Science - USA (2022-02-11)

11 FEBRUARY 2022 • VOL 375 ISSUE 6581 619

GRAPHIC: KELLIE HOLOSKI/

SCIENCE

BASED ON YUN AND GRECO

SCIENCE science.org

CELL BIOLOGY

From start to finish—a molecular

link in wound repair

By Sangwon Yun^1 and Valentina Greco1,2

D

uring epithelial wound repair, a

subset of epithelial cells become

“leaders” as the epithelial sheet col-

lectively migrates to close the gap.

These leader cells adopt distinct

morphological characteristics and

up-regulate migratory pathways (1, 2),

but the molecular mechanism by which

this subset emerges from an otherwise

homogeneous population remained to

be elucidated. On page 628 of this issue,

Kozyrska et al. ( 3 ) find that leader cell be-

havior initiates with the activation of the

tumor suppressor and transcription fac-

tor p53, which induces p21 expression and

attendant cell cycle inhibition. Once the

injury is resolved, leader cells are elimi-

nated through p53-dependent crowding

hypersensitivity. Classically, p53 becomes

activated by cell stressors, including DNA

damage, oncogenic expression, and hy-

poxia ( 4 ). In the case of mechanical disrup-

tion from wounding, p53 activation occurs

through the stress kinase p38 ( 5 ). These

newly found roles of p53 in leader cell

emergence and elimination provide impor-

tant insight into wound repair.

Under homeostatic conditions, epithe-

lial cells may become motile and move as

individuals or groups. These two forms

of cell migration play key roles in various

biological processes to reorganize a tissue

in response to stimuli ( 6 ). During collec-

tive cell migration, a subset of cells at the

leading edge, called leader cells, direct the

trajectory of the epithelial sheet. Using

Madin-Darby canine kidney (MDCK) cells

in culture, Kozyrska et al. observed that

some of these cells spontaneously lost epi-

thelial morphology and exhibited migra-

tory behavior consistent with that of leader

cells in collective migration. Because these

spontaneous leader cells tended to be bi-

nucleate, the authors sought to determine

whether this property was sufficient to

elicit the leader cell phenotype and blocked

cytokinesis, observing that the resulting

binucleate cells became leaders. Because

cytokinesis failure causes p53-mediated

cell cycle arrest, the authors reasoned and

verified that spontaneous leader cells also

had significantly higher expression of p53.

Indeed, pharmacologic p53 activation was

sufficient to provoke leader cell fate. Thus,

p53 plays a central role in leader cell emer-

gence and behavior. These findings are sur-

prising given prior studies that describe a

role of p53 in inhibiting cancer cell inva-

siveness and the link between loss of p53

and hallmarks of epithelial-mesenchymal

transition, a phenomenon in which epithe-

p53 mediates epithelial cell migration and leader cell

elimination during wound repair

Wound closure delay Aberrant wound resolution

Wound

resolution

Injury

Epithelial cells p53 inhibition or p21 ablation p21 overexpression

p53

activation

p21

up-regulation

CDK

inhibition

Leader

fate

p53 compaction

hypersensitivity and

loser cell elimination

(^1) Department of Genetics, Yale School of Medicine,
New Haven, CT, USA.^2 Departments of Cell Biology
and Dermatology, Yale Stem Cell Center, Yale Cancer
Center, Yale School of Medicine, New Haven, CT, USA.
Email: [email protected]; [email protected]
thought to be a critical factor responsible
for the large electric field–induced strain
observed in the CGO thin film. This is good
news for the design of piezoelectric actua-
tors based on thin films.
Notably, Park et al. have implemented
the same approach to other centrosymmet-
ric systems for inducing piezoelectricity.
They showed that by applying a DC elec-
tric field to yttria-stabilized zirconia and
CGO bulk ceramics, the induced piezoelec-
tric response can be comparable to those
piezoelectric materials currently used in
microelectromechanical systems.
Park et al. show that extremely high pi-
ezoelectricity can be achieved in centrosym-
metric oxides through the electric field–in-
duced redistribution of oxygen vacancies.
Although further research is required to
improve the frequency stability of the piezo-
electric response and to reduce the dielec-
tric loss for CGO thin films, the strategy of
utilizing mobile ions or defects to induce
high piezoelectricity in centrosymmetric
materials opens a new avenue for design-
ing future advanced piezoelectric materials.
Even higher piezoelectricity in ferroelec-
trics is also possible if this design strategy
can be incorporated with other design ap-
proaches already in use, such as the manip-
ulation of ferroelectric phase transition ( 4 ),
domain configuration ( 12 – 14 ), and struc-
tural fluctuation at the nanoscale ( 10 ). From
an application viewpoint, the electric field–
biased CGO thin film may not only benefit
state-of-the-art piezoelectric devices but
also expand the application space for piezo-
electric materials, including biocompatible
piezoelectric devices and piezoelectric sen-
sors with an operational temperature range
above 600°C and a pressure range above
250 MPa ( 15 ). j
REFERENCES AND NOTES

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2. E. Aksel, J. L. Jones, Sensors 10 , 1935 (2010).


3. D.-S. Park et al., Science 375 , 653 (2022).


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5. J. Wu, D. Xiao, J. Zhu, Chem. Rev. 115 , 2559 (2015).


6. W.-Q. Liao et al., Science 363 , 1206 (2019).


7. M. Höfling et al., Science 372 , 961 (2021).


8. H. Liu et al., Science 369 , 292 (2020).


9. S.-E. Park, T. R. Shrout, J. Appl. Phys. 82 , 1804 (1997).


10. F. Li et al., Science 364 , 264 (2019).


11. R. E. Newnham, Q. C. Xu, S. Kumar, L. E. Cross,
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12. B. Wang, F. Li, L.-Q. Chen, Adv. Mater. 33 , 2105071
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ACKNOWLEDGMENTS

This work was supported by the National Natural Science

Foundation of China (grant no. 51922083). The author thanks

L. Luo for helping design the figures.

10.1126/science.abn2903

Dual role of p53 in wound repair

Upon epithelial injury, p38 stress kinase–mediated p53 activation leads to p21 expression, which induces

cyclin-dependent kinase (CDK) inhibition and the leader cell phenotype. For wound resolution to occur, leader

cells become loser cells as a result of p53-mediated compaction hypersensitivity, resulting in their elimination

from the tissue.