In%20this%20study%2C%20however%2C%20we%20delineated%20their%20specific%20gene%20and%20protein%20expression%20profiles%20and%20identified%20several%20distinct%20goblet%20cell%20populations%20that%20form%20two%20differentiation%20trajectories.%20One%20distinct%20subtype%2C%20the%20intercrypt%20goblet%20cells%20%28icGCs%29%2C%20located%20at%20the%20colonic%20luminal%20surface%2C%20produced%20mucus%20with%20properties%20that%20differed%20from%20the%20mucus%20secreted%20by%20crypt-residing%20goblet%20cells.%20Mice%20with%20defective%20icGCs%20had%20increased%20sensitivity%20to%20chemically%20induced%20colitis%20and%20manifested%20spontaneous%20colitis%20with%20age.%20Furthermore%2C%20alterations%20in%20mucus%20and%20reduced%20numbers%20of%20icGCs%20were%20observed%20in%20patients%20with%20both%20active%20and%20remissive%20ulcerative%20colitis%2C%20which%20highlights%20the%20importance%20of%20icGCs%20in%20maintaining%20functional%20protection%20of%20the%20epithelium.%5CnMucus%20lining%20the%20mammalian%20gut%20is%20produced%20by%20anatomically%20distinct%20subpopulations%20of%20goblet%20cells%2C%20which%20produce%20mucus%20with%20different%20functions.%5CnMucus%20lining%20the%20mammalian%20gut%20is%20produced%20by%20anatomically%20distinct%20subpopulations%20of%20goblet%20cells%2C%20which%20produce%20mucus%20with%20different%20functions.%22%2C%22date%22%3A%222021%5C%2F04%5C%2F16%22%2C%22language%22%3A%22en%22%2C%22DOI%22%3A%2210.1126%5C%2Fscience.abb1590%22%2C%22ISSN%22%3A%220036-8075%2C%201095-9203%22%2C%22url%22%3A%22https%3A%5C%2F%5C%2Fscience.sciencemag.org%5C%2Fcontent%5C%2F372%5C%2F6539%5C%2Feabb1590%22%2C%22collections%22%3A%5B%5D%2C%22dateModified%22%3A%222021-04-19T18%3A06%3A50Z%22%7D%7D%5D%7D
Nyström, E. E. L., Martinez-Abad, B., Arike, L., Birchenough, G. M. H., Nonnecke, E. B., Castillo, P. A., Svensson, F., Bevins, C. L., Hansson, G. C., & Johansson, M. E. V. (2021). An intercrypt subpopulation of goblet cells is essential for colonic mucus barrier function. Science, 372(6539). https://doi.org/10.1126/science.abb1590 Cite
