Fibronectin and β-Catenin Act in a Regulatory Loop in Dermal Fibroblasts to Modulate Cutaneous Healing

Bielefeld, Kirsten A.; Amini-Nik, Saeid; Whetstone, Heather; Poon, Raymond; Youn, Andrew; Wang, Jian; Alman, Benjamin A.

doi:10.1074/jbc.m111.261677

Cited by 61 publications

(64 citation statements)

References 74 publications

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“…This has been demonstrated in mice treated with an adenovirus expressing the Wnt signaling inhibitor Dickkopf (DKK1, which binds LRP6/Arrow), without a significant decline in ß-catenin protein levels during the proliferative phase of skin wound healing, in contrast to the situation in bone repair. 39 This suggests that other factors play a role in regulating ß-catenin levels during the proliferative phase of healing. Indeed, ß-catenin levels in fibroblasts can be stimulated by growth factors, such as TGF-ß1, which are released during the early stages of wound repair.…”

Section: Proliferationmentioning

confidence: 99%

Wnt signaling induces epithelial differentiation during cutaneous wound healing

et al. 2015

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ABSTRACT. Cutaneous wound repair in adult mammals typically does not regenerate original dermal architecture. Skin that has undergone repair following injury is not identical to intact uninjured skin. This disparity may be caused by differences in the mechanisms that regulate postnatal cutaneous wound repair compared to embryonic skin development and thus we seek a deeper understanding of the role that Wnt signaling plays in the mechanisms of skin repair in both fetal and adult wounds. The influence of secreted Wnt signaling proteins in tissue homeostasis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. Wnt signaling is activated by wounding and participates in every subsequent stage of the healing process from the control of inflammation and programmed cell death, to the mobilization of stem cell reservoirs within the wound site. Endogenous Wnt signaling augmentation represents an attractive option to aid in the restoration of cutaneous wounds, as the complex mechanisms of the Wnt pathway have been increasingly investigated over the years. In this review, we summarize recent data elucidating the roles that Wnt signaling plays in cutaneous wound healing process.

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Section: Proliferationmentioning

confidence: 99%

Wnt signaling induces epithelial differentiation during cutaneous wound healing

et al. 2015

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“…Fibronectin has also previously been shown to play a role in fibroblast activation (53,54), so we tested whether addition of fibronectin alone to RSM could rescue FAK Fibroblast Activation in the TME clustering and fibroblast activation, but we did not see a rescue of FAK clustering (Fig. 5 C), or fibroblast activation (Fig.…”

Section: Both CCL Growth Factors and Serum Fibronectin Are Necessary mentioning

confidence: 68%

“…5). Others have suggested that the matrix FN-EDA can lead to fibroblast activation, but plasma fibronectin has also been shown to alter fibroblast activity in a wound healing model (53,63). Perhaps some fibronectin domains such as FNIII10, which is conserved between plasma and matrix FN and interacts with integrin avb3 (62), are necessary for proper integrin engagement and clustering to allow for activation, whereas other domains such as EDA actually stimulate activation.…”

Section: Discussionmentioning

confidence: 97%

Palladin Mediates Stiffness-Induced Fibroblast Activation in the Tumor Microenvironment

McLane

Ligon

2015

Biophysical Journal

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Mechanical properties of the tumor microenvironment have emerged as key factors in tumor progression. It has been proposed that increased tissue stiffness can transform stromal fibroblasts into carcinoma-associated fibroblasts. However, it is unclear whether the three to five times increase in stiffness seen in tumor-adjacent stroma is sufficient for fibroblast activation. In this study we developed a three-dimensional (3D) hydrogel model with precisely tunable stiffness and show that a physiologically relevant increase in stiffness is sufficient to lead to fibroblast activation. We found that soluble factors including CC-motif chemokine ligand (CCL) chemokines and fibronectin are necessary for this activation, and the combination of C-C chemokine receptor type 4 (CCR4) chemokine receptors and β1 and β3 integrins are necessary to transduce these chemomechanical signals. We then show that these chemomechanical signals lead to the gene expression changes associated with fibroblast activation via a network of intracellular signaling pathways that include focal adhesion kinase (FAK) and phosphoinositide 3-kinase (PI3K). Finally, we identify the actin-associated protein palladin as a key node in these signaling pathways that result in fibroblast activation.

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“…Color images available online at www.liebertpub.com/tea A significant role for macrophages has been shown during skin healing and hypertrophic scar formation. [41][42][43][44] While their presence is essential, increased numbers of macrophages lead to hypertrophic scarring, a morbidity that should be avoided. As such, it is important to evaluate whether the hydrogel augments inflammation to avoid unnecessary scarring.…”

mentioning

confidence: 99%

Cellularized Bilayer Pullulan-Gelatin Hydrogel for Skin Regeneration

Nicholas

Jeschke

Amini-Nik

2016

Tissue Engineering Part A

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Skin substitutes significantly reduce the morbidity and mortality of patients with burn injuries and chronic wounds. However, current skin substitutes have disadvantages related to high costs and inadequate skin regeneration due to highly inflammatory wounds. Thus, new skin substitutes are needed. By combining two polymers, pullulan, an inexpensive polysaccharide with antioxidant properties, and gelatin, a derivative of collagen with high water absorbency, we created a novel inexpensive hydrogel-named PG-1 for ''pullulan-gelatin first generation hydrogel''-suitable for skin substitutes. After incorporating human fibroblasts and keratinocytes onto PG-1 using centrifugation over 5 days, we created a cellularized bilayer skin substitute. Cellularized PG-1 was compared to acellular PG-1 and no hydrogel (control) in vivo in a mouse excisional skin biopsy model using newly developed dome inserts to house the skin substitutes and prevent mouse skin contraction during wound healing. PG-1 had an average pore size of 61.69 mm with an ideal elastic modulus, swelling behavior, and biodegradability for use as a hydrogel for skin substitutes. Excellent skin cell viability, proliferation, differentiation, and morphology were visualized through live/dead assays, 5-bromo-2¢-deoxyuridine proliferation assays, and confocal microscopy. Trichrome and immunohistochemical staining of excisional wounds treated with the cellularized skin substitute revealed thicker newly formed skin with a higher proportion of actively proliferating cells and incorporation of human cells compared to acellular PG-1 or control. Excisional wounds treated with acellular or cellularized hydrogels showed significantly less macrophage infiltration and increased angiogenesis 14 days post skin biopsy compared to control. These results show that PG-1 has ideal mechanical characteristics and allows ideal cellular characteristics. In vivo evidence suggests that cellularized PG-1 promotes skin regeneration and may help promote wound healing in highly inflammatory wounds, such as burns and chronic wounds.

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Fibronectin and β-Catenin Act in a Regulatory Loop in Dermal Fibroblasts to Modulate Cutaneous Healing

Cited by 61 publications

References 74 publications

Wnt signaling induces epithelial differentiation during cutaneous wound healing

Wnt signaling induces epithelial differentiation during cutaneous wound healing

Palladin Mediates Stiffness-Induced Fibroblast Activation in the Tumor Microenvironment

Cellularized Bilayer Pullulan-Gelatin Hydrogel for Skin Regeneration

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