{"id":1367,"date":"2020-11-03T21:40:56","date_gmt":"2020-11-03T12:40:56","guid":{"rendered":"http:\/\/mapkinhibitorlibrary.com\/?p=1367"},"modified":"2022-01-17T11:33:52","modified_gmt":"2022-01-17T02:33:52","slug":"attractive-hypothesis-proliferation-beneficial-epithelialization-initial-wound-margin","status":"publish","type":"post","link":"http:\/\/mapkinhibitorlibrary.com\/index.php\/2020\/11\/03\/attractive-hypothesis-proliferation-beneficial-epithelialization-initial-wound-margin\/","title":{"rendered":"An attractive hypothesis is that proliferation is only beneficial to epithelialization at the initial wound margin"},"content":{"rendered":"

In this study, we demonstrate the requirement for proper levels of TGF-\u00df3 in excisional wound healing in the mouse. Exogenous addition or specific inhibition of TGF-\u00df3 affects different phases of healing, with profound effect on keratinocyte proliferation and myofibroblasts. Our data suggest that the migration delay and increased proliferation of keratinocytes in the absence of TGF-\u00df3 in vivo is non-cell autonomous, and potentially mediated by a paracrine effect. To evaluate whether the levels of TGF-\u00df3 affect excisional wound healing in a murine model, we injected a well-established neutralizing antibody against TGF-\u00df3, as well as recombinant TGF-\u00df3 under the wounds. Initial macroscopic evaluation of wounds indicated a delay in healing in the presence of neutralizing TGF-\u00df3 antibody seven days post-wounding, while the addition of TGF-\u00df3 appeared to have no effect. ICI 182780<\/a> Detailed morphometric analyses allowed us to thoroughly evaluate the effect of TGF-\u00df3 on the different cutaneous compartments and phases of wound healing. The most striking finding of this examination was that in the absence of TGF-\u00df3, wounds were not epithelialized seven days post-wounding, despite an augmented epidermal volume. Proliferation and migration are the two main biological processes governing keratinocyte behavior during wound healing. We evaluated both in our system and both were altered in the absence of TGF-\u00df3 in vivo. Keratinocyte migration was delayed in the initial phase of epithelialization in vivo in the absence of TGF-\u00df3. However, our in vitro scratch wound assay confirmed the ability of Tgfb3- deficient keratinocytes to migrate at a similar rate than wild type cells, consistent with a previously described report. TGF-\u00df3 signals through TGFbR2 and has been shown to act as a \u2018\u2018traffic control\u2019\u2019 molecule in wounds because of its absence in plasma, and its increased level in serum. It is the level of TGFbR2 that makes cells responsive to TGF-\u00df3 and governs their migratory behavior. Keratinocytes express low levels of TGF\u00dfR2 compared to mesenchymal cells, in tissue culture as well as in vivo during tissue repair, rendering them fairly insensitive to the level of TGF-\u00df3. Although we did not evaluate the expression of TGF\u00dfR2 in Tgfb3-deficient keratinocytes, we would expect it to be similar between the two populations. Levels of integrin and composition of the extracellular matrix are other key modulators of keratinocyte migration, and could potentially be influenced by the level of TGF-\u00df3. The increase in keratinocyte proliferation in the absence of TGF-\u00df3, and the decreased proliferation in the presence of exogenous TGF-\u00df3 is consistent with an overall antiproliferative effect on keratinocytes associated with TGF-\u00df family members. Although Irf6, a new transcriptional regulator of epidermal proliferation, is decreased in skin from Tgfb3-deficient embryos compared to wild type, it is not significantly altered in cutaneous wounds. It stands to reason that an increased rate of proliferation in the epidermal compartment leads to faster epithelialization as reported for models of altered TGF-\u00df signaling in wounds. However, wounds treated with neutralizing TGF-\u00df3 antibody were still open seven days post-wounding. This observation is reminiscent of an overall increase in epidermal proliferation in human non-healing chronic wounds, and particularly in cells at the leading edge.<\/p>\n","protected":false},"excerpt":{"rendered":"

In this study, we demonstrate the requirement for proper levels of TGF-\u00df3 in excisional wound healing in the mouse. Exogenous addition or specific inhibition of TGF-\u00df3 affects different phases of healing, with profound effect on keratinocyte proliferation and myofibroblasts. Our data suggest that the migration delay and increased proliferation of keratinocytes in the absence of … Continue reading An attractive hypothesis is that proliferation is only beneficial to epithelialization at the initial wound margin<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[1],"tags":[],"_links":{"self":[{"href":"http:\/\/mapkinhibitorlibrary.com\/index.php\/wp-json\/wp\/v2\/posts\/1367"}],"collection":[{"href":"http:\/\/mapkinhibitorlibrary.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/mapkinhibitorlibrary.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/mapkinhibitorlibrary.com\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/mapkinhibitorlibrary.com\/index.php\/wp-json\/wp\/v2\/comments?post=1367"}],"version-history":[{"count":1,"href":"http:\/\/mapkinhibitorlibrary.com\/index.php\/wp-json\/wp\/v2\/posts\/1367\/revisions"}],"predecessor-version":[{"id":1368,"href":"http:\/\/mapkinhibitorlibrary.com\/index.php\/wp-json\/wp\/v2\/posts\/1367\/revisions\/1368"}],"wp:attachment":[{"href":"http:\/\/mapkinhibitorlibrary.com\/index.php\/wp-json\/wp\/v2\/media?parent=1367"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/mapkinhibitorlibrary.com\/index.php\/wp-json\/wp\/v2\/categories?post=1367"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/mapkinhibitorlibrary.com\/index.php\/wp-json\/wp\/v2\/tags?post=1367"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}