Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response

Ashcroft, Gillian S.; Yang, Xiao; Glick, Adam B.; Weinstein, Michael; Letterio, John J.; Mizel, Diane; Anzano, Mario A.; Greenwell-Wild, Teresa; Wahl, Sharon M.; Deng, Chu‐Xia; Roberts, Anita B.

doi:10.1038/12971

Cited by 838 publications

(767 citation statements)

References 32 publications

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“…This finding is consistent with the report that mice lacking Smad3 showed accelerated re-epithelialization during wound healing. 6 In addition to inducing keratinocyte hyperproliferation, Smad7 overexpression appeared to have a direct effect on keratinocyte migration. First, Smad7 expression was increased in migrating cells in comparison with nonmigrating cells.…”

Section: Smad7 Wounded Skin Demonstrates Reduced Smad Signaling Whichmentioning

confidence: 96%

“…4 Conversely, mice with Smad3 deletion exhibit accelerated wound healing with reduced inflammation. 6 Reduced inflammation in Smad7 tg wounds could be responsible, at least in part, for reduced angiogenesis and collagen production, as both occurred after the re-duction in inflammation was first observed. Many inflammatory cytokines and chemokines are released by leukocytes, which are angiogenic and fibrogenic, 3,30 could be reduced in Smad7 wounds as a result of reduced leukocyte infiltration.…”

Section: Stromal Effects Of Epithelial-specific Smad7 Overexpression mentioning

confidence: 99%

“…4 For instance, Smad3-deficient mice, in which TGF␤ signaling is partially abrogated, exhibit accelerated wound healing. 6 In contrast, the introduction of exogenous Smad3 to wound sites to enhance TGF␤ signaling also accelerated wound healing in a rabbit dermal ulcer model. 7 Skin wounds in Smad4-deficient mice exhibit dramatically increased inflammation and angiogenesis, causing a delay in wound closure and excessive scar formation.…”

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confidence: 99%

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Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing

Han

Dijke

et al. 2011

The American Journal of Pathology

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The expression of Smad7, a tumor growth factor-␤ (TGF␤) antagonist, is increased during cutaneous wound healing. To assess this significance, we temporally induced Smad7 transgene expression in wounded skin in gene-switch-Smad7 transgenic (Smad7 tg) mice. Smad7 induction in epidermal keratinocytes caused an increase in keratinocyte proliferation with reduced Smad2 activation, indicating that Smad7 abrogated TGF␤-mediated growth inhibition. Additionally, wounded skin from Smad7 tg mice exhibited accelerated re-epithelialization, with increased activation of extracellular signal-regulated kinase (Erk), and an in vitro migration assay revealed that Erk activation contributed to Smad7-mediated keratinocyte migration. Notably, epidermis-specific Smad7 transgene expression also has a profound effect on the wound stroma, resulting in reduced inflammation, angiogenesis, and production of type I collagen. Reduced Smad2 activation was observed in wounded stroma from Smad7 transgenic (Smad7 tg) mice, possibly owing to fewer infiltrated TGF␤-producing leukocytes compared to those in wounds from control mice. Because Smad7 is not secreted, these effects could reflect functional changes in Smad7 tg keratinocytes. Supporting this notion, the activation of NF-B, a nonsecreted protein complex that transcriptionally activates inflammatory cytokines, was reduced in wounded epidermis from Smad7 tg mice compared to that in wounded wildtype epidermis. In sum, epidermal Smad7 overexpression accelerated wound healing through its direct effects on keratinocyte proliferation and migration, and through indirect effects on wound stroma.

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Section: Smad7 Wounded Skin Demonstrates Reduced Smad Signaling Whichmentioning

confidence: 96%

Section: Stromal Effects Of Epithelial-specific Smad7 Overexpression mentioning

confidence: 99%

mentioning

confidence: 99%

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Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing

Han

Dijke

et al. 2011

The American Journal of Pathology

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“…Loss of Smad3 was found to result in an impaired mucosal immunity and the T-cell response to TGF-b was diminished Yang et al, 1999b). Furthermore, mice lacking Smad3 exhibit an accelerated wound healing due to an increased rate of re-epithelialization and reduced local in®ltration of monocytes (Ashcroft et al, 1999). Thus, the Smad3 pathway may play an important role in tissue repair and regulation of keratinocytes and monocyte function.…”

Section: Smad Knock-out Micementioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

398

278

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Transforming growth factor-b (TGF-b) family members which include TGF-bs, activins, and bone morphogenetic proteins (BMPs) regulate a broad spectrum of biological responses on a large variety of cell types. TGF-b family members initiate their cellular responses by binding to distinct receptors with intrinsic serine/ threonine kinase activity and activation of speci®c downstream intracellular effectors termed Smad proteins. Smads relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes. Smad activation, subcellular distribution, and stability have been found to be intricately regulated and a broad array of transcription factors have been identi®ed as Smad partners. Important activities of TGF-b are its potent anti-mitogenic and pro-apoptotic effects that, at least in part, are mediated via Smad proteins. Escape from TGF-b/ Smad-induced growth inhibition and apoptosis is frequently observed in tumors. Certain Smads have been found to be mutated in speci®c types of cancer and gene ablation of particular Smads in mice has revealed increased rate of tumorigenesis. In late stage tumors, TGF-b has been shown to function as a tumor promoter. TGFb can stimulate the de-differentiation of epithelial cells to malignant invasive and metastatic ®broblastic cells. Interestingly, TGF-b may mediate these effects directly on tumor cells via subverted Smad-dependent and/or Smad-independent pathways.

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“…9,10,[16][17][18][19] However, the specific TGFb role in keratinocytes during re-epithelialization is unclear, as genetic ablation of TGFb signaling pathway elements accelerates wound re-epithelialization in some settings. [20][21][22][23][24] We previously showed that integrin av is necessary for keratinocyte proliferation in organotypic skin, and thus we hypothesized that av integrins are essential for wound re-epithelialization. 6 Here, we develop a novel, human organotypic wound re-epithelialization assay and show, both in vivo and in vitro, that av integrin function in keratinocytes is required for keratinocyte proliferation and efficient wound reepithelialization.…”

Section: Introductionmentioning

confidence: 99%

The integrin αv-TGFβ signaling axis is necessary for epidermal proliferation during cutaneous wound healing

et al. 2016

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Proliferation and migration of epidermal keratinocytes are essential for proper cutaneous wound closure after injury. av integrins and several of their ligands-vitronectin, TGFb and thrombospondin-are upregulated in healing wounds. However, the role of av integrins in wound re-epithelialization is unknown. Here, we show that genetic depletion or antibody-mediated blockade of pan-integrin av, or the specific heterodimer avb6, in keratinocytes limited epidermal proliferation at the wound edge and prevented reepithelialization of wounded human organotypic skin both in vivo and in vitro. While we did not observe a migration defect upon av blockade in vivo, av was necessary for keratinocyte migration over longer distances in organotypic skin. Integrin av is required for local activation of latent TGFb, and the wound healing defect in the setting of integrin av loss was rescued by exogenous, active TGFb, indicating that the av-TGFb signaling axis is a critical component of the normal epidermal wound healing program. As chronic wounds are associated with decreased TGFb signaling, restoration of TGFb activity may have therapeutic utility in some clinical settings.

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Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response

Cited by 838 publications

References 32 publications

Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing

Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing

Regulation of cell proliferation by Smad proteins

The integrin αv-TGFβ signaling axis is necessary for epidermal proliferation during cutaneous wound healing

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