Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function

Horacio Maldonado; Bryan D. Savage; Harlan R. Barker; Ulrike May; Maria Vähätupa; Rahul K. Badiani; Katarzyna I. Wolanska; Craig M.L. Turner; Toini Pemmari; Tuomo Ketomäki; Stuart Prince; Martin J. Humphries; Erkki Ruoslahti; Mark R. Morgan; Tero A.H. Järvinen

doi:10.1038/s41467-023-43848-1

Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function

Horacio Maldonado, Bryan D. Savage, Harlan R. Barker, Ulrike May, Maria Vähätupa, Rahul K. Badiani, Katarzyna I. Wolanska, Craig M.L. Turner, Toini Pemmari, Tuomo Ketomäki, Stuart Prince, Martin J. Humphries, Erkki Ruoslahti, Mark R. Morgan, Tero A.H. Järvinen

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Abstract

CAR (CARSKNKDC) is a wound-homing peptide that recognises angiogenic neovessels. Here we discover that systemically administered CAR peptide has inherent ability to promote wound healing: wounds close and re-epithelialise faster in CAR-treated male mice. CAR promotes keratinocyte migration in vitro. The heparan sulfate proteoglycan syndecan-4 regulates cell migration and is crucial for wound healing. We report that syndecan-4 expression is restricted to epidermis and blood vessels in mice skin wounds. Syndecan-4 regulates binding and internalisation of CAR peptide and CAR-mediated cytoskeletal remodelling. CAR induces syndecan-4-dependent activation of the small GTPase ARF6, via the guanine nucleotide exchange factor cytohesin-2, and promotes syndecan-4-, ARF6- and Cytohesin-2-mediated keratinocyte migration. Finally, we show that genetic ablation of syndecan-4 in male mice eliminates CAR-induced wound re-epithelialisation following systemic administration. We propose that CAR peptide activates syndecan-4 functions to selectively promote re-epithelialisation. Thus, CAR peptide provides a therapeutic approach to enhance wound healing in mice; systemic, yet target organ- and cell-specific.

Original language	English
Article number	8069
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-43848-1
Publication status	Published - Dec 2023
Publication type	A1 Journal article-refereed

Funding

We thank Dr Venkata Ramana Kotamraju for peptide synthesis, Marianne Karlsberg, Anni Laitinen, Robbin Newlin, Fernanda Munoz Caro and Marja-Leena Koskinen for practical support and for performing the histochemical work. Guillermina Garcia is thanked for her technical expertise and help with quantitative microscopy. Dr Mark Bass (University of Sheffield, UK) provided SDC4 knockout mice (originally generated in the Centre for Animal Resources and Development, Kumamoto University, Japan by professor Tetsuhito Kojima, Nagoya University, Japan). Prof. Hiroyuki Sakagami (Kitasato University, Japan) provided anti-cytohesin-2 antibody. We thank the Biomedical Imaging Facility and Centre for Cell Imaging for support and access to equipment, provided by Liverpool Shared Research Facilities, University of Liverpool, and Dr Stacey Warwood, Dr Julian Selley and Dr David Knight, from the Biological Mass Spectrometry Core Facility at the University of Manchester (RRID code: SCR_020987), for running samples and data archiving/management. The schematic diagram in Fig. was created using elements from BioRender.com (wound image, vasculature and syringe). This work was funded by the US Armed Forces Institute for Regenerative Medicine (AFIRM) (E.R.), Sigrid Juselius Foundation (T.A.H.J.), the Academy of Finland (T.A.H.J.), Päivikki and Sakari Sohlberg Foundation (T.A.H.J.), Instrumentarium Research Foundation (T.A.H.J.), Tampere Tuberculosis Foundation (T.A.H.J.), Finnish Medical Foundation (T.A.H.J.), Pirkanmaa Hospital District Research Foundation (T.A.H.J.), the Finnish Cultural Foundation (T.A.H.J.), Breast Cancer Now (Grant Reference 2015MayPR507 - M.R.M. & H.M.), North West Cancer Research (Grant References CD2019.12 - M.R.M. & H.M., CR1010 - M.R.M. & K.I.W., CR1143 -M.R.M. & K.I.W., and CEMorgan2018 - M.R.M.) and Wellcome (Grant References 215191/Z/19/Z – M.R.M. & B.D.S., 092015 – M.J.H. & M.R.M.). We thank Dr Venkata Ramana Kotamraju for peptide synthesis, Marianne Karlsberg, Anni Laitinen, Robbin Newlin, Fernanda Munoz Caro and Marja-Leena Koskinen for practical support and for performing the histochemical work. Guillermina Garcia is thanked for her technical expertise and help with quantitative microscopy. Dr Mark Bass (University of Sheffield, UK) provided SDC4 knockout mice (originally generated in the Centre for Animal Resources and Development, Kumamoto University, Japan by professor Tetsuhito Kojima, Nagoya University, Japan)67. Prof. Hiroyuki Sakagami (Kitasato University, Japan) provided anti-cytohesin-2 antibody. We thank the Biomedical Imaging Facility and Centre for Cell Imaging for support and access to equipment, provided by Liverpool Shared Research Facilities, University of Liverpool, and Dr Stacey Warwood, Dr Julian Selley and Dr David Knight, from the Biological Mass Spectrometry Core Facility at the University of Manchester (RRID code: SCR_020987), for running samples and data archiving/management. The schematic diagram in Fig. 10 was created using elements from BioRender.com (wound image, vasculature and syringe). This work was funded by the US Armed Forces Institute for Regenerative Medicine (AFIRM) (E.R.), Sigrid Juselius Foundation (T.A.H.J.), the Academy of Finland (T.A.H.J.), Päivikki and Sakari Sohlberg Foundation (T.A.H.J.), Instrumentarium Research Foundation (T.A.H.J.), Tampere Tuberculosis Foundation (T.A.H.J.), Finnish Medical Foundation (T.A.H.J.), Pirkanmaa Hospital District Research Foundation (T.A.H.J.), the Finnish Cultural Foundation (T.A.H.J.), Breast Cancer Now (Grant Reference 2015MayPR507 - M.R.M. & H.M.), North West Cancer Research (Grant References CD2019.12 - M.R.M. & H.M., CR1010 - M.R.M. & K.I.W., CR1143 -M.R.M. & K.I.W., and CEMorgan2018 - M.R.M.) and Wellcome (Grant References 215191/Z/19/Z – M.R.M. & B.D.S., 092015 – M.J.H. & M.R.M.).

Funders	Funder number
Biological Mass Spectrometry Core Facility	SCR_020987
Biomedical Imaging Facility
Centre for Animal Resources and Development
Orion Research Foundation sr, Finland and Instrumentarium Science Foundation sr, Finland
Pirkanmaa Hospital District Research Foundation
Armed Forces Institute of Regenerative Medicine
Suomen Lääketieteen Säätiö
Wellcome Trust	092015, 215191/Z/19/Z
North West Cancer Research	CR1143, CEMorgan2018, CR1010, CD2019.12
University of Liverpool
Academy of Finland
Suomen Kulttuurirahasto
Kumamoto University, Research Center for Higher Education
Päivikki ja Sakari Sohlbergin Säätiö
Sigrid Juséliuksen Säätiö
Tampereen tuberkuloosisäätiö
Kitasato University Hospital
Breast Cancer Now	2015MayPR507

Publication forum classification

Publication forum level 3

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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s41467-023-43848-1Final published version, 8.99 MBLicence: CC BY

https://urn.fi/URN:NBN:fi:tuni-2023122011073Licence: CC BY

Cite this

Maldonado, H., Savage, B. D., Barker, H. R., May, U., Vähätupa, M., Badiani, R. K., Wolanska, K. I., Turner, C. M. L., Pemmari, T., Ketomäki, T., Prince, S., Humphries, M. J., Ruoslahti, E., Morgan, M. R., & Järvinen, T. A. H. (2023). Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function. Nature Communications, 14(1), Article 8069. https://doi.org/10.1038/s41467-023-43848-1

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title = "Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function",

abstract = "CAR (CARSKNKDC) is a wound-homing peptide that recognises angiogenic neovessels. Here we discover that systemically administered CAR peptide has inherent ability to promote wound healing: wounds close and re-epithelialise faster in CAR-treated male mice. CAR promotes keratinocyte migration in vitro. The heparan sulfate proteoglycan syndecan-4 regulates cell migration and is crucial for wound healing. We report that syndecan-4 expression is restricted to epidermis and blood vessels in mice skin wounds. Syndecan-4 regulates binding and internalisation of CAR peptide and CAR-mediated cytoskeletal remodelling. CAR induces syndecan-4-dependent activation of the small GTPase ARF6, via the guanine nucleotide exchange factor cytohesin-2, and promotes syndecan-4-, ARF6- and Cytohesin-2-mediated keratinocyte migration. Finally, we show that genetic ablation of syndecan-4 in male mice eliminates CAR-induced wound re-epithelialisation following systemic administration. We propose that CAR peptide activates syndecan-4 functions to selectively promote re-epithelialisation. Thus, CAR peptide provides a therapeutic approach to enhance wound healing in mice; systemic, yet target organ- and cell-specific.",

author = "Horacio Maldonado and Savage, {Bryan D.} and Barker, {Harlan R.} and Ulrike May and Maria V{\"a}h{\"a}tupa and Badiani, {Rahul K.} and Wolanska, {Katarzyna I.} and Turner, {Craig M.L.} and Toini Pemmari and Tuomo Ketom{\"a}ki and Stuart Prince and Humphries, {Martin J.} and Erkki Ruoslahti and Morgan, {Mark R.} and J{\"a}rvinen, {Tero A.H.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-43848-1",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

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Maldonado, H, Savage, BD, Barker, HR, May, U, Vähätupa, M, Badiani, RK, Wolanska, KI, Turner, CML, Pemmari, T, Ketomäki, T, Prince, S, Humphries, MJ, Ruoslahti, E, Morgan, MR & Järvinen, TAH 2023, 'Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function', Nature Communications, vol. 14, no. 1, 8069. https://doi.org/10.1038/s41467-023-43848-1

TY - JOUR

T1 - Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function

AU - Maldonado, Horacio

AU - Savage, Bryan D.

AU - Barker, Harlan R.

AU - May, Ulrike

AU - Vähätupa, Maria

AU - Badiani, Rahul K.

AU - Wolanska, Katarzyna I.

AU - Turner, Craig M.L.

AU - Pemmari, Toini

AU - Ketomäki, Tuomo

AU - Prince, Stuart

AU - Humphries, Martin J.

AU - Ruoslahti, Erkki

AU - Morgan, Mark R.

AU - Järvinen, Tero A.H.

PY - 2023/12

Y1 - 2023/12

N2 - CAR (CARSKNKDC) is a wound-homing peptide that recognises angiogenic neovessels. Here we discover that systemically administered CAR peptide has inherent ability to promote wound healing: wounds close and re-epithelialise faster in CAR-treated male mice. CAR promotes keratinocyte migration in vitro. The heparan sulfate proteoglycan syndecan-4 regulates cell migration and is crucial for wound healing. We report that syndecan-4 expression is restricted to epidermis and blood vessels in mice skin wounds. Syndecan-4 regulates binding and internalisation of CAR peptide and CAR-mediated cytoskeletal remodelling. CAR induces syndecan-4-dependent activation of the small GTPase ARF6, via the guanine nucleotide exchange factor cytohesin-2, and promotes syndecan-4-, ARF6- and Cytohesin-2-mediated keratinocyte migration. Finally, we show that genetic ablation of syndecan-4 in male mice eliminates CAR-induced wound re-epithelialisation following systemic administration. We propose that CAR peptide activates syndecan-4 functions to selectively promote re-epithelialisation. Thus, CAR peptide provides a therapeutic approach to enhance wound healing in mice; systemic, yet target organ- and cell-specific.

AB - CAR (CARSKNKDC) is a wound-homing peptide that recognises angiogenic neovessels. Here we discover that systemically administered CAR peptide has inherent ability to promote wound healing: wounds close and re-epithelialise faster in CAR-treated male mice. CAR promotes keratinocyte migration in vitro. The heparan sulfate proteoglycan syndecan-4 regulates cell migration and is crucial for wound healing. We report that syndecan-4 expression is restricted to epidermis and blood vessels in mice skin wounds. Syndecan-4 regulates binding and internalisation of CAR peptide and CAR-mediated cytoskeletal remodelling. CAR induces syndecan-4-dependent activation of the small GTPase ARF6, via the guanine nucleotide exchange factor cytohesin-2, and promotes syndecan-4-, ARF6- and Cytohesin-2-mediated keratinocyte migration. Finally, we show that genetic ablation of syndecan-4 in male mice eliminates CAR-induced wound re-epithelialisation following systemic administration. We propose that CAR peptide activates syndecan-4 functions to selectively promote re-epithelialisation. Thus, CAR peptide provides a therapeutic approach to enhance wound healing in mice; systemic, yet target organ- and cell-specific.

U2 - 10.1038/s41467-023-43848-1

DO - 10.1038/s41467-023-43848-1

M3 - Article

C2 - 38057316

AN - SCOPUS:85178928237

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 8069

ER -

Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function

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