It takes cellular teamwork to heal the intestine

Date:
November 3, 2021
Source:
Baylor College of Medicine
Summary:
A meticulous single-cell analytical approach to study the repair
process of rotavirus-caused injury in an animal model revealed that
the damaged epithelium contains a variety of cell types involved
in repairing it through broad coordinated responses that ultimately
heal the damaged tissue.



FULL STORY ========================================================================== Researchers at Baylor College of Medicine have uncovered a more detailed picture of how the intestinal epithelium -- the lining of the intestines -
- heals itself after infection with rotavirus. A meticulous single-cell analytical approach to study the repair process in an animal model
revealed that the damaged epithelium contains a variety of cell types
involved in repairing it through broad coordinated responses that
ultimately heal the damaged tissue.


==========================================================================
The researchers also unexpectedly discovered that, in addition to
enterocytes, which are the cell type typically infected by rotavirus,
tuft cells, another cell type in the intestinal epithelium, also are
infected and may contribute to the repair response of the epithelium
following damage. The findings, published in the Proceedings of the
National Academy of Sciences, not only provide a better understanding
of the healing process following rotavirus infection, but also may
contribute new clues about how the virus causes disease.

"Diseases of the digestive tract affect about 60 million Americans
each year.

These conditions often are associated with damage to the epithelium, which compromises its functions, including digestion of food and absorption
of nutrients, and affects overall health," said co-corresponding
author Dr. Sarah Blutt, associate professor of molecular virology and microbiology at Baylor.

The researchers' goal on this project was to contribute a better
understanding of the repair process following damage to the intestinal epithelium caused by rotavirus in a mouse model. This virus causes approximately 179 million cases of acute gastroenteritis and about 128,000 deaths annually, particularly in children. Getting into the details of
the cellular response to the damage resulting from the infection can
lead to improved therapies.

Intestinal healing requires teamwork The internal surface of the
intestines is lined with a layer of epithelial cells that folds multiple
times, forming many thin, finger-like projections called villi, with
crypts between them. Rotavirus infects and kills enterocyte cells residing
at the tips of the villi.



==========================================================================
"We know that the damage at the tip is quickly communicated to stem cells residing at the crypt, stimulating them to divide and develop into the specialized cells needed to repair the injury at the tip of the villi,"
Blutt said.

To get a closer look at how the epithelium heals, the team applied a
fairly new technology, single-cell transcriptomics, to determine which
genes were expressed at the single-cell level in all the cells between
the tip and the crypt. There are many different types of cells along the
villi, including tuft cells, goblet cells, enterocytes and stem cells,
each with specific functions.

"Our analyses revealed a complex cellular landscape characterized by
clusters of cells with specific transcriptomic profiles that depended
not only on the cell type but also on the cell's location along the
villi," said first author Carolyn Bomidi, senior research assistant in
the Dr. Mary Estes lab at Baylor.

"For example, the same cell type found in different locations may have different transcriptomic profiles." The researchers' findings also
support a new picture of how regeneration happens. They found that,
in response to the damage at the tips, subsets of stem cells at the
crypt divided more frequently and developed into numerous immature
enterocytes that migrated to the tip of the villi to replace those
injured by rotavirus.

An unexpected host for rotavirus Blutt, Bomidi and their colleagues
were surprised to find rotavirus genetic material inside tuft cells,
a cell type not previously reported to support rotavirus infection.



==========================================================================
"The fact that we can detect the virus at all is exciting, given
that tuft cells are rare in the intestinal epithelium," Bomidi
said. "Rotavirus-infected tuft cells increased the expression of
specific genes, including immune response genes, indicating that they are capable of mounting an antiviral response and contribute to the process following an infection." Altogether, the findings provide evidence
that rotavirus infection stimulates a repair program driven by stem
cells with involvement of tuft cells that results in the production of
immature enterocytes that repair the damaged epithelium.

"I am most excited about this being the first report of the
characterization of single-cell transcripts following an intestinal human
viral infection," Blutt said. "We consider this a valuable resource
of information for researchers involved in gastrointestinal research,
to see how each individual cell type responds in the context of a viral infection." "I anticipate that this approach also will provide new tools
to investigate unanswered aspects of how rotavirus and other infectious
or inflammatory conditions cause disease," said co-corresponding author
Dr. Mary Estes, Cullen Chair and professor of molecular virology and microbiology at Baylor.

Other contributors to this work include Matthew Robertson and Cristian
Coarfa, both at Baylor College of Medicine.

This work was supported by the Center for Comparative Medicine and several Advanced Technology Cores at Baylor College of Medicine. Funding was
provided by the Cancer Prevention and Research Institute of Texas (CPRIT)
Core Facility Support Award (CPRIT-RP180672) and the NIH (CA125123 and RR024574). Further support was provided by Public Health Service Grant
P30 DK56338, NIH (DK56338 and CA125123), CPRIT (RP150578 and RP170719),
the Dan L. Duncan Comprehensive Cancer Center and the John S. Dunn Gulf
Coast Consortium for Chemical Genomics.

Other funding was provided by P30 Digestive Disease Center Support
Grant NIDDK- DK56338, P30 Cancer Center Support Grant NCI-CA125123,
NIH S10 Grant 1S10OD02346901, NIH Shared Instrument Grants S10OD018033, S10OD023469, S10OD025240, and P30EY002520. Data analysis was partially supported by CPRIT core Grants RP170005 and RP200504, National Institute
of Environmental Health Sciences (NIEHS) P30 GC-CPEH ES030285 and NIEHS
P42 ES027725.

========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Original written by Graciela Gutierrez. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Carolyn Bomidi, Matthew Robertson, Cristian Coarfa, Mary K. Estes,
Sarah
E. Blutt. Single-cell sequencing of rotavirus-infected intestinal
epithelium reveals cell-type specific epithelial repair and tuft
cell infection. Proceedings of the National Academy of Sciences,
2021; 118 (45): e2112814118 DOI: 10.1073/pnas.2112814118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211103181252.htm

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