Thyroxine restores severely impaired cutaneous re-epithelialisation and angiogenesis in a novel preclinical assay for studying human skin wound healing under “pathological” conditions ex vivo
Impaired cutaneous wound healing remains a major healthcare challenge. The enormity of this challenge is compounded by the lack of preclinical human skin wound healing models that recapitulate selected key factors underlying impaired healing, namely hypoxia/poor tissue perfusion, oxidative damage, d...
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| Veröffentlicht in: | Archives of Dermatological Research 2021-04, Vol.313 (3), p.181-192 |
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| creator | Post, H. Hundt, J. E. Zhang, G. Depping, R. Rose, C. Langan, E. A. Paus, R. |
| description | Impaired cutaneous wound healing remains a major healthcare challenge. The enormity of this challenge is compounded by the lack of preclinical human skin wound healing models that recapitulate selected key factors underlying impaired healing, namely hypoxia/poor tissue perfusion, oxidative damage, defective innervation, and hyperglycaemia. Since organ-cultured human skin already represents a denervated and impaired perfusion state, we sought to further mimic “pathological” wound healing conditions by culturing experimentally wounded, healthy full-thickness frontotemporal skin from three healthy female subjects for three days in either serum-free supplemented Williams’ E medium or in unsupplemented medium under “pathological” conditions (i.e. hypoxia [5% O
2
], oxidative damage [10 mM H
2
O
2
], absence of insulin, excess glucose). Under these “pathological” conditions, dermal–epidermal split formation and dyskeratosis were prominent in organ-cultured human skin, and epidermal reepithelialisation was significantly impaired (
p
|
| doi_str_mv | 10.1007/s00403-020-02092-z |
| format | Article |
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2
], oxidative damage [10 mM H
2
O
2
], absence of insulin, excess glucose). Under these “pathological” conditions, dermal–epidermal split formation and dyskeratosis were prominent in organ-cultured human skin, and epidermal reepithelialisation was significantly impaired (
p
< 0.001), associated with reduced keratinocyte proliferation (
p
< 0.001), cytokeratin 6 expression (
p
< 0.001) and increased apoptosis (
p
< 0.001). Moreover, markers of intracutaneous angiogenesis (CD31 immunoreactivity and the number of of CD31 positive cells and CD31 positive vessel lumina) were significantly reduced. Since we had previously shown that thyroxine promotes wound healing in healthy human skin ex vivo, we tested whether this in principle also occurs under “pathological” wound healing conditions. Indeed, thyroxine administration sufficed to rescue re-epithelialisation (
p
< 0.001) and promoted both epidermal keratinocyte proliferation (
p
< 0.01) and angiogenesis in terms of CD31 immunoreactivity and CD31 positive cells under “pathological” conditions (
p
< 0.001) ex vivo. This demonstrates the utility of this pragmatic short-term ex vivo model, which recapitulates some key parameters of impaired human skin wound healing, for the preclinical identification of promising wound healing promoters.]]></description><identifier>ISSN: 0340-3696</identifier><identifier>EISSN: 1432-069X</identifier><identifier>DOI: 10.1007/s00403-020-02092-z</identifier><identifier>PMID: 32572565</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Angiogenesis ; Apoptosis ; Cytokeratin ; Dermatology ; Dyskeratosis ; Hydrogen peroxide ; Hyperglycemia ; Hypoxia ; Immunoreactivity ; Innervation ; Insulin ; Medicine ; Medicine & Public Health ; Original Paper ; Perfusion ; Skin tests ; Thyroxine ; Wound healing</subject><ispartof>Archives of Dermatological Research, 2021-04, Vol.313 (3), p.181-192</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-74a98c7a19df631f0f6a26c42de9798990fa2a406d5791d6c1337164822db1ca3</citedby><cites>FETCH-LOGICAL-c474t-74a98c7a19df631f0f6a26c42de9798990fa2a406d5791d6c1337164822db1ca3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00403-020-02092-z$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00403-020-02092-z$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32572565$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Post, H.</creatorcontrib><creatorcontrib>Hundt, J. E.</creatorcontrib><creatorcontrib>Zhang, G.</creatorcontrib><creatorcontrib>Depping, R.</creatorcontrib><creatorcontrib>Rose, C.</creatorcontrib><creatorcontrib>Langan, E. A.</creatorcontrib><creatorcontrib>Paus, R.</creatorcontrib><title>Thyroxine restores severely impaired cutaneous re-epithelialisation and angiogenesis in a novel preclinical assay for studying human skin wound healing under “pathological” conditions ex vivo</title><title>Archives of Dermatological Research</title><addtitle>Arch Dermatol Res</addtitle><addtitle>Arch Dermatol Res</addtitle><description><![CDATA[Impaired cutaneous wound healing remains a major healthcare challenge. The enormity of this challenge is compounded by the lack of preclinical human skin wound healing models that recapitulate selected key factors underlying impaired healing, namely hypoxia/poor tissue perfusion, oxidative damage, defective innervation, and hyperglycaemia. Since organ-cultured human skin already represents a denervated and impaired perfusion state, we sought to further mimic “pathological” wound healing conditions by culturing experimentally wounded, healthy full-thickness frontotemporal skin from three healthy female subjects for three days in either serum-free supplemented Williams’ E medium or in unsupplemented medium under “pathological” conditions (i.e. hypoxia [5% O
2
], oxidative damage [10 mM H
2
O
2
], absence of insulin, excess glucose). Under these “pathological” conditions, dermal–epidermal split formation and dyskeratosis were prominent in organ-cultured human skin, and epidermal reepithelialisation was significantly impaired (
p
< 0.001), associated with reduced keratinocyte proliferation (
p
< 0.001), cytokeratin 6 expression (
p
< 0.001) and increased apoptosis (
p
< 0.001). Moreover, markers of intracutaneous angiogenesis (CD31 immunoreactivity and the number of of CD31 positive cells and CD31 positive vessel lumina) were significantly reduced. Since we had previously shown that thyroxine promotes wound healing in healthy human skin ex vivo, we tested whether this in principle also occurs under “pathological” wound healing conditions. Indeed, thyroxine administration sufficed to rescue re-epithelialisation (
p
< 0.001) and promoted both epidermal keratinocyte proliferation (
p
< 0.01) and angiogenesis in terms of CD31 immunoreactivity and CD31 positive cells under “pathological” conditions (
p
< 0.001) ex vivo. This demonstrates the utility of this pragmatic short-term ex vivo model, which recapitulates some key parameters of impaired human skin wound healing, for the preclinical identification of promising wound healing promoters.]]></description><subject>Angiogenesis</subject><subject>Apoptosis</subject><subject>Cytokeratin</subject><subject>Dermatology</subject><subject>Dyskeratosis</subject><subject>Hydrogen peroxide</subject><subject>Hyperglycemia</subject><subject>Hypoxia</subject><subject>Immunoreactivity</subject><subject>Innervation</subject><subject>Insulin</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Original Paper</subject><subject>Perfusion</subject><subject>Skin tests</subject><subject>Thyroxine</subject><subject>Wound healing</subject><issn>0340-3696</issn><issn>1432-069X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><recordid>eNp9kstu1DAUhiMEoqPSF2CBLLFhE_At9niDhCpuUiU2RWJnuc5J4uKxg52kna76IPA0vEmfBA9TymWBJV_k853fPkd_VT0m-DnBWL7IGHPMakzxbipaX92rVoQzWmOhPt2vVphxXDOhxEF1lPM5LkNiTrF8WB0w2kjaiGZVfT8dtileugAoQZ5iWVCGBRL4LXKb0bgELbLzZALEOReohtFNA3hnvMtmcjEgE9oyexd7CJBdRq7coRAX8GhMYL0LzhqPTM5mi7qYUJ7mdutCj4Z5YwLKn0vGRZyLzgBFtwTKGRK6uf46mmmIPvY7hZvrb8jG0LrdsxnBJVrcEh9VDzrjMxzd7ofVxzevT4_f1Scf3r4_fnVSWy75VEtu1NpKQ1TbCUY63AlDheW0BSXVWincGWo4Fm0jFWmFJYxJIvia0vaMWMMOq5d73XE-20BrIUzJeD0mtzFpq6Nx-u9IcIPu46KlYs2arIvAs1uBFL_Mpd1647IF7_fN1ZQTQSUTlBf06T_oeZxTKOUVSslGNpQ0haJ7yqaYc4Lu7jME651N9N4mulhE_7SJvipJT_4s4y7llykKwPZALqHQQ_r99n9kfwCEf9FJ</recordid><startdate>20210401</startdate><enddate>20210401</enddate><creator>Post, H.</creator><creator>Hundt, J. E.</creator><creator>Zhang, G.</creator><creator>Depping, R.</creator><creator>Rose, C.</creator><creator>Langan, E. A.</creator><creator>Paus, R.</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20210401</creationdate><title>Thyroxine restores severely impaired cutaneous re-epithelialisation and angiogenesis in a novel preclinical assay for studying human skin wound healing under “pathological” conditions ex vivo</title><author>Post, H. ; Hundt, J. E. ; Zhang, G. ; Depping, R. ; Rose, C. ; Langan, E. A. ; Paus, R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-74a98c7a19df631f0f6a26c42de9798990fa2a406d5791d6c1337164822db1ca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Angiogenesis</topic><topic>Apoptosis</topic><topic>Cytokeratin</topic><topic>Dermatology</topic><topic>Dyskeratosis</topic><topic>Hydrogen peroxide</topic><topic>Hyperglycemia</topic><topic>Hypoxia</topic><topic>Immunoreactivity</topic><topic>Innervation</topic><topic>Insulin</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Original Paper</topic><topic>Perfusion</topic><topic>Skin tests</topic><topic>Thyroxine</topic><topic>Wound healing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Post, H.</creatorcontrib><creatorcontrib>Hundt, J. E.</creatorcontrib><creatorcontrib>Zhang, G.</creatorcontrib><creatorcontrib>Depping, R.</creatorcontrib><creatorcontrib>Rose, C.</creatorcontrib><creatorcontrib>Langan, E. A.</creatorcontrib><creatorcontrib>Paus, R.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Archives of Dermatological Research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Post, H.</au><au>Hundt, J. E.</au><au>Zhang, G.</au><au>Depping, R.</au><au>Rose, C.</au><au>Langan, E. A.</au><au>Paus, R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Thyroxine restores severely impaired cutaneous re-epithelialisation and angiogenesis in a novel preclinical assay for studying human skin wound healing under “pathological” conditions ex vivo</atitle><jtitle>Archives of Dermatological Research</jtitle><stitle>Arch Dermatol Res</stitle><addtitle>Arch Dermatol Res</addtitle><date>2021-04-01</date><risdate>2021</risdate><volume>313</volume><issue>3</issue><spage>181</spage><epage>192</epage><pages>181-192</pages><issn>0340-3696</issn><eissn>1432-069X</eissn><abstract><![CDATA[Impaired cutaneous wound healing remains a major healthcare challenge. The enormity of this challenge is compounded by the lack of preclinical human skin wound healing models that recapitulate selected key factors underlying impaired healing, namely hypoxia/poor tissue perfusion, oxidative damage, defective innervation, and hyperglycaemia. Since organ-cultured human skin already represents a denervated and impaired perfusion state, we sought to further mimic “pathological” wound healing conditions by culturing experimentally wounded, healthy full-thickness frontotemporal skin from three healthy female subjects for three days in either serum-free supplemented Williams’ E medium or in unsupplemented medium under “pathological” conditions (i.e. hypoxia [5% O
2
], oxidative damage [10 mM H
2
O
2
], absence of insulin, excess glucose). Under these “pathological” conditions, dermal–epidermal split formation and dyskeratosis were prominent in organ-cultured human skin, and epidermal reepithelialisation was significantly impaired (
p
< 0.001), associated with reduced keratinocyte proliferation (
p
< 0.001), cytokeratin 6 expression (
p
< 0.001) and increased apoptosis (
p
< 0.001). Moreover, markers of intracutaneous angiogenesis (CD31 immunoreactivity and the number of of CD31 positive cells and CD31 positive vessel lumina) were significantly reduced. Since we had previously shown that thyroxine promotes wound healing in healthy human skin ex vivo, we tested whether this in principle also occurs under “pathological” wound healing conditions. Indeed, thyroxine administration sufficed to rescue re-epithelialisation (
p
< 0.001) and promoted both epidermal keratinocyte proliferation (
p
< 0.01) and angiogenesis in terms of CD31 immunoreactivity and CD31 positive cells under “pathological” conditions (
p
< 0.001) ex vivo. This demonstrates the utility of this pragmatic short-term ex vivo model, which recapitulates some key parameters of impaired human skin wound healing, for the preclinical identification of promising wound healing promoters.]]></abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>32572565</pmid><doi>10.1007/s00403-020-02092-z</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Archives of Dermatological Research, 2021-04, Vol.313 (3), p.181-192 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7935818 |
| source | SpringerLink Journals |
| subjects | Angiogenesis Apoptosis Cytokeratin Dermatology Dyskeratosis Hydrogen peroxide Hyperglycemia Hypoxia Immunoreactivity Innervation Insulin Medicine Medicine & Public Health Original Paper Perfusion Skin tests Thyroxine Wound healing |
| title | Thyroxine restores severely impaired cutaneous re-epithelialisation and angiogenesis in a novel preclinical assay for studying human skin wound healing under “pathological” conditions ex vivo |
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