Deletion of single gene promotes growth of functional lymphatic valves
Targeting the gene Foxo1 may offer an early treatment approach for
hereditary lymphedema

Date:
August 10, 2021
Source:
University of South Florida (USF Health)
Summary:
A preclinical study unexpectedly identified the gene Foxo1 as a
potential treatment target for hereditary lymphedema. Valve loss
or dysfunction that disrupts the flow of lymph fluid is strongly
associated with lymphedema in patients. But no one has discovered
whether new valves can be grown or if defective ones can be
fixed. The new study, using a model of human primary lymphedema,
shows that both are possible.



FULL STORY ==========================================================================
A University of South Florida (USF Health) preclinical study unexpectedly identified the gene Foxo1 as a potential treatment target for hereditary lymphedema. The research, published July 15 in The Journal of Clinical Investigation, was done with colleagues from Tulane University and the University of Missouri.


========================================================================== Lymphedema -- a chronic condition in which lymphatic (lymph) fluid
accumulates in soft tissue under the skin, usually in the arms and legs -- causes minor to painfully disfiguring swelling. Primary, or hereditary, lymphedema is rare, present at birth and caused in part by genetic
mutations that regulate normal lymphatic valve development. Secondary,
or acquired, lymphedema is caused by damage to the lymphatic system from surgery, radiation therapy, trauma, or parasitic infection. In the U.S., lymphedema most commonly affects breast cancer patients, with prevalence ranging from 10 to 40% after lymph node removal and radiation therapy.

While lymphedema can be managed with massage and compression garments,
no treatment exists to address its underlying cause: the build-up of fluid
that eventually backs up in the lymph system like an overflowing sink with
a blocked drain. This stagnant lymph triggers an inflammatory response
that can induce connective and fatty tissue to form and harden the skin, restricting movement and increasing the risk of recurrent infections.

"The later fibrosis stage of lymphedema cannot be massaged away," said
study principal investigator Ying Yang, PhD, assistant professor of
molecular pharmacology and physiology at the USF Health Morsani College
of Medicine.

"Targeting lymph valves early in the disease is one critical aspect
in identifying an effective treatment for lymphedema. If the disease
progresses too far, it's difficult to reverse." Valve loss or dysfunction
that disrupts the flow of lymph fluid is strongly associated with
lymphedema in patients. But no one has discovered whether new valves
can be grown or if defective ones can be fixed.

The USF Health-led study shows that both are possible.

Dr. Yang's group hypothesized that the protein encoded by the gene
Foxo1plays a key role in lymph valve formation based on an earlier USF
Health discovery of cell signaling processes controlling formation of
lymph valves. The researchers showed that deleting a single gene --
lymphatic vessel-specific Foxo1 - - promoted the growth of markedly
more valves in both young postnatal mice and adult mice than in control littermates without Foxo1deletion. Furthermore, deleting Foxo1 in a mouse
model mimicking human lymphedema-distichiasis syndrome fully restored
the both the number of valves and valve function.

"It was exciting to see that Foxo1 is the only gene so far reported
that, when deleted, induces more lymphatic valves to form, instead of inhibiting valve growth," Dr. Yang said. "We actually reversed valve
loss and repaired the structure and function of defective valves in
a genetic mutation model of lymphedema...That type of discovery makes
a study clinically relevant." The lymphatic circulatory system -- a
parallel of the blood vessel circulatory system -- helps maintain healthy
fluid balance in the body by collecting and controlling the flow of extra
lymph fluid that leaks from tissue. This complex network propels watery
lymph fluid carrying proteins, nutrients and toxin- destroying immune
cells through the body in one direction before returning the fluid to circulating blood. Small valves inside lymph vessels open and close
in response to force exerted by the lymph fluid, moving it forward and preventing backward flow into tissues.

Among the key study findings:
* The protein FOXO1 (encoded by gene Foxo1) inhibits lymph valves from
developing by suppressing many genes, which collectively contribute
to the multi-step process of making a mature valve. FOXO1 behaves
like a brake on a set of valve-forming genes, Dr. Yang said. "Once
the brake is removed, all those genes can now be expressed so that
new valves can successfully grow."
* Inactivation (knockout) of Foxo1in lymphatic endothelial cells
(LEC) of
young postnatal mice promoted valve formation at multiple stages.

Likewise, deleting LEC-specific Foxo1 in adult mice also increased
valve formation, compared to control mice without the gene knockout.

* A mouse model of lymphedema-distichiasis syndrome had 50% fewer
lymphatic
valves and the remaining valves closed abnormally and exhibited
fluid backflow. But whenFoxo1 was deleted, the number of valves
increased to the same levels as those in healthy control mice and
the structure of defective valves was restored to normal. Further
analysis showed that the loss of Foxo1 also significantly improved
valve function in this mouse model of human primary lymphedema
disease.

This study was supported by grants from the National Heart, Lung, and
Blood Institute, a part of the National Institutes of Health.

========================================================================== Story Source: Materials provided by
University_of_South_Florida_(USF_Health). Original written by Anne
DeLotto Baier. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Joshua P. Scallan, Luz A. Knauer, Huayan Hou, Jorge A. Castorena-
Gonzalez, Michael J. Davis, Ying Yang. Foxo1 deletion promotes the
growth of new lymphatic valves. Journal of Clinical Investigation,
2021; 131 (14) DOI: 10.1172/JCI142341 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210810110953.htm

--- up 13 weeks, 4 days, 22 hours, 45 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)