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Mechanically induced development and maturation of human intestinal organoids in vivo

Nature Biomedical Engineeringvolume 2pages429442 (2018) | Download Citation


The natural ability of stem cells to self-organize into functional tissue has been harnessed for the production of functional human intestinal organoids. Although dynamic mechanical forces play a central role in intestinal development and morphogenesis, conventional methods for the generation of intestinal organoids have relied solely on biological factors. Here, we show that the incorporation of uniaxial strain, using compressed nitinol springs, in human intestinal organoids transplanted into the mesentery of mice induces growth and maturation of the organoids. Assessment of morphometric parameters, transcriptome profiling and functional assays of the strain-exposed tissue revealed higher similarities to native human intestine, with regard to tissue size and complexity, and muscle tone. Our findings suggest that the incorporation of physiologically relevant mechanical cues during the development of human intestinal tissue enhances its maturation and enterogenesis.

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The authors thank G. L. Keller and Veterinary Services staff for support in completing the animal work, J. M. Kofron for kind assistance with the IVIS Spectrum microCT imaging and B. Donnelly for assistance with the protein work. This work was funded in part by NIH grants P30 DK078392 (DHC Pilot and Feasibility Award to M.M.M.; DNA sequencing and iPSCs core facilities) and NIH NIDKK grant 1K99DK110414-02 (to M.M.M.), as well as an Athena Blackburn Research Scholar Award in neuroenteric diseases from the American Gastroenterology Association (to M.M.M.) and a ‘New Team’ grant (BOGUS to M.M.M.) from the Bioregate Regenerative Medicine Cluster, University of Nantes and Pays de la Loire Region. The Dunn, Helmrath and Wells laboratories are members of the Intestinal Stem Cell Consortium, supported by NIDDK and NIAID (U01DK103117 to M.A.H.). This research was also supported in part by the Cincinnati Children’s Research Foundation and the Cincinnati Biobank, as well as the Better Outcomes for Children Biorepository.

Author information

Author notes

    • James C. Y. Dunn

    Present address: Department of Pediatric Surgery, Stanford University, Stanford, CA, USA

    • Maxime M. Mahe

    Present address: INSERM UMR 1235–TENS, INSERM, University of Nantes, Nantes, France


  1. Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    • Holly M. Poling
    • , Nicole Brown
    • , Taylor A. Hausfeld
    • , Michael A. Helmrath
    •  & Maxime M. Mahe
  2. Department of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    • David Wu
    •  & Simon P. Hogan
  3. Department of Pathology, Dartmouth–Hitchcock Medical Center, Lebanon, NH, USA

    • Michael Baker
  4. Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA

    • Nhan Huynh
    •  & James C. Y. Dunn
  5. Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA

    • Nhan Huynh
    •  & James C. Y. Dunn
  6. CNRS UMR 6004-LS2N, CNRS, University of Nantes, Nantes, France

    • Samuel Chaffron
  7. Department of Bioengineering, Stanford University, Stanford, CA, USA

    • James C. Y. Dunn
  8. Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    • James M. Wells
  9. Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    • James M. Wells


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H.M.P. and M.M.M. conceived and designed the study. H.M.P., D.W., T.A.H., M.A.H. and M.M.M. performed the experiments and collected the data. N.B. generated the HIOs. N.H. and J.C.Y.D. manufactured the springs. H.M.P., D.W., S.C. and M.M.M. analysed the data. H.M.P., M.B., S.P.H., J.M.W., M.A.H. and M.M.M. interpreted the experimental findings. H.M.P. and M.M.M. prepared the figures and drafted the manuscript. H.M.P., S.P.H., J.M.W., M.A.H. and M.M.M. made critical revisions to the manuscript. All authors approved the final version of the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Maxime M. Mahe.

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