scholarly journals VEGF-A, PDGF-BB and HB-EGF engineered for promiscuous super affinity to the extracellular matrix improve wound healing in a model of type 1 diabetes

2021 ◽  
Author(s):  
MICHAEL John Victor WHITE ◽  
Priscilla Briquez ◽  
David Andrew Victor White ◽  
Jeffrey Hubbell
Keyword(s):  
Extracellular Matrix ◽  
Wound Healing ◽  
Growth Factors ◽  
Growth Factor ◽  
Mouse Model ◽  
Triple Therapy ◽  
Nod Mouse ◽  
Heparin Binding ◽  
Healing Wounds

Chronic non-healing wounds, frequently caused by diabetes, lead to lower quality of life, infection, and amputation. These wounds have limited treatment options. We have previously engineered growth factors to bind to exposed extracellular matrix (ECM) in the wound environment using the heparin-binding domain of placental growth factor-2 (PlGF-2123-144), which binds promiscuously to ECM proteins. Here, in the type 1 diabetic (T1D) NOD mouse model, engineered growth factors improved both re-epithelialization and granulation tissue formation. Engineered growth factors were even more potent in combination, and the *triple therapy* of vascular endothelial growth factor-A (VEGF-PlGF-2123-144), platelet-derived growth factor-BB (PDGF-BB-PlGF-2123-144), and heparin-binding epidermal-growth factor (EGF-PlGF-2123-144) both improved wound healing and remained at the site of administration for significantly longer than wild-type growth factors. In addition, we also found that changes in the cellular milieu of a wound, including changing amounts of M1 macrophages, M2 macrophages and effector T cells, are most predictive of wound healing success in the NOD mouse model. These results suggest that the triple therapy of VEGF-PlGF-2123-144, PDGF-BB-PlGF-2123-144, and EGF-PlGF-2123-144 may be an effective therapy for chronic non-healing wounds in that occur as a complication of diabetes.

scholarly journals VEGF-A, PDGF-BB and HB-EGF engineered for promiscuous super affinity to the extracellular matrix improve wound healing in a model of type 1 diabetes

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Michael J. V. White ◽  
Priscilla S. Briquez ◽  
David A. V. White ◽  
Jeffrey A. Hubbell
Keyword(s):  
Extracellular Matrix ◽  
Wound Healing ◽  
Growth Factors ◽  
Growth Factor ◽  
Mouse Model ◽  
Triple Therapy ◽  
Nod Mouse ◽  
Heparin Binding ◽  
Healing Wounds

AbstractChronic non-healing wounds, frequently caused by diabetes, lead to lower quality of life, infection, and amputation. These wounds have limited treatment options. We have previously engineered growth factors to bind to exposed extracellular matrix (ECM) in the wound environment using the heparin-binding domain of placental growth factor-2 (PlGF-2123–144), which binds promiscuously to ECM proteins. Here, in the type 1 diabetic (T1D) NOD mouse model, engineered growth factors (eGFs) improved both re-epithelialization and granulation tissue formation. eGFs were even more potent in combination, and the “triple therapy” of vascular endothelial growth factor-A (VEGF-PlGF-2123–144), platelet-derived growth factor-BB (PDGF-BB-PlGF-2123–144), and heparin-binding epidermal growth factor (HB-EGF-PlGF-2123–144) both improved wound healing and remained at the site of administration for significantly longer than wild-type growth factors. In addition, we also found that changes in the cellular milieu of a wound, including changing amounts of M1 macrophages, M2 macrophages and effector T cells, are most predictive of wound-healing success in the NOD mouse model. These results suggest that the triple therapy of VEGF-PlGF-2123–144, PDGF-BB-PlGF-2123–144, and HB-EGF-PlGF-2123–144 may be an effective therapy for chronic non-healing wounds in that occur as a complication of diabetes.

scholarly journals The heparin binding domain of von Willebrand factor binds to growth factors and promotes angiogenesis in wound healing

Blood ◽  
2019 ◽  
Vol 133 (24) ◽  
pp. 2559-2569 ◽  
Author(s):  
Jun Ishihara ◽  
Ako Ishihara ◽  
Richard D. Starke ◽  
Claire R. Peghaire ◽  
Koval E. Smith ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Wound Healing ◽  
Growth Factors ◽  
Growth Factor ◽  
Von Willebrand Factor ◽  
Binding Domain ◽  
Heparin Binding ◽  
Heparin Binding Domain ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract During wound healing, the distribution, availability, and signaling of growth factors (GFs) are orchestrated by their binding to extracellular matrix components in the wound microenvironment. Extracellular matrix proteins have been shown to modulate angiogenesis and promote wound healing through GF binding. The hemostatic protein von Willebrand factor (VWF) released by endothelial cells (ECs) in plasma and in the subendothelial matrix has been shown to regulate angiogenesis; this function is relevant to patients in whom VWF deficiency or dysfunction is associated with vascular malformations. Here, we show that VWF deficiency in mice causes delayed wound healing accompanied by decreased angiogenesis and decreased amounts of angiogenic GFs in the wound. We show that in vitro VWF binds to several GFs, including vascular endothelial growth factor-A (VEGF-A) isoforms and platelet-derived growth factor-BB (PDGF-BB), mainly through the heparin-binding domain (HBD) within the VWF A1 domain. VWF also binds to VEGF-A and fibroblast growth factor-2 (FGF-2) in human plasma and colocalizes with VEGF-A in ECs. Incorporation of the VWF A1 HBD into fibrin matrices enables sequestration and slow release of incorporated GFs. In vivo, VWF A1 HBD-functionalized fibrin matrices increased angiogenesis and GF retention in VWF-deficient mice. Treatment of chronic skin wounds in diabetic mice with VEGF-A165 and PDGF-BB incorporated within VWF A1 HBD-functionalized fibrin matrices accelerated wound healing, with increased angiogenesis and smooth muscle cell proliferation. Therefore, the VWF A1 HBD can function as a GF reservoir, leading to effective angiogenesis and tissue regeneration.

Potential Role of Growth Factors and Extracellular Matrix in Wound Healing after Laryngotracheal Reconstruction

2000 ◽  
Vol 122 (3) ◽  
pp. 363-366 ◽  
Author(s):  
David L. Walner ◽  
Sue C. Heffelfinger ◽  
Yoram Stern ◽  
Mark J. Abrams ◽  
Mary Ann Miller ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Vascular Endothelial Growth Factor ◽  
Wound Healing ◽  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Vascular Endothelial ◽  
Positive Correlation ◽  
Laryngotracheal Reconstruction ◽  
Endothelial Growth Factor

Laryngotracheal reconstruction (LTR) has been used for more than 20 years to treat infants and children with subglottic stenosis. Results after pediatric LTR have been satisfactory; however, approximately 10% of children have recurrent airway narrowing after LTR. The purpose of our study was to determine whether a correlation existed between specific growth factors and extracellular matrix in patients with adequate wound healing capability as compared with patients with poor wound healing capability. Histologic sections from 27 patients who underwent LTR were cut, and immunohistochemical staining was performed for transforming growth factor-β, platelet-derived growth factor, fibronectin, tenascin, transforming growth factor-α, and vascular endothelial growth factor. Results showed that patients with adequate wound healing capability had a positive correlation with vasculature fibronectin, vasculature tenascin, and stromal fibronectin. Patients with poor wound healing capability had a positive correlation with stromal vascular endothelial growth factor.

Potential role of growth factors and extracellular matrix in wound healing after laryngotracheal reconstruction

2000 ◽  
Vol 122 (3) ◽  
pp. 363-366 ◽  
Author(s):  
David L. Walner ◽  
Sue C. Heffelfinger ◽  
Yoram Stern ◽  
Mark J. Abrams ◽  
Mary Ann Miller ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Vascular Endothelial Growth Factor ◽  
Wound Healing ◽  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Vascular Endothelial ◽  
Positive Correlation ◽  
Laryngotracheal Reconstruction ◽  
Endothelial Growth Factor

Laryngotracheal reconstruction (LTR) has been used for more than 20 years to treat infants and children with subglottic stenosis. Results after pediatric LTR have been satisfactory; however, approximately 10% of children have recurrent airway narrowing after LTR. The purpose of our study was to determine whether a correlation existed between specific growth factors and extracellular matrix in patients with adequate wound healing capability as compared with patients with poor wound healing capability. Histologic sections from 27 patients who underwent LTR were cut, and immunohistochemical staining was performed for transforming growth factor-β, platelet-derived growth factor, fibronectin, tenascin, transforming growth factor-α, and vascular endothelial growth factor. Results showed that patients with adequate wound healing capability had a positive correlation with vasculature fibronectin, vasculature tenascin, and stromal fibronectin. Patients with poor wound healing capability had a positive correlation with stromal vascular endothelial growth factor.

scholarly journals Laminin heparin-binding peptides promiscuously bind growth factors and enhance diabetic wound healing

2018 ◽  
Author(s):  
Jun Ishihara ◽  
Ako Ishihara ◽  
Kazuto Fukunaga ◽  
Priscilla S. Briquez ◽  
Jeffrey A. Hubbell
Keyword(s):  
Wound Healing ◽  
Growth Factors ◽  
Growth Factor ◽  
Vascular Endothelial Cell ◽  
Diabetic Mouse ◽  
Heparin Binding ◽  
Surface Receptors ◽  
Binding Domains ◽  
Skin Healing

AbstractLaminin, as a key component of the basement membrane extracellular matrix (ECM), regulates tissue morphogenesis. We show that multiple laminin isoforms promiscuously bind to growth factors (GFs) with high affinity, through their heparin binding domains (HBDs) located in the a chain LG domains. Interestingly, these domains also bind to syndecan cell-surface receptors, promoting attachment of fibroblasts and endothelial cells. We next explore application of these multifunctional laminin HBDs in skin healing in the type 2 diabetic mouse. We demonstrate that covalent incorporation of laminin HBDs into fibrin matrix enables the slow-release of GFs. Incorporation of the α33043-3067 laminin HBD significantly enhances in vivo wound-healing efficacy of vascular endothelial cell growth factor (VEGF)-A165 and platelet-derived growth factor (PDGF)-BB, under conditions where the GFs alone in fibrin are inefficacious. This laminin HBD peptide may be clinically useful by improving biomaterials as both GF reservoirs and cell scaffolds, leading to effective tissue regeneration.

scholarly journals Growth factors in the regulation of reparative response in the presence of peritoneal damage

2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Irina A. Shurygina ◽  
Мichael G. Shurygin ◽  
Lubov V. Rodionova ◽  
Nataliya I. Ayushinova
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Extended Period ◽  
Tissue Growth ◽  
Tissue Response ◽  
Heparin Binding ◽  
Lower Quadrant ◽  
Male Wistar Rats ◽  
The Right ◽  
Endothelial Growth Factor

AbstractObjectivesTo study the expression of growth factors in the regulation of tissue repair after peritoneal damage tissue response to peritoneal damage.MethodsExperimental study in 35 male Wistar rats determining the evolution over time of the tissue response to aseptic peritoneal damage. A standardized bowel and peritoneal lesions were created in the right lower quadrant by laparotomy. Then, tissular expression of growth factors was evaluated by multiplex polymerase chain reaction at seven timepoints between 6 h and 30 days, postoperatively.ResultsTissular responses of granulocyte-stimulating factors (Csf2, Csf3), connective tissue growth factor (Ctgf), epidermal growth factors and receptor (Egf, Egfr), fibroblast growth factors (Fgf2, 7 and 10), heparin binding EGF-like growth factor (Hbegf), hepatocyte growth factor (Hgf), insulin-like growth factor-1 (Igf1), mitogenic transforming growth factors (Tgfa, Tgfb1, Tgfbr3), and vascular endothelial growth factor A (Vegfa) were biphasic with a first expression peak at day 3, followed by a more pronounced peak at day 14.ConclusionsWe observed a long-lasting, widespread response of tissular growth factors for at least two weeks after peritoneal damage. To be clinically effective, the prophylaxis of postoperative adhesions might be needed for an extended period of time.

scholarly journals The Role of the Extracellular Matrix Components in Cutaneous Wound Healing

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Pawel Olczyk ◽  
Łukasz Mencner ◽  
Katarzyna Komosinska-Vassev
Keyword(s):  
Extracellular Matrix ◽  
Wound Healing ◽  
Growth Factors ◽  
Wound Repair ◽  
Structural Integrity ◽  
Healing Process ◽  
Cellular Functions ◽  
Extracellular Matrix Components ◽  
Essential Components ◽  
Matrix Components

Wound healing is the physiologic response to tissue trauma proceeding as a complex pathway of biochemical reactions and cellular events, secreted growth factors, and cytokines. Extracellular matrix constituents are essential components of the wound repair phenomenon. Firstly, they create a provisional matrix, providing a structural integrity of matrix during each stage of healing process. Secondly, matrix molecules regulate cellular functions, mediate the cell-cell and cell-matrix interactions, and serve as a reservoir and modulator of cytokines and growth factors’ action. Currently known mechanisms, by which extracellular matrix components modulate each stage of the process of soft tissue remodeling after injury, have been discussed.

scholarly journals CD44 isoforms containing exon V3 are responsible for the presentation of heparin-binding growth factor.

1995 ◽  
Vol 128 (4) ◽  
pp. 687-698 ◽  
Author(s):  
K L Bennett ◽  
D G Jackson ◽  
J C Simon ◽  
E Tanczos ◽  
R Peach ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factors ◽  
Growth Factor ◽  
Binding Proteins ◽  
Vascular Endothelial Cells ◽  
Heparin Binding ◽  
Binding Studies ◽  
Cd44 Isoforms ◽  
Cultured Endothelial Cells ◽  
Alternatively Spliced

Glycosaminoglycan-modified isoforms of CD44 have been implicated in growth factor presentation at sites of inflammation. In the present study we show that COS cell transfectants expressing CD44 isoforms containing the alternatively spliced exon V3 are modified with heparan sulfate (HS). Binding studies with three HS-binding growth factors, basic-fibroblast growth factor (b-FGF), heparin binding-epidermal growth factor (HB-EGF), and amphiregulin, showed that the HS-modified CD44 isoforms are able to bind to b-FGF and HB-EGF, but not AR. b-FGF and HB-EGF binding to HS-modified CD44 was eliminated by pretreating the protein with heparitinase or by blocking with free heparin. HS-modified CD44 immunoprecipitated from keratinocytes, which express a CD44 isoform containing V3, also bound to b-FGF. We examined whether HS-modified CD44 isoforms were expressed by activated endothelial cells where they might present HS-binding growth factors to leukocytes during an inflammatory response. PCR and antibody-binding studies showed that activated cultured endothelial cells only express the CD44H isoform which does not contain any of the variably spliced exons including V3. Immunohistological studies with antibodies directed to CD44 extracellular domains encoded by the variably spliced exons showed that vascular endothelial cells in inflamed skin tissue sections do not express CD44 spliced variants. Keratinocytes, monocytes, and dendritic cells in the same specimens were found to express variably spliced CD44. 35SO4(-2)-labeling experiments demonstrated that activated cultured endothelial cells do not express detectable levels of chondroitin sulfate or HS-modified CD44. Our results suggest that one of the functions of CD44 isoforms expressing V3 is to bind and present a subset of HS-binding proteins. Furthermore, it is probable that HS-modified CD44 is involved in the presentation of HS-binding proteins by keratinocytes in inflamed skin. However, our data suggests that CD44 is not likely to be the proteoglycan principally involved in presenting HS-binding growth factors to leukocytes on the vascular cell wall.

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