Thrombospondin-4 Is a Soluble Dermal Inflammatory Signal That Selectively Promotes Fibroblast Migration and Keratinocyte Proliferation for Skin Regeneration and Wound Healing

Klaas, Mariliis; Mäemets-Allas, Kristina; Heinmäe, Elizabeth; Lagus, Heli; Cárdenas-León, Claudia Griselda; Arak, Terje; Eller, Mart; Kingo, Külli; Kankuri, Esko; Jaks, Viljar

doi:10.3389/fcell.2021.745637

Cited by 18 publications

(12 citation statements)

References 59 publications

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“…Additionally, osteopontin knockout mice have impaired wound closure (Wang et al, 2017). Thbs4 (Thrombospondin 4, an ECM protein; ear: log2(CAST/MRL) = -1.24, FDR = 6.55 x 10 -38 ; dorsal: log2(CAST/MRL) = -0.23, FDR = 0.048) has previously been shown to promote wound healing by stimulating fibroblast migration and keratinocyte proliferation (Klaas et al, 2021) and is reported to promote angiogenesis and reduce fibrosis (Stenina-Adognravi and Plow, 2019), with mouse Thbs4 knockout associated with damaging cardiac inflammation and fibrosis (Frolova et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

Allele-specific expression reveals genetic drivers of tissue regeneration in mice

Talbott

Mack

Guardino

et al. 2022

Preprint

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In adult mammals, skin wounds typically heal by scarring rather than through regeneration. In contrast, "super-healer" MRL mice have the unusual ability to regenerate ear punch wounds, yet the molecular basis for this regeneration remains elusive. Here, in hybrid crosses between MRL and non-regenerating mice, we use allele-specific gene expression to identify cis-regulatory variation associated with ear regeneration. Analyzing three major wound cell populations, we identified extensive strain- and tissue- specific cis-regulatory divergence associated with differences in healing outcomes. Genes with cis-regulatory differences specifically in fibroblasts were associated with wound healing phenotypes and pathways, and were enriched near genetic markers associated with ear-healing in a genetic cross. Finally, we demonstrated that one of these genes, Cfh, could be applied ectopically to accelerate wound repair and induce regeneration in typically fibrotic wounds. Overall, our results provide insight into the molecular drivers of regeneration in MRL mice with potential clinical implications.

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Section: Resultsmentioning

confidence: 99%

Allele-specific expression reveals genetic drivers of tissue regeneration in mice

Talbott

Mack

Guardino

et al. 2022

Preprint

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“…A variety of cell types and response modulators, such as growth factors, cytokines, matrix metalloproteinases, cellular receptors, and extracellular matrix components are involved in initiation and proper progression of wound healing. As demonstrated recently by us and others [ 2 , 3 ], coordinated signals from the ECM and from the mesenchymal and infiltrated cells instigate and promote the stepwise progression of wound healing towards re-epithelialization and scar maturation.…”

Section: Introductionmentioning

confidence: 88%

Olfactomedin-4 improves cutaneous wound healing by promoting skin cell proliferation and migration through POU5F1/OCT4 and ESR1 signalling cascades

Klaas

Mäemets-Allas

Heinmäe

et al. 2022

Cell. Mol. Life Sci.

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Olfactomedin-4 (OLFM4) is an olfactomedin-domain-containing glycoprotein, which regulates cell adhesion, proliferation, gastrointestinal inflammation, innate immunity and cancer metastasis. In the present study we investigated its role in skin regeneration. We found that OLFM4 expression is transiently upregulated in the proliferative phase of cutaneous wound healing in humans as well as in mice. Moreover, a significant increase in OLFM4 expression was detected in the skin of lesional psoriasis, a chronic inflammatory disease characterized by keratinocyte hyperproliferation. In vitro experiments demonstrated that OLFM4 selectively stimulated keratinocyte proliferation and increased both keratinocyte and fibroblast migration. Using proteotranscriptomic pathway analysis we revealed that transcription factors POU5F1/OCT4 and ESR1 acted as hubs for OLFM4-induced signalling in keratinocytes. In vivo experiments utilizing mouse splinted full-thickness cutaneous wound healing model showed that application of recombinant OLFM4 protein can significantly improve wound healing efficacy. Taken together, our results suggest that OLFM4 acts as a transiently upregulated inflammatory signal that promotes wound healing by regulating both dermal and epidermal cell compartments of the skin.

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“…LC-MS/MS protein analysis of this liquid demonstrated a significant increase in haptoglobin and thrombospondin-4 in the TGM-treated wounds (Fig. S3b, c), which are known to influence macrophage differentiation and epithelial cell migration, respectively (41)(42)(43)(44).…”

Section: Topical Tgm Treatment Accelerated Wound Closurementioning

confidence: 98%

A helminth mimic of TGF-β, TGM, enhances regenerative cutaneous wound healing and modulates immune cell recruitment and activation

Lothstein

Chen

Mishra

et al. 2022

Preprint

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Intestinal helminth parasites express excretory/secretory (ES) molecules, which modulate the type-2 immune response including anti-inflammatory and tissue repair pathways. TGF-β mimic (TGM), an ES molecule secreted by Heligmosomoides polygyrus (Hp), binds TGF-β receptors yet lacks structural homology to TGF-β and exhibits distinct receptor interactions. We demonstrate TGM treatment enhanced wound healing and tissue regeneration in an in vivo wound biopsy model. TGM, in a 1.5% carboxymethylcellulose solution, was topically administered beneath a Tegaderm layer. Through histological analysis, increased restoration of normal tissue structure in the wound beds of TGM-treated mice was observed during mid- to late-stage wound healing. These observations included accelerated re-epithelialization and hair follicle regeneration, without increased scarring. Flow cytometric and gene expression analysis showed differential expansion of myeloid populations at different stages of wound healing. This included enhanced early accumulation and persistence of macrophages in TGM-treated wounds during the initial inflammatory phase. Additionally, the percentage of alternatively activated (M2) macrophages expressing CD206 was reduced with TGM treatment during early and mid-stage wound healing. scRNAseq analysis of TGM-treated wounds indicate upregulation of multiple wound healing-associated genes without expression of CD206 within macrophage subsets. Experiments with truncated TGM constructs revealed that the TGFβ-R binding domain was essential in enhancing the wound healing response. In summary, TGM can accelerate skin wound healing and pro-restorative maturation through its interaction with the TGF-β receptor and stimulate the recruitment and reprogramming of specific macrophage subsets. This study indicates a role for TGM as a potential novel therapeutic option for enhanced wound healing.

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Thrombospondin-4 Is a Soluble Dermal Inflammatory Signal That Selectively Promotes Fibroblast Migration and Keratinocyte Proliferation for Skin Regeneration and Wound Healing

Cited by 18 publications

References 59 publications

Allele-specific expression reveals genetic drivers of tissue regeneration in mice

Allele-specific expression reveals genetic drivers of tissue regeneration in mice

Olfactomedin-4 improves cutaneous wound healing by promoting skin cell proliferation and migration through POU5F1/OCT4 and ESR1 signalling cascades

A helminth mimic of TGF-β, TGM, enhances regenerative cutaneous wound healing and modulates immune cell recruitment and activation

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