Transglutaminase 2 Facilitates Murine Wound Healing in a Strain-Dependent Manner
Transglutaminase 2 (TG2) plays a role in cellular processes that are relevant to wound healing, but to date no studies of wound healing in TG2 knockout mice have been reported. Here, using 129T2/SvEmsJ (129)- or C57BL/6 (B6)-backcrossed TG2 knockout mice, we show that TG2 facilitates murine wound he...
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/14/11475 |
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| author | Ting W. Yiu Sara R. Holman Xenia Kaidonis Robert M. Graham Siiri E. Iismaa |
| author_facet | Ting W. Yiu Sara R. Holman Xenia Kaidonis Robert M. Graham Siiri E. Iismaa |
| author_sort | Ting W. Yiu |
| collection | DOAJ |
| description | Transglutaminase 2 (TG2) plays a role in cellular processes that are relevant to wound healing, but to date no studies of wound healing in TG2 knockout mice have been reported. Here, using 129T2/SvEmsJ (129)- or C57BL/6 (B6)-backcrossed TG2 knockout mice, we show that TG2 facilitates murine wound healing in a strain-dependent manner. Early healing of in vivo cutaneous wounds and closure of in vitro scratch wounds in murine embryonic fibroblast (MEF) monolayers were delayed in 129, but not B6, TG2 knockouts, relative to their wild-type counterparts, with wound closure in 129 being faster than in B6 wild-types. A single dose of exogenous recombinant wild-type TG2 to 129 TG2<sup>−/−</sup> mice or MEFs immediately post-wounding accelerated wound closure. Neutrophil and monocyte recruitment to 129 cutaneous wounds was not affected by <i>Tgm2</i> deletion up to 5 days post-wounding. <i>Tgm2</i> mRNA and TG2 protein abundance were higher in 129 than in B6 wild-types and increased in abundance following cutaneous and scratch wounding. <i>Tgm1</i> and factor XIIA (<i>F13A</i>) mRNA abundance increased post-wounding, but there was no compensation by TG family members in TG2<sup>−/−</sup> relative to TG2<sup>+/+</sup> mice in either strain before or after wounding. 129 TG2<sup>+/+</sup> MEF adhesion was greater and spreading was faster than that of B6 TG2<sup>+/+</sup> MEFs, and was dependent on syndecan binding in the presence, but not absence, of RGD inhibition of integrin binding. Adhesion and spreading of 129, but not B6, TG2<sup>−/−</sup> MEFs was impaired relative to their wild-type counterparts and was accelerated by exogenous addition or transfection of TG2 protein or cDNA, respectively, and was independent of the transamidase or GTP-binding activity of TG2. Rho-family GTPase activation, central to cytoskeletal organization, was altered in 129 TG2<sup>−/−</sup> MEFs, with delayed RhoA and earlier Rac1 activation than in TG2<sup>+/+</sup> MEFs. These findings indicate that the rate of wound healing is different between 129 and B6 mouse strains, correlating with TG2 abundance, and although not essential for wound healing, TG2 facilitates integrin- and syndecan-mediated RhoA- and Rac1-activation in fibroblasts to promote efficient wound contraction. |
| first_indexed | 2024-03-11T01:01:05Z |
| format | Article |
| id | doaj.art-d04f414d3a024c06841d07e0f1f09d61 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T01:01:05Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d04f414d3a024c06841d07e0f1f09d612023-11-18T19:40:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124141147510.3390/ijms241411475Transglutaminase 2 Facilitates Murine Wound Healing in a Strain-Dependent MannerTing W. Yiu0Sara R. Holman1Xenia Kaidonis2Robert M. Graham3Siiri E. Iismaa4Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, AustraliaVictor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, AustraliaVictor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, AustraliaVictor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, AustraliaVictor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, AustraliaTransglutaminase 2 (TG2) plays a role in cellular processes that are relevant to wound healing, but to date no studies of wound healing in TG2 knockout mice have been reported. Here, using 129T2/SvEmsJ (129)- or C57BL/6 (B6)-backcrossed TG2 knockout mice, we show that TG2 facilitates murine wound healing in a strain-dependent manner. Early healing of in vivo cutaneous wounds and closure of in vitro scratch wounds in murine embryonic fibroblast (MEF) monolayers were delayed in 129, but not B6, TG2 knockouts, relative to their wild-type counterparts, with wound closure in 129 being faster than in B6 wild-types. A single dose of exogenous recombinant wild-type TG2 to 129 TG2<sup>−/−</sup> mice or MEFs immediately post-wounding accelerated wound closure. Neutrophil and monocyte recruitment to 129 cutaneous wounds was not affected by <i>Tgm2</i> deletion up to 5 days post-wounding. <i>Tgm2</i> mRNA and TG2 protein abundance were higher in 129 than in B6 wild-types and increased in abundance following cutaneous and scratch wounding. <i>Tgm1</i> and factor XIIA (<i>F13A</i>) mRNA abundance increased post-wounding, but there was no compensation by TG family members in TG2<sup>−/−</sup> relative to TG2<sup>+/+</sup> mice in either strain before or after wounding. 129 TG2<sup>+/+</sup> MEF adhesion was greater and spreading was faster than that of B6 TG2<sup>+/+</sup> MEFs, and was dependent on syndecan binding in the presence, but not absence, of RGD inhibition of integrin binding. Adhesion and spreading of 129, but not B6, TG2<sup>−/−</sup> MEFs was impaired relative to their wild-type counterparts and was accelerated by exogenous addition or transfection of TG2 protein or cDNA, respectively, and was independent of the transamidase or GTP-binding activity of TG2. Rho-family GTPase activation, central to cytoskeletal organization, was altered in 129 TG2<sup>−/−</sup> MEFs, with delayed RhoA and earlier Rac1 activation than in TG2<sup>+/+</sup> MEFs. These findings indicate that the rate of wound healing is different between 129 and B6 mouse strains, correlating with TG2 abundance, and although not essential for wound healing, TG2 facilitates integrin- and syndecan-mediated RhoA- and Rac1-activation in fibroblasts to promote efficient wound contraction.https://www.mdpi.com/1422-0067/24/14/11475TG2wound healingscratch woundcytoskeletal dynamicsmouse strainintegrin |
| spellingShingle | Ting W. Yiu Sara R. Holman Xenia Kaidonis Robert M. Graham Siiri E. Iismaa Transglutaminase 2 Facilitates Murine Wound Healing in a Strain-Dependent Manner International Journal of Molecular Sciences TG2 wound healing scratch wound cytoskeletal dynamics mouse strain integrin |
| title | Transglutaminase 2 Facilitates Murine Wound Healing in a Strain-Dependent Manner |
| title_full | Transglutaminase 2 Facilitates Murine Wound Healing in a Strain-Dependent Manner |
| title_fullStr | Transglutaminase 2 Facilitates Murine Wound Healing in a Strain-Dependent Manner |
| title_full_unstemmed | Transglutaminase 2 Facilitates Murine Wound Healing in a Strain-Dependent Manner |
| title_short | Transglutaminase 2 Facilitates Murine Wound Healing in a Strain-Dependent Manner |
| title_sort | transglutaminase 2 facilitates murine wound healing in a strain dependent manner |
| topic | TG2 wound healing scratch wound cytoskeletal dynamics mouse strain integrin |
| url | https://www.mdpi.com/1422-0067/24/14/11475 |
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