Nuclear softening allows cells to move into dense tissue, encouraging
injury repair

Date:
June 22, 2020
Source:
University of Pennsylvania School of Medicine
Summary:
Using an enzyme inhibitor in meniscus cells, a new study was
able to soften their nucleus and promote access to previously
impassible areas.



FULL STORY ==========================================================================
By softening a cell's nucleus so that it can squeeze its way through dense connective tissues, a group of researchers believe they've demonstrated
a new way to help the body efficiently repair injuries. The team of
researchers from the University of Pennsylvania tested this theory by
using a medication to inhibit enzymes in the nucleus of knee's meniscus
cells, which allowed the cells to move through environments that were previously impenetrable. This study was published in Science Advances.


==========================================================================
The study focuses on cells in the meniscus, which is a thin layer of
dense connective tissue in the human knee. However, the approach could
prove effective beyond that specific area.

"In this case, we studied how meniscus cell nuclei can be softened to
promote their migration through meniscus tissues. We have also shown
similar enhancement of cell migration in other types of connective
tissues, such as tendons or the cartilage covering the ends of bones,"
said the study's first author, Su Chin Heo, PhD, an assistant professor
of research of Orthopaedic Surgery, who works within the McKay Orthopaedic Research Lab.

The paper's corresponding author, Robert L Mauck, PhD, the Mary Black
Ralston Professor of Orthopaedic Surgery and director of the McKay Lab,
noted that "this finding may pave the way for new therapeutics to improve endogenous repair of a number of dense connective tissues that have poor natural healing capacity and are prone to failure." After an injury,
the body requires cells to move into the afflicted area and deposit
new tissues so that the tissue can be repaired, like a truck delivering
cement to a construction site. Allowing cells to move more freely into
these areas could make healing quicker and/or more efficient. However,
the team believed that stiff nuclei were the limiting factor, especially
when it came to dense tissue such as the meniscus in the knee. Moving
through this type of tissue could rupture or otherwise damage a repair
cell's nucleus as it tried to squeeze through the tight spaces between
cells. As such, damage to tissue like the meniscus could heal poorly,
if at all, and result in frequent reinjury.

To remedy that, the team of researchers applied an inhibitor drug to
cells called trichostatin A (TCA) that makes the proteins within their
nuclei soften up, allowing for the nucleus as a whole to become more
malleable. In the truck analogy, this would be like switching from a rigid truck trailer to one with a canvas cover so that it could access a job
site at the end of a road with low- hanging trees. The cover could bend
as it made its way through the branches but not get hung up or damaged
like a boxy, metal trailer would.

In the study, the teams saw that isolated meniscus cells that had been
treated with TCA were able to move through areas that were once thought to
be impassible to reach defects in tissue. This is important becomes some
of the repair methods used for injuries involve fibrous scaffolding, which
can also be dense and impenetrable. These areas, too, could be infiltrated
with the repair cells whose nuclei were softened, the study showed.

Moving forward, the researchers are preparing to conduct trials of this technique in meniscus tears in large animals. There is also a possibility
that this work has applicability beyond just musculoskeletal injuries.

"This isn't something we've tested yet, but this approach could
potentially be used to enhance the wound healing process of other types
of tissues, such as in the skin," Mauck said.


========================================================================== Story Source: Materials provided by University_of_Pennsylvania_School_of_Medicine. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Su-Jin Heo, Kwang Hoon Song, Shreyasi Thakur, Liane M. Miller,
Xuan Cao,
Ana P. Peredo, Breanna N. Seiber, Feini Qu, Tristan P. Driscoll,
Vivek B.

Shenoy, Melike Lakadamyali, Jason A. Burdick, Robert
L. Mauck. Nuclear softening expedites interstitial cell migration
in fibrous networks and dense connective tissues. Science Advances,
2020; 6 (25): eaax5083 DOI: 10.1126/sciadv.aax5083 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200622133055.htm

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