Reduced Granulation Tissue and Wound Strength in the Absence of α11β1 Integrin

Schulz, Jan-Niklas; Zeltz, Cédric; Sørensen, Ida Wiig; Barczyk, Malgorzata; Carracedo, Sergio; Hallinger, Ralf; Niehoff, Anja; Eckes, Beate; Gullberg, Donald

doi:10.1038/jid.2015.24

Cited by 70 publications

(85 citation statements)

References 42 publications

(58 reference statements)

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“…The picture of collagen-binding integrins playing a relatively minor role in normal physiology contrasts with the severe phenotypes that have been documented when the ligands of these integrins -members of the collagen family -are defective . Recent data, however, have highlighted the contribution of the collagen-binding integrins to fibroblast function in wounds (Schulz et al, 2015), in fibrotic tissue (TaliorVolodarsky et al, 2015) and tumor models (Lu et al, 2014;Navab et al, 2015). These findings, which establish important roles for collagen-binding integrins in relation to fibroblasts, are timely and fit well into the recent awareness that wound healing, fibrosis and tumor-stroma interactions share key mechanisms at the molecular level (Rybinski et al, 2014).…”

Section: Introductionsupporting

confidence: 61%

The integrin–collagen connection – a glue for tissue repair?

Zeltz

Gullberg

2016

Journal of Cell Science

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176

126

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There was an error published in J. Cell Sci. 129, 653-664.In Fig. 2A, the fibroblasts were incorrectly labelled. The correct annotation should have been α11 −/− fibroblast (left) and α11 +/+ fibroblast (right). The correct Fig. 2 is shown below. We apologise to the readers for any confusion that this error might have caused. Journal of Cell Science COMMENTARYThe integrin-collagen connection -a glue for tissue repair?Cedric Zeltz and Donald Gullberg* ABSTRACTThe α1β1, α2β1, α10β1 and α11β1 integrins constitute a subset of the integrin family with affinity for GFOGER-like sequences in collagens.Integrins α1β1 and α2β1 were originally identified on a subset of activated T-cells, and have since been found to be expressed on a number of cell types including platelets (α2β1), vascular cells (α1β1, α2β1), epithelial cells (α1β1, α2β1) and fibroblasts (α1β1, α2β1).Integrin α10β1 shows a distribution that is restricted to mesenchymal stem cells and chondrocytes, whereas integrin α11β1 appears restricted to mesenchymal stem cells and subsets of fibroblasts. The bulk of the current literature suggests that collagen-binding integrins only have a limited role in adult connective tissue homeostasis, partly due to a limited availability of cell-binding sites in the mature fibrillar collagen matrices. However, some recent data suggest that, instead, they are more crucial for dynamic connective tissue remodeling events -such as wound healing -where they might act specifically to remodel and restore the tissue architecture. This Commentary discusses the recent development in the field of collagen-binding integrins, their roles in physiological and pathological settings with special emphasis on wound healing, fibrosis and tumor-stroma interactions, and include a discussion of the most recently identified newcomers to this subfamilyintegrins α10β1 and α11β1.

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Section: Introductionsupporting

confidence: 61%

The integrin–collagen connection – a glue for tissue repair?

Zeltz

Gullberg

2016

Journal of Cell Science

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176

126

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“…Decreased stiffness and tensile strength were seen in scars from P311 À/À mice compared with scars from WT animals. Reduced scar collagen formation and tensile strength have also been observed in mice lacking a11b1 integrin 41 and in diabetic rats, in which these abnormalities lead to higher incidence of dehiscence. 42 Of interest, reduced collagen deposition is not necessarily coupled with decreased tensile strength, because the opposite has been shown with poly-N-acetyl-glucosamine nanofiber treatment 43 or with the use of a selective adenosine A2AR-antagonist.…”

Section: Discussionmentioning

confidence: 94%

“…Significantly, the hypocollagenization and decrease in scar tensile strength observed in a11b1 integrin-null mice were also linked to defective TGF-b signaling. 41 As part of our in vitro characterization effort, we performed functional studies using MFs and HFs. These showed that P311 stimulated smooth muscle actin production, increased proliferation, promoted migration, and increased contractility of both MFs and HFs, all consistent with induction of the activated state 49 and the transition to myofibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Neuronal Protein 3.1 Deficiency Leads to Reduced Cutaneous Scar Collagen Deposition and Tensile Strength due to Impaired Transforming Growth Factor-β1 to -β3 Translation

Cheng

Yue

Aslam

et al. 2017

The American Journal of Pathology

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Neuronal protein 3.1 (P311), a conserved RNA-binding protein, represents the first documented protein known to stimulate transforming growth factor (TGF)-b1 to -b3 translation in vitro and in vivo. Because TGF-bs play critical roles in fibrogenesis, we initiated efforts to define the role of P311 in skin scar formation. Here, we show that P311 is up-regulated in skin wounds and in normal and hypertrophic scars. Genetic ablation of p311 resulted in a significant decrease in skin scar collagen deposition. Lentiviral transfer of P311 corrected the deficits, whereas down-regulation of P311 levels by lentiviral RNA interference reproduced the deficits seen in P311 À/À mice. The decrease in collagen deposition resulted in scars with reduced stiffness but also reduced scar tensile strength. In vitro studies using murine and human dermal fibroblasts showed that P311 stimulated TGF-b1 to -b3 translation, a process that involved eukaryotic translation initiation factor 3 subunit b as a P311 binding partner. This resulted in increased TGF-b levels/activity and increased collagen production. In addition, P311 induced dermal fibroblast activation and proliferation. Finally, exogenous TGF-b1 to -b3, each restituted the normal scar phenotype. These studies demonstrate that P311 is required for the production of normal cutaneous scars and place P311 immediately up-stream of TGF-bs in the process of fibrogenesis. Conditions that decrease P311 levels could result in less tensile scars, which could potentially lead to higher incidence of dehiscence after surgery. (Am J Pathol 2017, 187: 292e303; http://dx

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“…Wounds were created and harvested according to standard protocols (Blumbach et al, 2010;Schulz et al, 2015;Zweers et al, 2007). In brief, female mice at the age of 10 weeks were anesthetized by intraperitoneal injection of ketamine (10 g/l) and xylazine (8 g/l) solution (10 µl/g body weight) (Park Davis, Karlsruhe, Germany and Erlangen, Germany, respectively).…”

Section: Wound Healing and Fibrosismentioning

confidence: 99%

“…To determine the in vivo relevance of COMP for collagen secretion, COMP-null and control mice were subjected to repeated intradermal injections of bleomycin (Yamamoto et al, 1999) or to excisional wounding (Blumbach et al, 2010;Gurtner et al, 2008;Schulz et al, 2015;Zweers et al, 2007).…”

Section: Comp Facilitates Collagen Secretion In Dermal Fibroblastsmentioning

confidence: 99%

COMP-assisted collagen secretion - a novel intracellular function required for fibrosis

Schulz

Nüchel

Niehoff

et al. 2016

Journal of Cell Science

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Cartilage oligomeric matrix protein (COMP) is an abundant component in the extracellular matrix (ECM) of load-bearing tissues such as tendons and cartilage. It provides adaptor functions by bridging different ECM structures. We have previously shown that COMP is also a constitutive component of healthy human skin and is strongly induced in fibrosis. It binds directly and with high affinity to collagen I and to collagen XII that decorates the surface of collagen I fibrils. We demonstrate here that lack of COMP-collagen interaction in the extracellular space leads to changes in collagen fibril morphology and density, resulting in altered skin biomechanical properties. Surprisingly, COMP also fulfills an important intracellular function in assisting efficient secretion of collagens, which were retained in the endoplasmic reticulum of COMP-null fibroblasts. Accordingly, COMPnull mice showed severely attenuated fibrotic responses in skin. Collagen secretion was fully restored by introducing wild-type COMP. Hence, our work unravels a new, non-structural and intracellular function of the ECM protein COMP in controlling collagen secretion.

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Reduced Granulation Tissue and Wound Strength in the Absence of α11β1 Integrin

Cited by 70 publications

References 42 publications

The integrin–collagen connection – a glue for tissue repair?

The integrin–collagen connection – a glue for tissue repair?

Neuronal Protein 3.1 Deficiency Leads to Reduced Cutaneous Scar Collagen Deposition and Tensile Strength due to Impaired Transforming Growth Factor-β1 to -β3 Translation

COMP-assisted collagen secretion - a novel intracellular function required for fibrosis

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