p53 directs leader cell behavior, migration, and clearance during epithelial repair

Kasia Kozyrska; Giulia Pilia; Medhavi Vishwakarma; Laura Wagstaff; Maja Goschorska; Silvia Cirillo; Saad Mohamad; Kelli Gallacher; Rafael E Carazo Salas; Eugenia Piddini

doi:10.1126/science.abl8876

p53 directs leader cell behavior, migration, and clearance during epithelial repair

Kasia Kozyrska, Giulia Pilia, Medhavi Vishwakarma, Laura Wagstaff, Maja Goschorska, Silvia Cirillo, Saad Mohamad, Kelli Gallacher, Rafael E Carazo Salas, Eugenia Piddini^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

Epithelial cells migrate across wounds to repair injured tissue. Leader cells at the front of migrating sheets often drive this process. However, it is unclear how leaders emerge from an apparently homogeneous epithelial cell population. We characterized leaders emerging from epithelial monolayers in cell culture and found that they activated the stress sensor p53, which was sufficient to initiate leader cell behavior. p53 activated the cell cycle inhibitor p21WAF1/CIP1, which in turn induced leader behavior through inhibition of cyclin-dependent kinase activity. p53 also induced crowding hypersensitivity in leader cells such that, upon epithelial closure, they were eliminated by cell competition. Thus, mechanically induced p53 directs emergence of a transient population of leader cells that drive migration and ensures their clearance upon epithelial repair.

Original language	English
Article number	eabl8876
Number of pages	11
Journal	Science
Volume	375
Issue number	6581
DOIs	https://doi.org/10.1126/science.abl8876
Publication status	Published - 11 Feb 2022

Bibliographical note

Funding Information:
This work was supported by a Human Frontier Science Program (HFSP) grant RGP0043/ 2019 to R.E.C.S., a Cambridge Cancer Centre PhD studentship to M.G., a Cancer Research UK Programme Grant to E.P. (A12460), a Cancer Research UK Programme Foundation Award to E.P. (C38607/A26831), and a Royal Society University Research fellowship to E.P. (UF0905080). E.P. is a Wellcome Trust Senior Research Fellow (205010/Z/16/Z).

Publisher Copyright:
© 2022 American Association for the Advancement of Science. All rights reserved.

Keywords

p53
collective cell migration
Cell competition
leader cells
epithelial repair
p21

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title = "p53 directs leader cell behavior, migration, and clearance during epithelial repair",

abstract = "Epithelial cells migrate across wounds to repair injured tissue. Leader cells at the front of migrating sheets often drive this process. However, it is unclear how leaders emerge from an apparently homogeneous epithelial cell population. We characterized leaders emerging from epithelial monolayers in cell culture and found that they activated the stress sensor p53, which was sufficient to initiate leader cell behavior. p53 activated the cell cycle inhibitor p21WAF1/CIP1, which in turn induced leader behavior through inhibition of cyclin-dependent kinase activity. p53 also induced crowding hypersensitivity in leader cells such that, upon epithelial closure, they were eliminated by cell competition. Thus, mechanically induced p53 directs emergence of a transient population of leader cells that drive migration and ensures their clearance upon epithelial repair.",

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author = "Kasia Kozyrska and Giulia Pilia and Medhavi Vishwakarma and Laura Wagstaff and Maja Goschorska and Silvia Cirillo and Saad Mohamad and Kelli Gallacher and {Carazo Salas}, {Rafael E} and Eugenia Piddini",

note = "Funding Information: This work was supported by a Human Frontier Science Program (HFSP) grant RGP0043/ 2019 to R.E.C.S., a Cambridge Cancer Centre PhD studentship to M.G., a Cancer Research UK Programme Grant to E.P. (A12460), a Cancer Research UK Programme Foundation Award to E.P. (C38607/A26831), and a Royal Society University Research fellowship to E.P. (UF0905080). E.P. is a Wellcome Trust Senior Research Fellow (205010/Z/16/Z). Publisher Copyright: {\textcopyright} 2022 American Association for the Advancement of Science. All rights reserved.",

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AU - Kozyrska, Kasia

AU - Pilia, Giulia

AU - Vishwakarma, Medhavi

AU - Wagstaff, Laura

AU - Goschorska, Maja

AU - Cirillo, Silvia

AU - Mohamad, Saad

AU - Gallacher, Kelli

AU - Carazo Salas, Rafael E

AU - Piddini, Eugenia

N1 - Funding Information: This work was supported by a Human Frontier Science Program (HFSP) grant RGP0043/ 2019 to R.E.C.S., a Cambridge Cancer Centre PhD studentship to M.G., a Cancer Research UK Programme Grant to E.P. (A12460), a Cancer Research UK Programme Foundation Award to E.P. (C38607/A26831), and a Royal Society University Research fellowship to E.P. (UF0905080). E.P. is a Wellcome Trust Senior Research Fellow (205010/Z/16/Z). Publisher Copyright: © 2022 American Association for the Advancement of Science. All rights reserved.

PY - 2022/2/11

Y1 - 2022/2/11

N2 - Epithelial cells migrate across wounds to repair injured tissue. Leader cells at the front of migrating sheets often drive this process. However, it is unclear how leaders emerge from an apparently homogeneous epithelial cell population. We characterized leaders emerging from epithelial monolayers in cell culture and found that they activated the stress sensor p53, which was sufficient to initiate leader cell behavior. p53 activated the cell cycle inhibitor p21WAF1/CIP1, which in turn induced leader behavior through inhibition of cyclin-dependent kinase activity. p53 also induced crowding hypersensitivity in leader cells such that, upon epithelial closure, they were eliminated by cell competition. Thus, mechanically induced p53 directs emergence of a transient population of leader cells that drive migration and ensures their clearance upon epithelial repair.

AB - Epithelial cells migrate across wounds to repair injured tissue. Leader cells at the front of migrating sheets often drive this process. However, it is unclear how leaders emerge from an apparently homogeneous epithelial cell population. We characterized leaders emerging from epithelial monolayers in cell culture and found that they activated the stress sensor p53, which was sufficient to initiate leader cell behavior. p53 activated the cell cycle inhibitor p21WAF1/CIP1, which in turn induced leader behavior through inhibition of cyclin-dependent kinase activity. p53 also induced crowding hypersensitivity in leader cells such that, upon epithelial closure, they were eliminated by cell competition. Thus, mechanically induced p53 directs emergence of a transient population of leader cells that drive migration and ensures their clearance upon epithelial repair.

KW - p53

KW - collective cell migration

KW - Cell competition

KW - leader cells

KW - epithelial repair

KW - p21

U2 - 10.1126/science.abl8876

DO - 10.1126/science.abl8876

M3 - Article (Academic Journal)

C2 - 35143293

SN - 0036-8075

VL - 375

JO - Science

JF - Science

IS - 6581

M1 - eabl8876

ER -

p53 directs leader cell behavior, migration, and clearance during epithelial repair

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