It takes a villus to build a career

12/1/2025

By Brenda Pardo

Your small intestine—all 20 or so feet of it—is lined with millions of finger-like projections called villi that absorb nutrients from your food. Tyler Huycke, a new Assistant Professor at the University of Michigan, studies how these extensions of the mammalian gut epithelium take shape during embryonic development. 

Huycke began this work as a postdoctoral researcher, driven by curiosity about how biological structures acquire their final shape and size. After years of perseverance and discovery, he now leads his own lab, continuing to pursue the questions that first inspired him. Obtaining a faculty position is not easy, but Huycke credits the Society for Developmental Biology’s GetHIRED! program with supporting him in navigating the challenging application process.

GetHIRED! is a twelve-week course that supports postdoctoral researchers in preparing their academic job applications. For Huycke, it provided structure, accountability, and a sense of community. He said having access to reference materials and peers with whom to exchange drafts of his research statement made the process manageable and built up his confidence. Perhaps most importantly, the program connected him to others who had already been through the experience, reminding him that “you don’t have to go through this totally obscure process alone.”

In his research, Huycke focuses on how the tissues of the embryonic gut interact to form villi, using the mouse embryo as his experimental platform. The gut is a tube lined by an inner epithelium and an outer mesenchyme. The villi begin to form when mesenchymal cells form clusters and the epithelium above them starts to fold. Soon after Huycke began studying villus formation, he realized the phenomenon held a story far more fascinating than he had expected.

A breakthrough came after a long holiday weekend. Before leaving the lab, Huycke had removed a piece of embryonic mouse gut tube, cut it lengthwise, removed the epithelial layer, flattened it out, and placed it in tissue culture. When he returned, he observed that the mesenchymal cells had formed a pattern of aggregates even without the epithelium. Intrigued as to how the cells clustered together, he watched them through live microscopy. What he saw motivated him to study in detail the physical mechanisms by which the mesenchymal cells aggregate to drive villus formation.

What Huycke discovered is that the aggregate-forming mesenchymal cells possess distinct physical properties that allow them to behave like a fluid. Their high surface tension allows the cells to minimize their surface area and aggregate. An analogy that Huycke uses to describe the phenomenon is when a thin liquid film on the surface of a wet leaf breaks up into droplets. The cells’ fluid-like behavior arises from extracellular matrix remodeling by metalloproteinases and actomyosin activity, which, together with integrin-mediated cohesion, enables diffusive cell motility. The resulting mesenchymal aggregates deform the overlying epithelium and initiate villi formation. This research also demonstrates that the mesenchymal cells’ clustering behavior is cell-autonomous—it occurs independently of signals from the overlying epithelium.

Top-down view of villi in the mouse intestive.
Top-down view of villi in the mouse intestine. The epithelial layer is shown in yellow (E-Cadherin staining), and the mesenchymal cores of the villi are shown in blue (PDGFRα staining).

his discovery provides a mechanical framework for understanding the principles of self-organization. It involves translating insights from the properties and behaviors of well-characterized non-living materials to explain the tissue phase transitions underlying morphogenetic events in development. Although Huycke’s work begins with the gut, the principles may apply to many organs composed of mesenchyme and epithelium. 

From a developmental and evolutionary standpoint, Huycke thinks studying the formation of biological structures during embryonic development offers insights into how nature has evolved multiple strategies to build similar structures and adapt them
to different environments. For instance, he seeks to understand how ground squirrels maintain and
restore gut function during and after hibernation. By examining what happens to their intestinal villi during fasting, he hopes that insights from these natural adaptations can inform advances in regenerative medicine.

Future work from the Huycke lab also aims to address the clinical implications of defects in villi formation. Multiple human conditions involve the absence or loss of these essential gut structures. Congenital diseases such as microvillus inclusion disease prevent proper villus formation during embryonic development. In adults, various factors, such as chemotherapy, viral infections, or celiac disease, can damage intestinal villi. Uncovering how these structures form, Huycke and the scientific community can better understand these diseases and explore whether it is possible to reprogram cells to reproduce similar structures to regenerate villi in the body and restore gut function.

References

  1. K. D. Walton, A. M. Freddo, S. Wang, and D. L. Gumucio, “Generation of intestinal surface: an absorbing tale,” Development, vol. 143, no. 13, pp. 2261–2272, July 2016, doi: 10.1242/dev.135400.
  2. T. R. Huycke et al., “Patterning and folding of intestinal villi by active mesenchymal dewetting,” Cell, vol. 187, no. 12, pp. 3072-3089.e20, June 2024, doi: 10.1016/j.cell.2024.04.039.
  3. G. A. Stooke-Vaughan and O. Campàs, “Physical control of tissue morphogenesis across scales,” Current Opinion in Genetics & Development, vol. 51, pp. 111–119, Aug. 2018, doi: 10.1016/j.gde.2018.09.002.
  4. A. E. Shyer et al., “Villification: How the Gut Gets Its Villi,” Science, vol. 342, no. 6155, pp. 212–218, Oct. 2013, doi: 10.1126/science.1238842.
  5. T. Xiang, J. Wang, and H. Li, “Current applications of intestinal organoids: a review,” Stem Cell Research & Therapy, vol. 15, no. 1, p. 155, May 2024, doi: 10.1186/s13287-024-03768-3.
  6. A. Ensari and M. N. Marsh, “Exploring the villus,” Gastroenterol Hepatol Bed Bench, vol. 11, no. 3, pp. 181–190, 2018.

Last Updated 12/01/2025