A Cedars-Sinai research collaboration has described the first steps in how the body forms villi, the finger-like projections that cover the surface of the small intestine.
Newswise — LOS ANGELES (May 22, 2024) -- Scientists with Cedars-Sinai Guerin Children’s, the University of California, San Francisco (UCSF), and other institutions have identified the critical first steps in how the digestive system develops.
The findings, published in Cell, could help scientists develop interventions that repair damaged intestines.
“This study moves forward our knowledge about how the villi, the long and narrow microscopic protrusions that line the small intestine, are first formed,” said Ophir Klein, MD, PhD, executive vice dean of Children’s Health at Cedars-Sinai, executive director of Guerin Children’s and co-corresponding author of the study.
“Understanding villi creation in detail could lead to new treatments for digestive disorders,” said Klein, who is also the David and Meredith Kaplan Distinguished Chair in Children’s Health.
Villi help the body absorb nutrients. They can become damaged by autoimmune disorders, such as celiac disease, or as a result of radiation or chemotherapy to treat cancer.
This study involved a collaboration between scientists working with Klein at Guerin Children’s and with Zev Gartner, PhD, at UCSF. Investigators at the California Institute of Technology and University of Michigan also contributed to the study.
The research teams used high-resolution microscopic techniques to observe how fetal intestines form in laboratory mice, which build their villi similarly to how humans create villi.
The investigators grew intestinal tissue from mouse embryos in laboratory dishes to see in real time how cells began constructing villi. The researchers labeled cell populations with fluorescent proteins to observe which ones were involved in building tissue.
By doing so, they discovered that fibroblasts, a type of connective tissue cell, behave like a sheet of water that breaks up into droplets. They describe this mechanism, which under a microscope looks like rain on a windshield, as “dewetting.” Using a mathematical model, the investigators found that cells follow the same physical principles as water to form droplet-like cellular aggregates that fold tissue into villi.
“Some people have atrophied villi that are blunted or completely flattened due to disease or damage, causing malabsorption and other digestive disorders,” said Tyler Huycke, PhD, a postdoctoral scholar in the School of Pharmacy at UCSF and one of the three co-first authors of the study. “If we can induce cells to undergo this aggregation and tissue-folding behavior that we observe during normal development, we might be able to create more villi and more absorptive surface area for people with digestive disease.”
The investigators plan to study additional steps involved in villi creation, including learning how the tissues continue to elongate into their final form and the cell signaling involved.
“The mechanism we describe in this paper is used by cells to create a patterned curvature in tissues that eventually form villi,” said Gartner, a professor in the Department of Pharmaceutical Chemistry at UCSF and co-corresponding author of the study. “We seek to understand if this mechanism forms other parts of the body. This work lays the foundation for engineering functional human tissues for applications ranging from regenerative medicine to disease modeling and drug testing.”
Cedars-Sinai investigators Emilie Barruet, Dedeepya Vaka and Dario Boffelli also worked on the study. Other investigators include Teemu Häkkinen, Hikaru Miyazaki, Vasudha Srivastava, Emilie Barruet, Christopher McGinnis, Ali Kalantari, Jake Cornwall-Scoones, Qin Zhu, Hyunil Jo, Roger Oria, Valerie Weaver, William DeGrado, Matt Thomson and Krishna Garikipati.
Funding: The study was funded by R01DK126376, R35DE026602, F32DK128949, U01CA244109, R01GM135462, and U01DK103147 from the Intestinal Stem Cell Consortium, a collaborative research project funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases. This work was further supported by funding for the UCSF Center for Cellular Construction by the National Science Foundation.
Read more on the Cedars-Sinai Blog: New Organ-Chip Can Re-Create the Cells of Your Intestines
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