Nature 459, 262-265 (14 May 2009) | doi:10.1038/nature07935; Received 16 July 2008; Accepted 24 February 2009; Published online 29 March 2009

Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche

Toshiro Sato1, Robert G. Vries1, Hugo J. Snippert1, Marc van de Wetering1, Nick Barker1, Daniel E. Stange1, Johan H. van Es1, Arie Abo2, Pekka Kujala3, Peter J. Peters3 & Hans Clevers1

  1. Hubrecht Institute and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands
  2. Nuvelo, Inc., 201 Industrial Road, Suite 310, San Carlos, California 94070-6211, USA
  3. The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Correspondence to: Hans Clevers1 Correspondence and requests for materials should be addressed to H.C. (Email: h.clevers@niob.knaw.nl).

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5+ stem cells at the bottoms of small-intestinal crypts1. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5+ stem cells can also initiate these crypt–villus organoids. Tracing experiments indicate that the Lgr5+ stem-cell hierarchy is maintained in organoids. We conclude that intestinal crypt–villus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.


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