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SUMMARY:Lgr5 Stem Cells in self-renewal and cancer - Hans Clevers\, Hubrec
 ht Institute\, Utrecht
DTSTART:20111207T161500Z
DTEND:20111207T180000Z
UID:TALK34213@talks.cam.ac.uk
CONTACT:Scientific Meetings Co-ordinator
DESCRIPTION:The intestinal epithelium is the most rapidly self-renewing ti
 ssue in adult mammals. We originally defined Lgr5 as a Wnt target gene\, t
 ranscribed in colon cancer cells. Two knock-in alleles revealed exclusive 
 expression of Lgr5 in cycling\, columnar cells at the crypt base. Using an
  inducible Cre knock-in allele and the Rosa26-LacZ reporter strain\, linea
 ge tracing experiments were performed in adult mice. The Lgr5+ve crypt bas
 e columnar cells (CBC) generated all epithelial lineages throughout life\,
  implying that it represents the stem cell of the small intestine and colo
 n. Similar obserations were made in hair follicles and stomach epithelium.
  \nSingle sorted Lgr5+ve stem cells can initiate ever-expanding crypt-vill
 us organoids in 3D culture. Tracing experiments indicate that the Lgr5+ve 
 stem cell hierarchy is maintained in these organoids. We conclude that int
 estinal crypt-villus units are self-organizing structures\, which can be b
 uilt from a single stem cell in the absence of a non-epithelial cellular n
 iche. The same technology has now been developed for the Lgr5+ve stomach s
 tem cells. \nIntestinal cancer is initiated by Wnt pathway-activating muta
 tions in genes such as APC.  As in most cancers\, the cell of origin has r
 emained elusive. Deletion of APC in stem cells\, but not in other crypt ce
 lls results in progressively growing neoplasia\, identifying the stem cell
  as the cell-of-origin of adenomas. Moreover\, a stem cell/progenitor cell
  hierarchy is maintained in early stem cell-derived adenomas\, lending sup
 port to the “cancer stem cell”-concept. \nFate mapping of individual c
 rypt stem cells using a multicolor Cre-reporter revealed that\, as a popul
 ation\, Lgr5 stem cells persist life-long\, yet crypts drift toward clonal
 ity within a period of 1-6 months. Lgr5 cell divisions occur symmetrically
 . The cellular dynamics are consistent with a model in which the resident 
 stem cells double their numbers each day and stochastically adopt stem or 
 TA fates after cell division. Lgr5 stem cells are interspersed between ter
 minally differentiated Paneth cells that are known to produce bactericidal
  products. We find that Paneth cells are CD24+ and express EGF\, TGF-a\, W
 nt3 and the Notch ligand Dll4\, all essential signals for stem-cell mainte
 nance in culture. Co-culturing of sorted stem cells with Paneth cells dram
 atically improves organoid formation. This Paneth cell requirement can be 
 substituted by a pulse of exogenous Wnt. Genetic removal of Paneth cells i
 n vivo results in the concomitantloss of Lgr5 stem cells. In colon crypts\
 , CD24+ cells residing between Lgr5 stem cells may represent the Paneth ce
 ll equivalents. We conclude that Lgr5 stem cells compete for essential nic
 he signals provided by a specialized daughter cell\, the Paneth cell.\n
LOCATION:Max Perutz Lecture Theatre\, Medical Research Council (MRC) (MRC 
 Laboratory of Molecular Biol
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