Effects of erythropoietin in skin wound healing are dose related

Sorg, Heiko; Krueger, Christian G.; Schulz, T.; Menger, Michael D.; Schmitz, Frank; Vollmar, Brigitte

doi:10.1096/fj.08-109991

Cited by 77 publications

(71 citation statements)

References 56 publications

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“…5,[7][8][9] We extend the current knowledge providing evidence that EPO improves skin wound healing by activation of the TGF-b signaling pathway. This hypothesis is supported by our data, demonstrating that blockade of TGF-b using an anti-TGF-b antibody almost completely reversed the EPO-associated salutary effects on skin repair.…”

Section: Discussionmentioning

confidence: 55%

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Erythropoietin improves skin wound healing and activates the TGF-β signaling pathway

Siebert

Grambow

et al. 2011

Laboratory Investigation

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We could recently report that erythropoietin (EPO) accelerates skin wound healing in mice. Now, we provide insight into the molecular mechanisms of this non-hematopoietic property of EPO analyzing the transforming growth factor (TGF)-b signaling pathway. EPO receptor was found expressed in both non-wounded and wounded skin tissue as well as in fibroblasts and keratinocytes. In saline-treated control animals, wounds exhibited a significant upregulation of TGF-b1 and of a-smooth muscle actin (a-SMA) compared with non-wounded skin. EPO treatment accelerated wound epithelialization and induced mRNA expression of TGF-b1 and a-SMA. In addition, EPO significantly enhanced phosphorylation of Smad2 and Smad3 in fibroblasts and also elevated phosphorylation of Smad3 in wound tissue. Blockade of TGF-b using a neutralizing anti-TGF-b antibody attenuated EPO-induced acceleration of wound epithelialization in vivo and markedly reversed EPO effects on mRNA expression of TGF-b1 and a-SMA. In conclusion, EPO caused activation of the Smad-dependent TGF-b signaling pathway, enhanced differentiation of myofibroblasts, and accelerated skin wound closure.

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Section: Discussionmentioning

confidence: 55%

“…In line with our previous experimental protocol, 8 animals received either a single i.p. injection of EPO (Epoetin-a of ovarian cells of the Chinese hamster cell line CHO-K1 (Janssen-Gilag, Neuss, Germany); 5000 U/kg bw i.p.…”

Section: Materials and Methods Animal Modelmentioning

confidence: 99%

Erythropoietin improves skin wound healing and activates the TGF-β signaling pathway

Siebert

Grambow

et al. 2011

Laboratory Investigation

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“…According to Sorg et al (2007;2009), a modified dorsal skinfold chamber model was used for the in vivo analysis of ad-MVF-seeded implants (Fig. 1e).…”

Section: Modified Dorsal Skinfold Chamber Modelmentioning

confidence: 99%

Seeding density is a crucial determinant for the in vivo vascularisation capacity of adipose tissue-derived microvascular fragments

Später

Körbel

Frueh

et al. 2017

eCM

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Adipose tissue-derived microvascular fragments (ad-MVF) represent effective vascularisation units for the seeding of dermal substitutes. However, particularly in case of extensive skin defects, the required amounts of donor fat tissue for the harvesting of ad-MVF may not always be available. Therefore, we herein determined the lowest ad-MVF density needed to induce a sufficient vascularisation and incorporation of seeded implants. Collagen-glycosaminoglycan matrices (Integra ® ; diameter: 4 mm) were seeded with 15,000 (HD), 10,000 (MD) and 5,000 (LD) ad-MVF and implanted into full-thickness skin defects within mouse dorsal skinfold chambers, to analyse their in vivo vascularisation and incorporation. Intravital fluorescence microscopy showed a comparable vascularisation of HD and MD ad-MVF-seeded Integra ® , which was significantly higher when compared to LD ad-MVF-seeded Integra ® . As assessed by photoacoustic imaging, this was associated with an increased oxygenation of the implants. Additional histological and immunohistochemical analyses revealed an enhanced cellular infiltration, collagen content, microvessel density and epithelialisation of HD and MD ad-MVF-seeded Integra ® , indicating a better incorporation compared to LD ad-MVF-seeded implants. These findings demonstrate that 80,000 ad-MVF/cm² is the least required density to guarantee an effective vascularisation of the dermal substitute.

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“…For the in vivo analysis of the ad-MVF-seeded matrices, we used a modified dorsal skinfold chamber model according to Sorg et al (2007;2009). For the implantation of the dorsal skinfold chamber (Irola Industriekomponenten GmbH & Co. KG, Schonach, Germany), the mice were anaesthetised by intraperitoneal injection of ketamine (75 mg/kg body weight; Ursotamin ® ; Serumwerke Bernburg, Bernburg, Germany) and xylazine (25 mg/kg body weight; Rompun ® , Bayer, Leverkusen, Germany).…”

Section: Modified Dorsal Skinfold Chamber Modelmentioning

confidence: 99%

Potentials and limitations of Integra® flowable wound matrix seeded with adipose tissue-derived microvascular fragments

Später

Frueh

Menger

et al. 2017

eCM

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Adipose tissue-derived microvascular fragments (ad-MVF) represent promising vascularisation units for bioengineered Integra ® matrix wound dressing (MWD). However, due to the sheet-like structure with small pore sizes, the seeding of this matrix with ad-MVF is mainly limited to its surface. Integra ® flowable wound matrix (FWM) may be suitable to achieve a more homogeneous distribution and, thus, improved vascularisation, because this gel-like matrix allows for the direct admixture of ad-MVF during sample preparation. To test this hypothesis, we seeded MWD and FWM with an identical number of ad-MVF and assessed their distribution and inter-fragment distance within both matrices. Moreover, ad-MVF-seeded MWD and FWM were implanted into full-thickness skin defects within mouse dorsal skinfold chambers to analyse their vascularisation, epithelialisation and tissue incorporation using intravital fluorescence microscopy, histology and immunohistochemistry. Seeded FWM exhibited a more homogeneous ad-MVF distribution, when compared to MWD. This resulted in a significantly increased interfragment distance, preventing the reassembly of ad-MVF into new microvascular networks. Accordingly, the vascularisation of FWM was diminished after implantation, as indicated by a reduced functional microvessel density and blood perfusion. This was associated with a decreased tissue incorporation and epithelialisation of the matrix, when compared to ad-MVF-seeded MWD. Hence, the use of FWM as a carrier system may require a tremendous amount of ad-MVF to shorten their inter-fragment distance and, thus, to maintain their vascularisation capacity for tissue engineering applications.

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Effects of erythropoietin in skin wound healing are dose related

Cited by 77 publications

References 56 publications

Erythropoietin improves skin wound healing and activates the TGF-β signaling pathway

Erythropoietin improves skin wound healing and activates the TGF-β signaling pathway

Seeding density is a crucial determinant for the in vivo vascularisation capacity of adipose tissue-derived microvascular fragments

Potentials and limitations of Integra® flowable wound matrix seeded with adipose tissue-derived microvascular fragments

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