Patterning and folding of intestinal villi by active mesenchymal dewetting

Creators: Huycke, Tyler R.¹; Häkkinen, Teemu J.¹; Miyazaki, Hikaru¹; Srivastava, Vasudha¹; Barruet, Emilie²; McGinnis, Christopher S.¹; Kalantari, Ali¹; Cornwall-Scoones, Jake³; Vaka, Dedeepya²; Zhu, Qin¹; Jo, Hyunil¹; Oria, Roger¹; Weaver, Valerie M.¹; DeGrado, William F.¹; Thomson, Matt³; Garikipati, Krishna⁴; Boffelli, Dario²; Klein, Ophir D.^{1, 5}; Gartner, Zev J.^{1, 6}

1. University of California, San Francisco
2. Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA.
3. California Institute of Technology
4. University of Michigan–Ann Arbor
5. Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA. Electronic address: ophir.klein@cshs.org.
6. CZ Biohub

Abstract

Tissue folds are structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi, finger-like protrusions that enable nutrient absorption. However, the molecular and mechanical processes driving villus morphogenesis remain unclear. Here, we identify an active mechanical mechanism that simultaneously patterns and folds the intestinal epithelium to initiate villus formation. At the cellular level, we find that PDGFRA+ subepithelial mesenchymal cells generate myosin II-dependent forces sufficient to produce patterned curvature in neighboring tissue interfaces. This symmetry-breaking process requires altered cell and extracellular matrix interactions that are enabled by matrix metalloproteinase-mediated tissue fluidization. Computational models, together with in vitro and in vivo experiments, revealed that these cellular features manifest at the tissue level as differences in interfacial tensions that promote mesenchymal aggregation and interface bending through a process analogous to the active dewetting of a thin liquid film.

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Acknowledgement

We are grateful for all members of the Gartner and Klein labs, Jeremy Green, and the CZI Biohub Theory Group for their helpful feedback. We are additionally grateful for constant support from Pauline Marangoni, as well as Aimee Cortez, Evelyn Sandoval, Kelly Pan, and Hadis Najibi and for assistance with mouse maintenance and genotyping. We thank the UCSF Biological Imaging Development Colab (BIDC) and the Parnassus Flow Core for providing essential equipment for these studies. This work was funded by R01DK126376, R35DE026602, F32DK128949, U01CA244109, and R01GM135462 and by U01DK103147 from the Intestinal Stem Cell Consortium (ISCC), a collaborative research project funded by the NIDDK and the NIAID. This work was further supported by funding for the UCSF Center for Cellular Construction (CCC) by NSF DBI-1548297. Z.J.G. is an investigator of the Chan Zuckerberg Biohub San Francisco.

Contributions

T.R.H., H.M., T.J.H., Z.J.G., and O.D.K. conceived the project. T.R.H. wrote the manuscript with assistance from T.J.H., input from H.M., Z.J.G., and O.D.K., and feedback from the other authors. T.R.H. and H.M. performed the experiments and data analysis with assistance from E.B., V.S., R.O., and A.K. T.J.H. performed the computational modeling with assistance from J.C.-S., M.T., and K.G. and input from T.R.H. and Z.J.G. D.B., D.V., C.S.M., and Q.Z. assisted in the processing and analysis of the scRNA-seq data. Key resources were provided by H.J., V.M.W., and W.F.D.

Conflict of Interest

Z.J.G. and C.S.M. hold patents related to the MULTI-seq barcoding method.

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