Specific disruption of Lnk in murine endothelial progenitor cells promotes dermal wound healing via enhanced vasculogenesis, activation of myofibroblasts, and suppression of inflammatory cell recruitment

Lee, Jun Hee; Ji, Seung Taek; Kim, Jae-Ho; Takaki, Satoshi; Asahara, Takayuki; Hong, Young Joon; Kwon, Sang‐Mo

doi:10.1186/s13287-016-0403-3

Cited by 18 publications

(9 citation statements)

References 42 publications

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“…After evaluating the ability of biodegradation of the hydrogels, we further assessed the biosafety of these hydrogels in vitro and in vivo . Dermal fibroblasts, endothelial cells, and stem cells take part in wound repair. , Therefore, we examined the cytocompatibility of the hydrogels using L929 cells, human dermal fibroblasts (HDFs), human umbilical vein endothelial cells (HUVECs), and HUMSCs (as shown in Figure ). HDFs cultured with hydrogel extracts were observed to show vimentin-positive expression (red).…”

Section: Resultsmentioning

confidence: 99%

Improving Chronic Diabetic Wound Healing through an Injectable and Self-Healing Hydrogel with Platelet-Rich Plasma Release

Qian

Wang²,

Bai

et al. 2020

ACS Appl. Mater. Interfaces

150

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Diabetic skin ulcer is one of the severe complications of diabetes mellitus, which has a high incidence and may cause death or disability. Platelet-rich plasma (PRP) is widely used in the treatment of diabetic wounds due to the effect of growth factors (GFs) derived from it. However, the relatively short half-life of GFs limits their applications in clinics. In addition, the presence of a large amount of proteases in the diabetic wound microenvironment results in the degradation of GFs, which further impedes angiogenesis and diabetic wound healing. In our study, we fabricated a self-healing and injectable hydrogel with a composite of chitosan, silk fibroin, and PRP (CBPGCTS–SF@PRP) for promoting diabetic wound healing. CBPGCTS–SF@PRP could protect PRP from enzymatic hydrolysis, release PRP sustainably, and enhance the chemotaxis of mesenchymal stem cells. The results showed that it could promote the proliferation of repair cells in vitro. Moreover, it could enhance wound healing by expediting collagen deposition, angiogenesis, and nerve repair in a type 2 diabetic rat model and a rat skin defect model. We hope that this study will offer a new treatment for diabetic nonhealing wounds in clinics.

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Section: Resultsmentioning

confidence: 99%

Improving Chronic Diabetic Wound Healing through an Injectable and Self-Healing Hydrogel with Platelet-Rich Plasma Release

Qian

Wang²,

Bai

et al. 2020

ACS Appl. Mater. Interfaces

150

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“…Potential mechanisms of impaired angiogenesis response may be either the anti-angiogenic interference of inflammatory cytokines, such as IP10, or NT-proBNP that may influence EPC proliferation or release mechanisms ( Strieter et al, 1995 , Stamm et al, 2003 , Cesari et al, 2008 ). In this context, the first description of upregulated SH2B3 gene expression enhancement in the peripheral blood of non-responders associated with reduced EPC and thrombocyte counts suggests a potential regulatory role of SH2B3 with respect to suppression of the bone marrow response ( Cesari et al, 2008 , Kwon et al, 2009 , Lee et al, 2016 ). Experimental models have depicted the potential importance and diagnostic or therapeutic relevance of SH2B3 gene expression and lnk adaptor protein SH2B3 for regulation of bone marrow responses and impairment of angiogenesic capacity ( Ishige-Wada et al, 2016 , Takizawa et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

Cardiac Function Improvement and Bone Marrow Response –

Steinhoff¹,

Nesteruk²,

Wolfien

et al. 2017

EBioMedicine

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ObjectiveThe phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair.DesignMulticentre, double-blinded, randomised placebo controlled trial.SettingThe study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015.ParticipantsPost-infarction patients with chronic ischemia and reduced LVEF (25–50%). Interventions: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5 ml placebo or a suspension of 0.5–5 × 106 CD133+.OutcomePrimary endpoint was delta (∆) LVEF at 180 days (d) compared to baseline measured in MRI.Findings (prespecified)Safety (n = 77): 180 d survival was 100%, MACE n = 2, SAE n = 49, without difference between placebo and CD133+. Efficacy (n = 58): The LVEF improved from baseline LVEF 33.5% by + 9.6% at 180 d, p = 0.001 (n = 58). Treatment groups were not different in ∆ LVEF (ANCOVA: Placebo + 8.8% vs. CD133+ + 10.4%, ∆ CD133+ vs placebo + 2.6%, p = 0.4).Findings (post hoc)Responders (R) classified by ∆ LVEF ≥ 5% after 180 d were 60% of the patients (35/58) in both treatment groups. ∆ LVEF in ANCOVA was + 17.1% in (R) vs. non-responders (NR) (∆ LVEF 0%, n = 23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p = 0.005) and thrombocytes (p = 0.004) in contrast to increased Erythropoeitin (p = 0.02), and SH2B3 mRNA expression (p = 0.073). Actuarial computed mean survival time was 76.9 ± 3.32 months (R) vs. + 72.3 ± 5.0 months (NR), HR 0.3 [Cl 0.07–1.2]; p = 0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation.InterpretationThe PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133 + EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature.TRIAL REGISTRATION: ClinicalTrials.govNCT00950274.

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“…Endothelial progenitor cells (EPCs) are a type of cell able to differentiate into mature endothelial cells and are involved in postnatal neovascularization (Takahashi et al, 1999 ; Asahara et al, 1999a , b ; Aicher et al, 2005 ; Real et al, 2008 ). Evidence continues to accumulate regarding the importance of EPCs for restoring endothelial function in injured blood vessels and neovascularization in ischemic tissues (Asahara et al, 1999a ; Assmus et al, 2002 ; Iba et al, 2002 ; Griese et al, 2003 ; Krankel et al, 2012 ; Galasso et al, 2013 ; Lee et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Role of NADPH Oxidase-4 in Human Endothelial Progenitor Cells

et al. 2017

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Introduction: Endothelial progenitor cells (EPCs) display a unique ability to promote angiogenesis and restore endothelial function in injured blood vessels. NADPH oxidase 4 (NOX4)-derived hydrogen peroxide (H2O2) serves as a signaling molecule and promotes endothelial cell proliferation and migration as well as protecting against cell death. However, the role of NOX4 in EPC function is not completely understood.Methods: EPCs were isolated from human saphenous vein and mammary artery discarded during bypass surgery. NOX4 gene and protein expression in EPCs were measured by real time-PCR and Western blot analysis respectively. NOX4 gene expression was inhibited using an adenoviral vector expressing human NOX4 shRNA (Ad-NOX4i). H2O2 production was measured by Amplex red assay. EPC migration was evaluated using a transwell migration assay. EPC proliferation and viability were measured using trypan blue counts.Results: Inhibition of NOX4 using Ad-NOX4i reduced Nox4 gene and protein expression as well as H2O2 formation in EPCs. Inhibition of NOX4-derived H2O2 decreased both proliferation and migration of EPCs. Interestingly, pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) decreased NOX4 expression and reduced survival of EPCs. However, the survival of EPCs was further diminished by TNF-α in NOX4-knockdown cells, suggesting that NOX4 has a protective role in EPCs.Conclusion: These findings suggest that NOX4-type NADPH oxidase is important for proliferation and migration functions of EPCs and protects against pro-inflammatory cytokine induced EPC death. These properties of NOX4 may facilitate the efficient function of EPCs which is vital for successful neovascularization.

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Specific disruption of Lnk in murine endothelial progenitor cells promotes dermal wound healing via enhanced vasculogenesis, activation of myofibroblasts, and suppression of inflammatory cell recruitment

Cited by 18 publications

References 42 publications

Improving Chronic Diabetic Wound Healing through an Injectable and Self-Healing Hydrogel with Platelet-Rich Plasma Release

Improving Chronic Diabetic Wound Healing through an Injectable and Self-Healing Hydrogel with Platelet-Rich Plasma Release

Cardiac Function Improvement and Bone Marrow Response –

Role of NADPH Oxidase-4 in Human Endothelial Progenitor Cells

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