Mikaël Martino

Cytoprotection, proliferation and epidermal differentiation of adipose tissue-derived stem cells on emu oil based electrospun nanofibrous mat

Publisher: Elsevier BV

Date: 08-2017

DOI: 10.1016/J.YEXCR.2017.05.015

Abstract: Electrospun nanofibrous scaffolds containing natural substances with wound healing properties such as Emu oil (EO) may have a great potential for increasing the efficiency of stem cell-based skin bioengineering. For this purpose, EO blended PCL/PEG electrospun nanofibrous mats were successfully fabricated and characterized using FE-SEM, FTIR and Universal Testing Machine. The efficiency of the scaffolds in supporting the adherence, cytoprotection, proliferation and differentiation of adipose tissue-derived stem cells (ADSCs) to keratinocyte was evaluated. GC/MS and HPLC were used to determine the composition of pure EO, which revealed to be mainly fatty acids and carotenoids. FE-SEM and cell proliferation assays showed that adhesion and proliferation of ADSCs on EO-PCL/PEG nanofibers was significantly higher than on PCL/PEG nanofibers. Additionally, EO-PCL/PEG nanofibers with free radical scavenging properties conferred a cytoprotective effect against cell-damaging free radicals, while the ability to support cell adhesion and growth was maintained or even improved. Immunostaining of ADSCs on EO-PCL/PEG nanofibers confirmed the change in morphology of ADSCs from spindle to polygonal shape suggesting their differentiation toward an epidermal linage. Moreover, the expression levels of the keratin 10, filaggrin, and involucrin that are involved in epidermal differentiation were upregulated in a stage-specific manner. This preliminary study shows that EO-PCL/PEG nanofibers could be a good candidate for the fabrication of wound dressings and skin bioengineered substitutes with ADSCs.

Strawberry notch homologue 2 regulates osteoclast fusion by enhancing the expression of DC-STAMP

Publisher: Rockefeller University Press

Date: 26-08-2013

DOI: 10.1084/JEM.20130512

Abstract: Osteoclasts are multinucleated cells formed by fusion of mononuclear precursors in response to receptor activator of nuclear factor κB (NF-κB) ligand (RANKL). We found that RANKL induced expression of the DExD/H helicase family corepressor strawberry notch homologue 2 (Sbno2). Previous in vitro studies showed that Sbno2 is induced by IL-10 and is involved in NF-κB repression. However, the role of Sbno2 in vivo and its pleiotropic functions are unknown. Sbno2 gene targeting resulted in normal NF-κB activation by TLR ligands. However, Sbno2-deficient mice exhibited increased bone mass due to impaired osteoclast fusion. Expression of dendritic cell–specific transmembrane protein (DC-STAMP), a critical player in osteoclast fusion, was significantly attenuated, and cell fusion of Sbno2-deficient osteoclasts was rescued by DC-STAMP. Sbno2 directly bound to T cell acute lymphocytic leukemia 1 (Tal1) and attenuated its inhibition of DC-STAMP expression, leading to activation of the DC-STAMP promoter by microphthalmia-associated transcription factor (MITF). Thus, Sbno2 plays a pivotal role in bone homeostasis in vivo by fine-tuning osteoclast fusion.

In situ cell manipulation through enzymatic hydrogel photopatterning

Publisher: Springer Science and Business Media LLC

Date: 13-10-2013

DOI: 10.1038/NMAT3766

Abstract: The physicochemical properties of hydrogels can be manipulated in both space and time through the controlled application of a light beam. However, methods for hydrogel photopatterning either fail to maintain the bioactivity of fragile proteins and are thus limited to short peptides, or have been used in hydrogels that often do not support three-dimensional (3D) cell growth. Here, we show that the 3D invasion of primary human mesenchymal stem cells can be spatiotemporally controlled by micropatterning the hydrogel with desired extracellular matrix (ECM) proteins and growth factors. A peptide substrate of activated transglutaminase factor XIII (FXIIIa)--a key ECM crosslinking enzyme--is rendered photosensitive by masking its active site with a photolabile cage group. Covalent incorporation of the caged FXIIIa substrate into poly(ethylene glycol) hydrogels and subsequent laser-scanning lithography affords highly localized biomolecule tethering. This approach for the 3D manipulation of cells within gels should open up avenues for the study and manipulation of cell signalling.

Promoting tissue regeneration by modulating the immune system

Publisher: Elsevier BV

Date: 04-2017

DOI: 10.1016/J.ACTBIO.2017.01.056

Abstract: The immune system plays a central role in tissue repair and regeneration. Indeed, the immune response to tissue injury is crucial in determining the speed and the outcome of the healing process, including the extent of scarring and the restoration of organ function. Therefore, controlling immune components via biomaterials and drug delivery systems is becoming an attractive approach in regenerative medicine, since therapies based on stem cells and growth factors have not yet proven to be broadly effective in the clinic. To integrate the immune system into regenerative strategies, one of the first challenges is to understand the precise functions of the different immune components during the tissue healing process. While remarkable progress has been made, the immune mechanisms involved are still elusive, and there is indication for both negative and positive roles depending on the tissue type or organ and life stage. It is well recognized that the innate immune response comprising danger signals, neutrophils and macrophages modulates tissue healing. In addition, it is becoming evident that the adaptive immune response, in particular T cell subset activities, plays a critical role. In this review, we first present an overview of the basic immune mechanisms involved in tissue repair and regeneration. Then, we highlight various approaches based on biomaterials and drug delivery systems that aim at modulating these mechanisms to limit fibrosis and promote regeneration. We propose that the next generation of regenerative therapies may evolve from typical biomaterial-, stem cell-, or growth factor-centric approaches to an immune-centric approach. Most regenerative strategies have not yet proven to be safe or reasonably efficient in the clinic. In addition to stem cells and growth factors, the immune system plays a crucial role in the tissue healing process. Here, we propose that controlling the immune-mediated mechanisms of tissue repair and regeneration may support existing regenerative strategies or could be an alternative to using stem cells and growth factors. The first part of this review we highlight key immune mechanisms involved in the tissue healing process and marks them as potential target for designing regenerative strategies. In the second part, we discuss various approaches using biomaterials and drug delivery systems that aim at modulating the components of the immune system to promote tissue regeneration.

Bioluminescent and micro-computed tomography imaging of bone repair induced by fibrin-binding growth factors

Publisher: Elsevier BV

Date: 10-2014

DOI: 10.1016/J.ACTBIO.2014.05.028

Abstract: In this work we have evaluated the capacity of bone morphogenetic protein-2 (BMP-2) and fibrin-binding platelet-derived growth factor-BB (PDGF-BB) to support cell growth and induce bone regeneration using two different imaging technologies to improve the understanding of structural and organizational processes participating in tissue repair. Human mesenchymal stem cells from adipose tissue (hAMSCs) expressing two luciferase genes, one under the control of the cytomegalovirus (CMV) promoter and the other under the control of a tissue-specific promoter (osteocalcin or platelet endothelial cell adhesion molecule), were seeded in fibrin matrices containing BMP-2 and fibrin-binding PDGF-BB, and further implanted intramuscularly or in a mouse calvarial defect. Then, cell growth and bone regeneration were monitored by bioluminescence imaging (BLI) to analyze the evolution of target gene expression, indicative of cell differentiation towards the osteoblastic and endothelial lineages. Non-invasive imaging was supplemented with micro-computed tomography (μCT) to evaluate bone regeneration and high-resolution μCT of vascular casts. Results from BLI showed hAMSC growth during the first week in all cases, followed by a rapid decrease in cell number as well as an increment of osteocalcin but not PECAM-1 expression 3weeks after implantation. Results from μCT show that the delivery of BMP-2 and PDGF-BB by fibrin induced the formation of more bone and improves vascularization, resulting in more abundant and thicker vessels, in comparison with controls. Although the inclusion of hAMSCs in the fibrin matrices made no significant difference in any of these parameters, there was a significant increment in the connectivity of the vascular network in defects treated with hAMSCs.

Design principles for therapeutic angiogenic materials

Publisher: Springer Science and Business Media LLC

Date: 11-01-2016

DOI: 10.1038/NATREVMATS.2015.6

Evaluation of Injectable Constructs for Bone Repair with a Subperiosteal Cranial Model in the Rat

Publisher: Public Library of Science (PLoS)

Date: 13-08-2013

DOI: 10.1371/JOURNAL.PONE.0071683

Nociceptor-derived Reg3γ prevents endotoxic death by targeting kynurenine pathway in microglia.

Publisher: Elsevier BV

Date: 03-2022

DOI: 10.1016/J.CELREP.2022.110462

Abstract: Nociceptors can fine-tune local or systemic immunity, but the mechanisms of nociceptive modulation in endotoxic death remain largely unknown. Here, we identified C-type lectin Reg3γ as a nociceptor-enriched hormone that protects the host from endotoxic death. During endotoxemia, nociceptor-derived Reg3γ penetrates the brain and suppresses the expression of microglial indoleamine dioxygenase 1, a critical enzyme of the kynurenine pathway, via the Extl3-Bcl10 axis. Endotoxin-administered nociceptor-null mice and nociceptor-specific Reg3γ-deficient mice exhibit a high mortality rate accompanied by decreased brain HK1 phosphorylation and ATP production despite normal peripheral inflammation. Such metabolic arrest is only observed in the brain, and aberrant production of brain quinolinic acid, a neurotoxic metabolite of the kynurenine pathway, causes HK1 suppression. Strikingly, the central administration of Reg3γ protects mice from endotoxic death by enhancing brain ATP production. By identifying nociceptor-derived Reg3γ as a microglia-targeted hormone, this study provides insights into the understanding of tolerance to endotoxic death.

Editorial: Vascularization for Regenerative Medicine

Publisher: Frontiers Media SA

Date: 21-11-2018

DOI: 10.3389/FBIOE.2018.00175

Is faster better? An economic evaluation of rapid and ultra-rapid genomic testing in critically ill infants and children

Publisher: Elsevier BV

Date: 05-2022

DOI: 10.1016/J.GIM.2022.01.013

Abstract: To evaluate whether the additional cost of providing increasingly faster genomic results in pediatric critical care is outweighed by reductions in health care costs and increases in personal utility. Hospital costs and medical files from a cohort of 40 children were analyzed. The health economic impact of rapid and ultra-rapid genomic testing, with and without early initiation, relative to standard genomic testing was evaluated. Shortening the time to results led to substantial economic and personal benefits. Early initiation of ultra-rapid genomic testing was the most cost-beneficial strategy, leading to a cost saving of AU$26,600 per child tested relative to standard genomic testing and a welfare gain of AU$12,000 per child tested. Implementation of early ultra-rapid testing of critically ill children is expected to lead to an annual cost saving of AU$7.3 million for the Australian health system and an aggregate welfare gain of AU$3.3 million, corresponding to a total net benefit of AU$10.6 million. Early initiation of ultra-rapid genomic testing can offer substantial economic and personal benefits. Future implementation of rapid genomic testing programs should focus not only on optimizing the laboratory workflow to achieve a fast turnaround time but also on changing clinical practice to expedite test initiation.

Fibrin gels engineered with pro‐angiogenic growth factors promote engraftment of pancreatic islets in extrahepatic sites in mice

Publisher: Wiley

Date: 07-07-2015

DOI: 10.1002/BIT.25589

Abstract: With a view toward reduction of graft loss, we explored pancreatic islet transplantation within fibrin matrices rendered pro-angiogenic by incorporation of minimal doses of vascular endothelial growth factor-A165 and platelet-derived growth factor-BB presented complexed to a fibrin-bound integrin-binding fibronectin domain. Engineered matrices allowed for extended release of pro-angiogenic factors and for their synergistic signaling with extracellular matrix-binding domains in the post-transplant period. Aprotinin addition delayed matrix degradation and prolonged pro-angiogenic factor availability within the graft. Both subcutaneous (SC) and epididymal fat pad (EFP) sites were evaluated. We show that in the SC site, diabetes reversal in mice transplanted with 1,000 IEQ of syngeneic islets was not observed for islets transplanted alone, while engineered matrices resulted in a diabetes median reversal time (MDRT) of 38 days. In the EFP site, the MDRT with 250 IEQ of syngeneic islets within the engineered matrices was 24 days versus 86 days for islets transplanted alone. Improved function of engineered grafts was associated with enhanced and earlier (by day 7) angiogenesis. Our findings show that by engineering the transplant site to promote prompt re-vascularization, engraftment and long-term function of islet grafts can be improved in relevant extrahepatic sites.

Proangiogenic Hydrogels Within Macroporous Scaffolds Enhance Islet Engraftment in an Extrahepatic Site

Publisher: Mary Ann Liebert Inc

Date: 12-2013

DOI: 10.1089/TEN.TEA.2012.0686

Engineering the Growth Factor Microenvironment with Fibronectin Domains to Promote Wound and Bone Tissue Healing

Publisher: American Association for the Advancement of Science (AAAS)

Date: 14-09-2011

DOI: 10.1126/SCITRANSLMED.3002614

Abstract: A multifunctional fibronectin fragment enhances the regenerative effects of growth factors in vivo in animal models of chronic wounds and critical-size bone defects.

Improving the osteogenic potential of BMP-2 with hyaluronic acid hydrogel modified with integrin-specific fibronectin fragment

Publisher: Elsevier BV

Date: 2013

DOI: 10.1016/J.BIOMATERIALS.2012.10.015

Abstract: While human bone morphogenetic protein-2 (rhBMP-2) is a promising growth factor for bone regeneration, its clinical efficacy has recently shown to be below expectation. In order to improve the clinical translation of rhBMP-2, there exists strong motivation to engineer better delivery systems. Hyaluronic acid (HA) hydrogel is a suitable carrier for the delivery of rhBMP-2, but a major limitation of this scaffold is its low cell adhesive properties. In this study, we have determined whether covalent grafting of an integrin-specific ligands into HA hydrogel could improve cell attachment and further enhance the osteogenic potential of rhBMP-2. A structurally stabilized fibronectin (FN) fragment containing the major integrin-binding domain of full-length FN (FN III9*-10) was engineered, in order to be incorporated into HA hydrogel. Compared to non-functionalized HA hydrogel, HA-FN hydrogel remarkably improved the capacity of the material to support mesenchymal stem cell attachment and spreading. In an ectopic bone formation model in the rat, delivery of rhBMP-2 with HA-FN hydrogel resulted in the formation of twice as much bone with better organization of collagen fibers compared to delivering the growth factor in non-functionalized HA hydrogel. This engineered hydrogel carrier for rhBMP-2 can be relevant in clinical bone repair.

A superior extracellular matrix binding motif to enhance the regenerative activity and safety of therapeutic proteins

Publisher: Springer Science and Business Media LLC

Date: 22-05-2023

DOI: 10.1038/S41536-023-00297-0

Abstract: Among therapeutic proteins, cytokines and growth factors have great potential for regenerative medicine applications. However, these molecules have encountered limited clinical success due to low effectiveness and major safety concerns, highlighting the need to develop better approaches that increase efficacy and safety. Promising approaches leverage how the extracellular matrix (ECM) controls the activity of these molecules during tissue healing. Using a protein motif screening strategy, we discovered that hiregulin possesses an exceptionally strong binding motif for ECM components. We used this motif to confer the pro-regenerative therapeutics platelet-derived growth factor-BB (PDGF-BB) and interleukin-1 receptor antagonist (IL-1Ra) a very high affinity to the ECM. In mouse models, the approach considerably extended tissue retention of the engineered therapeutics and reduced leakage in the circulation. Prolonged retention and minimal systemic diffusion of engineered PDGF-BB abolished the tumour growth-promoting adverse effect that was observed with wild-type PDGF-BB. Moreover, engineered PDGF-BB was substantially more effective at promoting diabetic wound healing and regeneration after volumetric muscle loss, compared to wild-type PDGF-BB. Finally, while local or systemic delivery of wild-type IL-1Ra showed minor effects, intramyocardial delivery of engineered IL-1Ra enhanced cardiac repair after myocardial infarction by limiting cardiomyocyte death and fibrosis. This engineering strategy highlights the key importance of exploiting interactions between ECM and therapeutic proteins for developing effective and safer regenerative therapies.

5-Azacytidine-induced Protein 2 (AZI2) Regulates Bone Mass by Fine-tuning Osteoclast Survival

Publisher: Elsevier BV

Date: 04-2015

DOI: 10.1074/JBC.M114.631374

Genomic sequencing for the diagnosis of childhood mitochondrial disorders: a health economic evaluation

Publisher: Springer Science and Business Media LLC

Date: 08-06-2021

DOI: 10.1038/S41431-021-00916-8

Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration

Publisher: Springer Science and Business Media LLC

Date: 22-03-2016

DOI: 10.1038/NCOMMS11051

Abstract: Tissue injury and the healing response lead to the release of endogenous danger signals including Toll-like receptor (TLR) and interleukin-1 receptor, type 1 (IL-1R1) ligands, which modulate the immune microenvironment. Because TLRs and IL-1R1 have been shown to influence the repair process of various tissues, we explored their role during bone regeneration, seeking to design regenerative strategies integrating a control of their signalling. Here we show that IL-1R1/MyD88 signalling negatively regulates bone regeneration, in the mouse. Furthermore, IL-1β which is released at the bone injury site, inhibits the regenerative capacities of mesenchymal stem cells (MSCs). Mechanistically, IL-1R1/MyD88 signalling impairs MSC proliferation, migration and differentiation by inhibiting the Akt/GSK-3β/β-catenin pathway. Lastly, as a proof of concept, we engineer a MSC delivery system integrating inhibitors of IL-1R1/MyD88 signalling. Using this strategy, we considerably improve MSC-based bone regeneration in the mouse, demonstrating that this approach may be useful in regenerative medicine applications.

Modulation of the Activity of Stem and Progenitor Cells by Immune Cells

Publisher: Oxford University Press (OUP)

Date: 03-2022

DOI: 10.1093/STCLTM/SZAB022

Abstract: Numerous components of the immune system, including inflammatory mediators, immune cells and cytokines, have a profound modulatory effect on the homeostatic regulation and regenerative activity of endogenous stem cells and progenitor cells. Thus, understanding how the immune system interacts with stem rogenitor cells could build the foundation to design novel and more effective regenerative therapies. Indeed, utilizing and controlling immune system components may be one of the most effective approaches to promote tissue regeneration. In this review, we first summarize the effects of various immune cell types on endogenous stem rogenitor cells, focusing on the tissue healing context. Then, we present interesting regenerative strategies that control or mimic the effect of immune components on stem rogenitor cells, in order to enhance the regenerative capacity of endogenous and transplanted stem cells. We highlight the potential clinical translation of such approaches for multiple tissues and organ systems, as these novel regenerative strategies could considerably improve or eventually substitute stem cell-based therapies. Overall, harnessing the power of the cross-talk between the immune system and stem rogenitor cells holds great potential for the development of novel and effective regenerative therapies.

Growth Factor and Cytokine Delivery Systems for Wound Healing

Publisher: Cold Spring Harbor Laboratory

Date: 06-06-2022

DOI: 10.1101/CSHPERSPECT.A041234

Engineering the Regenerative Microenvironment with Biomaterials

Publisher: Wiley

Date: 03-09-2012

DOI: 10.1002/ADHM.201200197

Abstract: Modern synthetic biomaterials are being designed to integrate bioactive ligands within hydrogel scaffolds for cells to respond and assimilate within the matrix. These advanced biomaterials are only beginning to be used to simulate the complex spatio-temporal control of the natural healing microenvironment. With increasing understanding of the role of growth factors and cytokines and their interactions with components of the extracellular matrix, novel biomaterials are being developed that more closely mimic the natural healing environments of tissues, resulting in increased efficacy in applications of tissue repair and regeneration. Herein, the important aspects of the healing microenvironment, and how these features can be incorporated within innovative hydrogel scaffolds, are presented.

Growth Factor Engineering Strategies for Regenerative Medicine Applications

Publisher: Frontiers Media SA

Date: 21-01-2020

DOI: 10.3389/FBIOE.2019.00469

The 12th–14th type III repeats of fibronectin function as a highly promiscuous growth factor-binding domain

Publisher: Wiley

Date: 12-2010

DOI: 10.1096/FJ.09-151282

Abstract: It has recently been shown that some growth factors (GFs) have strong interactions with nonproteoglycan extracellular matrix proteins. Relevant here, the 12th-14th type three repeats of fibronectin (FN III12-14) have been shown to bind insulin-like growth factor binding-protein-3, fibroblast growth factor (FGF)-2, and vascular endothelial growth factor (VEGF)-A with high affinity. Since FN III12-14 is known to bind GFs from different families, we hypothesized that this domain could be highly promiscuous in its GF-binding capacity. We used biochemical approaches and surface plasmon resonance to investigate such interactions with recombinant FN III12-14. We found that FN III12-14 binds most of the GFs from the platelet-derived growth factor (PDGF)/VEGF and FGF families and some GFs from the transforming growth factor-β and neurotrophin families, with K(D) values in the nanomolar range, without inhibiting GF activity. Overall, 25 new binding interactions were identified. In a clinically relevant fibrin matrix, a fibrin-binding variant of FN III12-14 was highly effective as a GF delivery system. For instance, in matrices functionalized with FN III12-14, PDGF-BB-induced sprouting of human smooth muscle cell spheroids was greatly enhanced. We show that FN III12-14 is a highly promiscuous ligand for GFs and also holds great potential in clinical healing applications.

Growth factors with enhanced syndecan binding generate tonic signalling and promote tissue healing

Publisher: Springer Science and Business Media LLC

Date: 04-11-2019

DOI: 10.1038/S41551-019-0469-1

Abstract: Growth factors can stimulate tissue regeneration, but the side effects and low effectiveness associated with suboptimal delivery systems have impeded their use in translational regenerative medicine. Physiologically, growth factor interactions with the extracellular matrix control their bioavailability and spatiotemporal cellular signalling. Growth factor signalling is also controlled at the cell surface level via binding to heparan sulfate proteoglycans, such as syndecans. Here we show that vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) that were engineered to have a syndecan-binding sequence trigger sustained low-intensity signalling (tonic signalling) and reduce the desensitization of growth factor receptors. We also show in mouse models that tonic signalling leads to superior morphogenetic activity, with syndecan-binding growth factors inducing greater bone regeneration and wound repair than wild-type growth factors, as well as reduced tumour growth (associated with PDGF-BB delivery) and vascular permeability (triggered by VEGF-A). Tonic signalling via syndecan binding may also enhance the regenerative capacity of other growth factors.

Immune Regulation of Skin Wound Healing: Mechanisms and Novel Therapeutic Targets

Publisher: Mary Ann Liebert Inc

Date: 07-2018

DOI: 10.1089/WOUND.2017.0761

Extracellular Matrix and Growth Factor Engineering for Controlled Angiogenesis in Regenerative Medicine

Publisher: Frontiers Media SA

Date: 04-2015

DOI: 10.3389/FBIOE.2015.00045

Quality of life in caregivers of a child with a developmental and epileptic encephalopathy

Publisher: Wiley

Date: 08-07-2023

DOI: 10.1111/DMCN.15695

Abstract: To explore the relationship between social care‐related quality of life (SCrQoL) for caregivers of a child with a developmental and epileptic encephalopathy (DEE such as SCN2A and Dravet syndrome) and health literacy, illness perceptions, and caregiver activation. As part of a larger pre‐post pilot study of an information linker service, caregivers completed a baseline questionnaire which included demographics and measures to assess SCrQoL, health literacy, illness perceptions, and caregiver activation. We used Spearman's Rho to determine relationships between variables. Seventy‐two caregivers completed the questionnaire. Total SCrQoL varied widely, ranging from an ‘ideal state’ to ‘high needs state’. Caregivers most frequently reported high needs regarding doing activities they enjoy and looking after themselves. Total SCrQoL was correlated with cognitive (r[70] = −0.414, p 0.000) and emotional representations of illness (r[70] = −0.503, p 0.000), but not coherence (r = −0.075, p = 0.529). Total SCrQoL was not correlated with health literacy (r[70] = 0.125, p = 0.295) or caregiver activation (r[70] = 0.181, p = 0.127). Future research should explore whether interventions that help caregivers cognitively reframe the negative experiences of having a child with a DEE, and support them to partake in activities they enjoy, boost their SCrQoL.

Enhancing the regenerative effectiveness of growth factors by local inhibition of interleukin-1 receptor signaling

Publisher: American Association for the Advancement of Science (AAAS)

Date: 12-06-2020

DOI: 10.1126/SCIADV.ABA7602

Abstract: A novel engineered form of interleukin-1 receptor antagonist augments the regenerative activity of recombinant growth factors.

The ATP Transporter VNUT Mediates Induction of Dectin-1-Triggered Candida Nociception

Publisher: Elsevier BV

Date: 08-2018

DOI: 10.1016/J.ISCI.2018.08.007

Fibronectin Binding Modulates CXCL11 Activity and Facilitates Wound Healing

Publisher: Public Library of Science (PLoS)

Date: 25-10-2013

DOI: 10.1371/JOURNAL.PONE.0079610

Extracellular Matrix-Inspired Growth Factor Delivery Systems for Skin Wound Healing

Publisher: Mary Ann Liebert Inc

Date: 08-2015

DOI: 10.1089/WOUND.2014.0603

Netrins as prophylactic targets in skeletal diseases: A double-edged sword?

Publisher: Elsevier BV

Date: 08-2017

DOI: 10.1016/J.PHRS.2017.05.011

Abstract: The netrin family of proteins are involved in axon guidance during central nervous system development. In vertebrates, two membrane bound forms and five secreted forms of netrin have been reported. In addition to their critical role in neural morphogenesis, a growing number of reports suggest that netrin family proteins also play a role in inflammatory conditions, angiogenesis, and tumorigenesis. In these processes, Unc5 and DCC family proteins serve as receptors of netrin proteins. Recently, it was reported that some netrin family proteins may be involved in the pathogenesis of skeletal diseases including osteoporosis and arthritis. For ex le, administration of secreted netrin family proteins such as netrin 1 and netrin 4 has prophylactic potential in pathogenic bone degradation in mice. However, netrin 1 blocking antibody also protects mice from inflammatory bone destruction. Therefore, netrin family proteins are involved in the regulation of bone homeostasis, but their bona fide roles in the skeletal system remain controversial. In this review, we discuss the osteo-innate-immune functions of the netrin family of proteins, and summarize their therapeutic potential.

Regulatory T-Cells: Potential Regulator of Tissue Repair and Regeneration

Publisher: Frontiers Media SA

Date: 23-03-2018

DOI: 10.3389/FIMMU.2018.00585

Restoration of the healing microenvironment in diabetic wounds with matrix-binding IL-1 receptor antagonist

Publisher: Springer Science and Business Media LLC

Date: 26-03-2021

DOI: 10.1038/S42003-021-01913-9

Abstract: Chronic wounds are a major clinical problem where wound closure is prevented by pathologic factors, including immune dysregulation. To design efficient immunotherapies, an understanding of the key molecular pathways by which immunity impairs wound healing is needed. Interleukin-1 (IL-1) plays a central role in regulating the immune response to tissue injury through IL-1 receptor (IL-1R1). Generating a knockout mouse model, we demonstrate that the IL-1–IL-1R1 axis delays wound closure in diabetic conditions. We used a protein engineering approach to deliver IL-1 receptor antagonist (IL-1Ra) in a localised and sustained manner through binding extracellular matrix components. We demonstrate that matrix-binding IL-1Ra improves wound healing in diabetic mice by re-establishing a pro-healing microenvironment characterised by lower levels of pro-inflammatory cells, cytokines and senescent fibroblasts, and higher levels of anti-inflammatory cytokines and growth factors. Engineered IL-1Ra has translational potential for chronic wounds and other inflammatory conditions where IL-1R1 signalling should be d ened.

Zinc Finger Protein St18 Protects against Septic Death by Inhibiting VEGF-A from Macrophages

Publisher: Elsevier BV

Date: 07-2020

DOI: 10.1016/J.CELREP.2020.107906

Cost Analysis of Orthoptist-Led Neurofibromatosis Type 1 Screening Clinics

Publisher: White Rose University Press

Date: 10-04-2023

DOI: 10.22599/BIOJ.288

Abstract: Purpose: To conduct a costing study comparing orthoptist-led with consultant-led clinics screening for optic pathway gliomas (OPGs) in children with neurofibromatosis Type 1 (NF1) attending the Royal Children’s Hospital (RCH), Melbourne. Methods: Patients with NF1 examined in the orthoptist-led NF1 screening clinic and/or consultant-led clinics during the study period were identified. The workflow management software Q-Flow 6® provided data documenting patient’s time spent with the orthoptist, nurse, and ophthalmologist. Time points were converted into minutes and multiplied by the cost-per-minute for each profession. A bottom-up micro-costing approach was used to estimate appointment level costs. Bootstrap simulations with 1000 replications were used to estimate 95% confidence intervals (CIs) for the difference in mean appointment time and cost between clinics. Results: Data for 130 consultant-led clinic appointments and 234 orthoptist-led clinic appointments were extracted for analysis. The mean time per appointment for the consultant-led clinic was 45.11 minutes, and the mean time per appointment for the orthoptist-led clinic was 25.85 minutes. The mean cost per appointment for the consultant-led clinic was A $84.15 (GBP £39.60) compared to the orthoptist-led clinic at A $20.40 (GBP £9.60). This represents a mean reduction of 19.25 minutes per appointment (95% CI, –24.85 to –13.66) and a mean reduction of A $63.75 (GBP £30.00) per appointment (95% CI, (A $-75.40 to $-52.10 [GBP £ -35.48 to £ -24.52]). Conclusion: An orthoptist-led clinic screening for OPGs in patients with NF1 can be a more cost-efficient model of care for ophthalmic screening in this patient group.

Heparin-binding domain of fibrin(ogen) binds growth factors and promotes tissue repair when incorporated within a synthetic matrix

Publisher: Proceedings of the National Academy of Sciences

Date: 04-03-2013

DOI: 10.1073/PNAS.1221602110

Abstract: By binding growth factors (GFs), the ECM tightly regulates their activity. We recently reported that the heparin-binding domain II of fibronectin acts as a promiscuous high-affinity GF-binding domain. Here we hypothesized that fibrin, the provisional ECM during tissue repair, also could be highly promiscuous in its GF-binding capacity. Using multiple affinity-based assays, we found that fibrin(ogen) and its heparin-binding domain bind several GFs from the PDGF/VEGF and FGF families and some GFs from the TGF-β and neurotrophin families. Overall, we identified 15 unique binding interactions. The GF binding ability of fibrinogen caused prolonged retention of many of the identified GFs within fibrin. Thus, based on the promiscuous and high-affinity interactions in fibrin, GF binding may be one of fibrin’s main physiological functions, and these interactions may potentially play an important and ubiquitous role during tissue repair. To prove this role in a gain-of-function model, we incorporated the heparin-binding domain of fibrin into a synthetic fibrin-mimetic matrix. In vivo, the multifunctional synthetic matrix could fully mimic the effect of fibrin in a diabetic mouse model of impaired wound healing, demonstrating the benefits of generating a hybrid biomaterial consisting of a synthetic polymeric scaffold and recombinant bioactive ECM domains. The reproduction of GF–ECM interactions with a fibrin-mimetic matrix could be clinically useful, and has the significant benefit of a more straightforward regulatory path associated with chemical synthesis rather than human sourcing.

Australian public perspectives on genomic data governance: responsibility, regulation, and logistical considerations

Publisher: Springer Science and Business Media LLC

Date: 10-05-2023

DOI: 10.1038/S41431-023-01381-1

Extracellular matrix-inspired growth factor delivery systems for bone regeneration

Publisher: Elsevier BV

Date: 11-2015

DOI: 10.1016/J.ADDR.2015.04.007

Abstract: Growth factors are very promising molecules to enhance bone regeneration. However, their translation to clinical use has been seriously limited, facing issues related to safety and cost-effectiveness. These problems derive from the vastly supra-physiological doses of growth factor used without optimized delivery systems. Therefore, these issues have motivated the development of new delivery systems allowing better control of the spatiotemporal release and signaling of growth factors. Because the extracellular matrix (ECM) naturally plays a fundamental role in coordinating growth factor activity in vivo, a number of novel delivery systems have been inspired by the growth factor regulatory function of the ECM. After introducing the role of growth factors during the bone regeneration process, this review exposes different issues that growth factor-based therapies have encountered in the clinic and highlights recent delivery approaches based on the natural interaction between growth factor and the ECM.

PPS nanoparticles as versatile delivery system to induce systemic and broad mucosal immunity after intranasal administration

Publisher: Elsevier BV

Date: 2011

DOI: 10.1016/J.VACCINE.2010.11.010

Abstract: Degradable polymer nanoparticles (NPs, 50 nm) based on polypropylene sulfide (PPS) were conjugated to thiolated antigen and adjuvant proteins by reversible disulfide bonds and evaluated in mucosal vaccination. Ovalbumin was used as a model antigen, and antigen-conjugated NPs were administered intranasally in the mouse. We show penetration of nasal mucosae, transit via M cells, and uptake by antigen-presenting cells in the nasal-associated lymphoid tissue. Ovalbumin-conjugated NPs induced cytotoxic T lymphocytic responses in lung and spleen tissues, as well as humoral response in mucosal airways. Co-conjugation of the TLR5 ligand flagellin further enhanced humoral responses in the airways as well as in the distant vaginal and rectal mucosal compartments and induced cellular immune responses with a Th1 bias, in contrast with free flagellin. The PPS NP platform thus appears interesting as a platform for intranasally-administered mucosal vaccination for inducing broad mucosal immunity.

Macrophages provide a transient muscle stem cell niche via NAMPT secretion.

Publisher: Springer Science and Business Media LLC

Date: 10-02-2021

DOI: 10.1038/S41586-021-03199-7

Abstract: Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals

The promotion of endothelial cell attachment and spreading using FNIII10 fused to VEGF-A165

Publisher: Elsevier BV

Date: 08-2013

DOI: 10.1016/J.BIOMATERIALS.2013.04.050

Abstract: Synergy in the downstream signaling pathways of the vascular endothelial growth factor receptor-2 (VEGFR-2) and the integrin αvβ3 is critical for blood vessel formation. Thus, agents that activate both receptors could possess efficient pro-angiogenic potential. Here, we created a fibrin-binding bi-functional protein (FNIII10-VEGF) consisting of the 10th type III domain of fibronectin (FNIII10) fused to a plasmin-resistant VEGF-A165 mutant (VEGF) that potentiated angiogenic processes when compared to the effect of the separate molecules. FNIII10-VEGF was able to bind both VEGFR-2 and integrin αvβ3. Intriguingly, cell attachment and spreading to immobilized FNIII10-VEGF was significantly enhanced compared to in idual FNIII10 or VEGF proteins. Delivery of immobilized FNIII10-VEGF by covalent linkage to a fibrin matrix significantly enhanced the angiogenic response in an in vivo wound healing assay compared to soluble VEGF. Unexpectedly, the angiogenic response to fibrin-immobilized FNIII10-VEGF was reduced in comparison to the pro-angiogenic effect of fibrin-immobilized VEGF. Collectively, findings of this study corroborate a critical role for a subtle balance of the integrin-VEGF interplay in angiogenesis and provide insight in how engineered growth factors in concert with biomaterial matrices may offer a potent molecular/material approach to harness these interactions for therapeutic angiogenesis.

Growth Factors Engineered for Super-Affinity to the Extracellular Matrix Enhance Tissue Healing

Publisher: American Association for the Advancement of Science (AAAS)

Date: 21-02-2014

DOI: 10.1126/SCIENCE.1247663

Abstract: The therapeutic use of growth factors in tissue regeneration has suffered from safety and efficacy issues. Reasoning that the unmet potential may be because of nonphysiological delivery, Martino et al. (p. 885 ) engineered growth factors to bind strongly to extracellular matrix proteins. These variants were able to induce superior tissue repair, compared to the wild-type proteins. Furthermore, unwanted side effects were decreased: For ex le, the engineered angiogenic growth factor VEGF showed reduced vascular permeability, a concern that has limited the therapeutic efficacy of wild-type VEGF.

Controlled Release Strategies in Tissue Engineering

Publisher: Elsevier

Date: 2014

DOI: 10.1016/B978-0-12-420145-3.00011-0

Controlling integrin specificity and stem cell differentiation in 2D and 3D environments through regulation of fibronectin domain stability

Publisher: Elsevier BV

Date: 02-2009

DOI: 10.1016/J.BIOMATERIALS.2008.10.047

École Polytechnique Fédérale De Lausanne

Location: Switzerland

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Osaka University

Location: Japan

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Monash University

Location: Australia

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Linkage Projects - Grant ID: LP210200908

Start Date: 03-2023

End Date: 03-2026

Amount: $857,800.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE190100084

Start Date: 2019

End Date: 12-2019

Amount: $898,450.00

Funder: Australian Research Council

Discovery Early Career Researcher Award - Grant ID: DE170100398

Start Date: 2017

End Date: 12-2019

Amount: $410,507.00

Funder: Australian Research Council

Special Research Initiatives - Grant ID: SR1101002

Start Date: 07-2011

End Date: 12-2019

Amount: $21,000,000.00

Funder: Australian Research Council