Biology subjects

Lally, C.

Publications and source records attributed to Lally, C..

16 recordsLinked to original sources

bioRxiv2025

Ex Vivo Testing of Inflatable Penile Prosthesis in Human Cadaveric Penis with Paired in Silico Model offering Surgical and Biomechanical Insights

BackgroundInflatable penile prostheses (IPPs) are a critical solution for patients with erectile dysfunction refractory to medical therapy. However, a detailed understanding of their mechanical interaction with penile tissues remains limited. AimTo develop and validate an innovative experimental-computational framework for studying IPP behaviour through ex vivo implantation and inflation testing in human cadaveric penile tissue, paired with a finite element-based (FE-based) computational model. MethodsAn AMS 700 IPP was surgically implanted into a human cadaveric penis (including the glans and [~]15 cm of shaft) using standard clinical techniques. The cylinders were placed within the corpora cavernosa, with the pump and reservoir positioned externally in a closed hydraulic loop. An inflation test was performed ex vivo, with real-time ultrasound imaging used to monitor cylinder expansion. Internal pressure was recorded using a digital barometer. Following inflation, sectional analysis enabled 3D approximation of penile shaft geometry. A representative FE-based computational model was developed, incorporating anatomically accurate tissue layers--tunica albuginea (TA), corpus cavernosa (CC), corpus spongiosum (CS), and fascia--with realistic material properties to simulate the inflation process. OutcomesThis study enabled the mechanical response of penile tissues to IPP inflation to be quantified using both experimental and computational modalities. ResultsThe combined use of ultrasound imaging and digital pressure monitoring successfully captured dynamic IPP behaviour during inflation. The FE model reproduced experimental outcomes with good fidelity, providing a detailed understanding of stress distribution and tissue deformation. Clinical ImplicationsThis integrated approach can inform future IPP design improvements and aid surgeons in preoperative planning by offering predictive insights into prosthesis-tissue interaction. Strengths & LimitationsA major strength of this study is the novel integration of cadaveric experimentation with computational modelling. However, limitations include the absence of active physiological responses and potential variability due to cadaveric tissue properties. ConclusionThis pioneering work establishes a robust platform for studying IPP mechanics in realistic anatomical contexts, with promising implications for optimising device design and improving patient outcomes in urologic surgery.

bioengineering↗

bioRxiv2025

FE-DOE: Finite element informed design of experiments to optimise bioinspired melt electrowritten (MEW) polymeric heart valves

Aortic stenosis is predominantly treated through transcatheter bioprosthetic heart valve implantation. The materials used in these devices, however, suffer from premature failure. Polymer heart valves have the potential to improve current commercial devices, offering materials with extended durability and customisation through fibre-reinforcement. Due to the wide range of available materials and structures, there is a need for a methodical approach to the design and optimisation of novel, bioinspired polymeric leaflets. This work presents a framework using FE and DOE tools to enable the creation of optimised bioinspired, 3D-printed, fibre-reinforced polymer leaflets using MEW. Here, FE models are created to represent MEW fibre-reinforced polymer leaflets for application in a transcatheter aortic heart valve. The behaviour of this valve under physiological loading conditions is modelled to predict valve performance and leaflet material response. These models were first used to investigate the impact of fibre orientation on valve performance and leaflet response, showing the benefit of using a bioinspired fibre reinforcement structure. Using DOE, the structural combination of MEW fibre-reinforcement and elastomeric matrix was optimised based on valve performance and leaflet stress and strain. Overall, the framework offers an efficient and versatile methodology for optimising fibre-reinforced polymer leaflets by utilising an in-silico approach to remove the need for manufacturing and testing of these devices.

bioengineering↗

bioRxiv2025

Low ultimate tensile strain in atherosclerotic plaques is linked to the presence of neovascularisation: insights from ex vivo uniaxial tensile testing

BackgroundNeovascularisation, the formation of new vessels within atherosclerotic plaques, has been associated with plaque progression and intraplaque haemorrhage. However, the relationship between neovascularisation and mechanical failure of plaques remains unclear. A better understanding of this link could improve rupture risk prediction beyond traditional reliance on arterial stenosis. MethodsHuman carotid plaques (n=7) from endarterectomy were sectioned into circumferential strips (n=25) and tested under uniaxial tension with digital image correlation (DIC) to determine ultimate tensile (UT) stress, UT strain, and elastic moduli. Immunohistochemistry with CD31 staining quantified neovascularisation. K-means clustering based on UT stress and strain identified mechanical phenotypes. A decision tree classifier was trained using neovascularisation percentage as the predictor. ResultsNeovascularisation showed a moderate negative correlation with UT strain (r = -0.46, p = 0.028), indicating plaques with greater neovascularisation failed at lower strains. K-means clustering identified two groups: Cluster 1 (lower UT strain) had significantly higher neovascularisation (median 2.21%) and greater initial stiffness than Cluster 2 (median 1.27%, p < 0.01). The decision tree using neovascularisation alone achieved 78.3% classification accuracy, with an area under the curve of 0.78. DIC analysis revealed rupture consistently occurred at regions of elevated local strain. ConclusionThis study demonstrates a link between neovascularisation and mechanical failure in atherosclerotic plaques. Higher neovascularisation was associated with lower UT strain, suggesting it contributes to mechanical instability. These findings support the role of neovascularisation as a marker of plaque vulnerability and encourage its integration into ultrasound-based risk assessment strategies, such as contrast-enhanced ultrasound.

bioengineering↗

bioRxiv2025

Urological benchtop and in silico models validated by human penile tissue inflation tests

PurposeInflatable penile prosthesis (IPP) implantation is a well-established treatment for erectile dysfunction (ED). A comprehensive understanding of the mechanical interactions between the IPP and penile tissues is crucial for improving surgical outcomes and device performance. This study aims to develop and validate preclinical testbeds, including a polymer-based benchtop model and a finite element (FE) model, to replicate the biomechanical behaviour of penile tissues during IPP inflation. MethodsA polymer-based benchtop model was developed using porous and non-porous polyvinyl alcohol (PVA) hydrogels, with the porous PVA mimicking the spongy corpus cavernosum (CC) and the non-porous PVA representing the tunica albuginea (TA) and fascial layers. IPP inflation tests were conducted on three benchtop models and three human penile tissue segments. Additionally, 3D FE simulations of IPP inflation were performed on both the benchtop and human tissue models for comparative analysis. ResultsThe experimental results demonstrated strong agreement between the human penile tissues, the benchtop model, and the FE simulations, validating the preclinical testbeds. Parametric studies using the FE model revealed that CC layer size and stiffness significantly influence IPP inflation mechanics, highlighting the importance of these factors in device performance. These validated preclinical testbeds provide a robust platform for optimising IPP design, guiding surgical procedures, and mitigating post-implantation complications associated. ConclusionThe developed benchtop and FE models effectively replicate human penile tissue responses to IPP inflation and can serve as valuable preclinical tools for device manufacturers and clinicians. Their use may enhance surgical decision-making and improve long-term IPP outcomes.

bioengineering↗

bioRxiv2024

Inverse Finite Element Framework Combining Ultrasound Imaging and Inflation Testing of PVA Artery Phantoms

The clinical decision to establish if a patient with carotid disease should undergo surgical intervention is primarily based on the percent stenosis. Whilst this applies for high-grade stenosed vessels (>70%), it falls short for other cases. Due to the heterogeneity of plaque tissue, probing the mechanics of the tissue would likely provide further insights into why some plaques are more prone to rupture. Mechanical characterisation of such tissue is nontrivial, however, due to the difficulties in collecting fresh, intact plaque tissue and using physiologically relevant mechanical testing of such material. The use of polyvinyl alcohol (PVA) is thus highly convenient because of its acoustic properties and tuneable mechanical properties. MethodsThe aim of this study is to demonstrate the potential of polyvinyl alcohol phantoms to simulate atherosclerotic features. In addition, a testing and simulation framework is developed for full PVA vessel material characterization using ring tensile testing and inflation testing combined with non-invasive ultrasound imaging and computational modelling. ResultsStrain stiffening behaviour was observed in PVA through ring tensile tests, particularly at high freeze-thaw cycles. Inflation testing of bi-layered phantoms featuring lipid pool inclusions demonstrated high strains at shoulder regions. The application of an inverse finite element framework successfully recovered boundaries and determined the shear moduli for the PVA wall to lie within the range 27 kPa to 53 kPa. ConclusionThe imaging-modelling framework presented facilitates the use and characterisation of arterial mimicking phantoms to further explore plaque rupture. It also shows translational potential for non-invasive mechanical characterisation of atherosclerotic plaques to improve the identification of clinically relevant metrics of plaque vulnerability.

bioengineering↗

bioRxiv2022

Microstructural and mechanical insight into atherosclerotic plaques - an ex vivo DTI study to better assess plaque vulnerability

Non-invasive microstructural characterisation has the potential to determine the stability, or lack thereof, of atherosclerotic plaques and ultimately aid in better assessing plaques risk to rupture. If linked with mechanical characterisation using a clinically relevant imaging technique, mechanically sensitive rupture risk indicators could be possible. This study aims to provide this link - between a clinically relevant imaging technique and mechanical characterisation within human atherosclerotic plaques. Ex vivo diffusion tensor imaging, mechanical testing, and histological analysis were carried out on human carotid atherosclerotic plaques. DTI-derived tractography was found to yield significant mechanical insight into the mechanical properties of more stable and more vulnerable microstructures. Coupled with insights from digital image correlation and histology, specific failure characteristics of different microstructural arrangements furthered this finding. More circumferentially uniform microstructures failed at higher stresses and strains when compared to samples which had multiple microstructures, like those seen in a plaque cap. The novel findings in this study motivate diagnostic measures which use non-invasive characterisation of the underlying microstructure of plaques to determine their vulnerability to rupture. Statements and DeclarationsThe authors have no competing interests or declarations to declare. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/508689v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@15174d8org.highwire.dtl.DTLVardef@ce3db1org.highwire.dtl.DTLVardef@344257org.highwire.dtl.DTLVardef@ef8f19_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2022

Exploring DTI-derived metrics to non-invasively track recellularisation in vascular tissue engineering

Despite significant growth in the field of tissue engineering over the past decades, non-invasive, non-destructive methods to characterise recellularisation of grafts are lacking. Here, we investigate a non-invasive magnetic resonance imaging technique, diffusion tensor imaging (DTI), within acellular and recellularised vascular grafts. Using two decellularised porcine carotid grafts, smooth muscle cells were cultured dynamically for two weeks with terminal time points at day 3, 7, and 14. Grafts were fixed at each time point and investigated by DTI in an ex vivo set up. Semi-quantitative histology was carried out to investigate collagen, elastin, and cell density changes over time. DTI-derived metrics, namely the fractional anisotropy, mean diffusivity and tractography, not only were significantly different between day 3 and day 7 grafts, but also distinguished between acellular and recellularised grafts. Specifically, within the wet decellularised grafts, increasing fractional anisotropy was strongly correlated to increasing cell density. The results from this study show, for the first time, DTIs place in the field of tissue engineering, offering non-invasive, non-destructive insight into graft recellularisation.

bioengineering↗

bioRxiv2022

Phosphotungstic acid (PTA) preferentially binds to collagen-rich regions of porcine carotid arteries and human atherosclerotic plaques using 3D micro-computed tomography (CE-μCT)

Background and aimsAtherosclerotic plaque rupture in the carotid artery can cause small emboli to travel to cerebral arteries, causing blockages and preventing blood flow leading to stroke. Contrast enhanced micro computed tomography (CECT) using a novel stain, phosphotungstic acid (PTA) can provide insights into the microstructure of the vessel wall and atherosclerotic plaque, and hence their likelihood to rupture. Furthermore, it has been suggested that collagen content and orientation can be related to mechanical integrity. This study aims to build on existing literature and establish a robust and reproducible staining and imaging technique to non-destructively quantify the collagen content within arteries and plaques as an alternative to routine histology. MethodsPorcine carotid arteries and human atherosclerotic plaques were stained with a concentration of 1% PTA staining solution and imaged using MicroCT to establish the in-situ architecture of the tissue and measure collagen content. A histological assessment of the collagen content was also performed from picrosirius red (PSR) staining. ResultsPTA stained arterial samples highlight the reproducibility of the PTA staining and MicroCT imaging technique used with a quantitative analysis showing a positive correlation between the collagen content measured from CECT and histology. Furthermore, collagen-rich areas can be clearly visualised in both the vessel wall and atherosclerotic plaque. 3D reconstruction was also performed showing that different layers of the vessel wall and various atherosclerotic plaque components can be differentiated using Hounsfield Unit (HU) values. ConclusionsThe work presented here is unique as it offers a quantitative method of segmenting the vessel wall into its individual components and non-destructively quantifying the collagen content withing these tissues, whilst also delivering a visual representation of the fibrous structure using a single contrast agent. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

bioengineering↗

bioRxiv2022

A short-term decellularisation technique for porcine carotid arteries that conveys a structural stimulus to cells

In many cases, treatment for stenotic atherosclerotic lesions requires the use of bypass grafts to divert blood flow around the diseased vessel sections. Autologous vessels are considered the "gold standard" for bypass conduits; however, the shortage of healthy autologous vessels has resulted in an increasing focus on optimising synthetic, biological and/or tissue engineered vascular bypass grafts. While many of the previously published methods have been shown to fall short of producing an ideal TEVG, this report presents a decellularisation process that produces an acellular vascular graft that is efficient, cost effective, and could be readily automated. The resulting graft can be used "off the shelf", has preserved arterial structure and mechanical properties, and conforms to decellularisation criteria regarding the sufficient removal of cellular and genetic components. Additionally, the graft does not require any priming, supports molecular transport, can withstand supraphysiological pressures, and can support cell attachment and growth under physiological strain conditions whilst providing structural cues for cell adhesion and growth. Impact statementVascular disease remains the leading cause of mortality worldwide. In the absence of suitable autologous vessels, there currently exists a clear clinical need for off the shelf vascular grafts that can successfully bypass diseased arteries. This paper outlines a short-term method for obtaining such a graft. The technique used involves decellularising porcine carotid arteries whilst preserving arterial structure and mechanical properties and is compliant with the international standard for implantable vascular prostheses: EN ISO 7198:2017. Additionally, this protocol is cost and time effective, and produces reproducible "ready to use" acellular grafts that support molecular transport, can withstand supraphysiological pressures, and can support cell attachment and growth with controlled structural cues under physiological strain conditions.

bioengineering↗

bioRxiv2022

Inverse Material Parameter Estimation of Patient Specific Finite Element Models at the Carotid Bifurcation: The Impact of Excluding the Zero Pressure Configuration and Residual Stress

Abstract SummaryThe carotid bifurcation experiences a complex loading environment due to its anatomical structure. Previous in-vivo material parameter estimation methods often use simplified model geometries, isotropic hyperelastic constitutive equations or neglect key aspects of the vessel, such as the zero-pressure configuration or residual stress. These factors have independently been shown to alter the stress environment of the vessel wall. Characterising the location of high stress in the vessel wall has often been proposed as a potential indicator of structural weakness. However, excluding the afore-mentioned zero-pressure configuration, residual stress and patient specific material parameters can lead to an incorrect estimation of the true stress values observed, meaning stress alone as a risk indicator of rupture is insufficient. In this study, we investigate how the estimated material parameters and overall stress distributions in geometries of carotid bifurcations, extracted from in-vivo MR images, alter with the inclusion of the zero-pressure configuration and residual stress. This approach consists of the following steps: (1) geometry segmentation and hexahedral meshing from in-vivo MRI images at two known phases; (2) computation of the zero-pressure configuration and the associated residual stresses; (3) minimisation of an objective function built on the difference between the stress states of an " almost true" stress field at two known phases and a "deformed" stress field by altering the input material parameters to determine patient specific material properties; and (4) comparison of the stress distributions throughout these carotid bifurcations for all cases with estimated material parameters. This numerical approach provides insights into the need for estimation of both the zero-pressure configuration and residual stress for accurate material property estimation and stress analysis for the carotid bifurcation, establishing the reliability of stress as a rupture risk metric. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=56 SRC="FIGDIR/small/487823v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@a63f0forg.highwire.dtl.DTLVardef@7612f1org.highwire.dtl.DTLVardef@1d5beb7org.highwire.dtl.DTLVardef@1dbfbfd_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2021

Quantitative susceptibility mapping of carotid arterial tissue ex vivo: assessing sensitivity to vessel microstructural composition

PurposeTo characterise microstructural contributions to the magnetic susceptibility of carotid arteries. MethodArterial vessels were scanned using high resolution quantitative susceptibility mapping (QSM) at 7T. Models of vessel degradation were generated using ex vivo porcine carotid arteries that were subjected to several different enzymatic digestion treatments that selectively removed microstructural components (smooth muscle cells, collagen and elastin). Magnetic susceptibilities measured in these tissue models were compared to those in untreated (native) porcine arteries. Magnetic susceptibility measured in native porcine carotid arteries was further compared to the susceptibility of cadaveric human carotid arteries to investigate their similarity. ResultsThe magnetic susceptibility of native porcine vessels was diamagnetic ([X]native = -0.1820ppm), with higher susceptibilities in all models of vessel degradation ([X]elastin degraded = -0.0163ppm; [X]collagen degraded = -0.1158ppm; [X]decellularised = -0.1379ppm; [X]fixed native = -0.2199ppm). Magnetic susceptibility was significantly higher in collagen degraded compared to native porcine vessels (Tukey-Kramer, p<0.01) and between elastin degraded and all other models (including native, Tukey-Kramer, p<0.001). The susceptibility of fixed healthy human arterial tissue was diamagnetic and no significant difference was found between fixed human and fixed porcine arterial tissue susceptibilities (ANOVA, p>0.05). ConclusionsMagnetic susceptibility measured using QSM is sensitive to the microstructural composition of arterial vessels - most notably to collagen. The similarity of human and porcine arterial tissue susceptibility values provides a solid basis for translational studies. As vessel microstructure becomes disrupted during the onset and progression of carotid atherosclerosis, QSM has the potential to provide a sensitive and specific marker of vessel disease.

bioengineering↗

bioRxiv2020

Native Extracellular Matrix Orientation Determines Multipotent Vascular Stem Cell Proliferation in Response to Cyclic Uniaxial Tensile Strain and Simulated Stent Indentation

Cardiovascular disease is the leading cause of death worldwide, with multipotent vascular stem cells (MVSC) implicated in contributing to diseased vessels. MVSC are mechanosensitive cells which align perpendicular to cyclic uniaxial tensile strain. Within the blood vessel wall, collagen fibers constrain cells so that they are forced to align circumferentially, in the primary direction of tensile strain. In these experiments, MVSC were seeded onto the medial layer of decellularized porcine carotid arteries, then exposed to 10%, 1 Hz cyclic tensile strain for 10 days with the collagen fiber direction either parallel or perpendicular to the direction of strain. Cells aligned with the direction of the collagen fibers regardless of the orientation to strain. Cells aligned with the direction of strain showed an increased number of proliferative Ki67 positive cells, while those strained perpendicular to the direction of cell alignment showed no change in cell proliferation. A bioreactor system was designed to simulate the indentation of a single, wire stent strut. After 10 days of cyclic loading to 10% strain, MVSC showed regions of densely packed, highly proliferative cells. Therefore, MVSC may play a significant role in in-stent restenosis, and this proliferative response could potentially be controlled by controlling MVSC orientation relative to applied strain.

bioengineering↗

bioRxiv2020

Collagen fibre-mediated mechanical damage increases calcification of bovine pericardium for use in bioprosthetic heart valves

In cases of aortic stenosis, bioprosthetic heart valves (BHVs), with leaflets made from glutaraldehyde fixed bovine pericardium (GLBP), are often implanted to replace the native diseased valve. Widespread use of these devices, however, is restricted due to inadequate long-term durability owing specifically to premature leaflet failure. Mechanical fatigue damage and calcification remain the primary leaflet failure modes, where glutaraldehyde treatment is known to accelerate calcification. The literature in this area is limited, with some studies suggesting mechanical damage increases calcification and others that they are independent degenerative mechanisms. In this study, specimens which were non-destructively pre-sorted according to collagen fibre architecture and then uniaxially cyclically loaded until failure or 1 million cycles, were placed in an in-vitro calcification solution. Measurements of percentage volume calcification demonstrated that the weakest specimen group (those with fibres aligned perpendicular to the load) had statistically significantly higher volumes of calcification when compared to those with a high fatigue life. Moreover, SEM imaging revealed that ruptured and damaged fibres presented binding sites for calcium to attach; resulting in more than 4 times the volume of calcification in fractured samples when compared to those which did not fail by fatigue. To the authors knowledge, this study quantifies for the first time, that mechanical damage drives calcification in commercial-grade GLBP and that this calcification varies spatially according to localised levels of damage. These findings illustrate that not only is calcification potential in GLBP exacerbated by fatigue damage, but that both failure phenomena are underpinned by the unloaded collagen fibre organisation. Consequently, controlling for GLBP collagen fibre architecture in leaflets could minimise the progression of these prevalent primary failure modes in patient BHVs.

bioengineering↗

bioRxiv2020

An investigation into the critical role of fibre orientation in the ultimate tensile strength and stiffness of human carotid plaque caps

The development and subsequent rupture of atherosclerotic plaques in human carotid arteries is a major cause of ischemic stroke. Mechanical characterization of atherosclerotic plaques can aid our understanding of this rupture risk. Despite this however, experimental studies on human atherosclerotic carotid plaques, and fibrous plaque caps in particular, are very limited. This study aims to provide further insights into atherosclerotic plaque rupture by mechanically testing human fibrous plaque caps, the region of the atherosclerotic lesion most often attributed the highest risk of rupture. The results obtained highlight the variability in the ultimate tensile stress, strain and stiffness experienced in atherosclerotic plaque caps. By pre-screening all samples using small angle light scattering (SALS) to determine the dominant fibre direction in the tissue, along with supporting histological analysis, this work suggests that the collagen fibre alignment in the circumferential direction plays the most dominant role for determining plaque structural stability. The work presented in this study could provide the basis for new diagnostic approaches to be developed, which non-invasively identify carotid plaques at greatest risk of rupture. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/264457v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@185109forg.highwire.dtl.DTLVardef@1067820org.highwire.dtl.DTLVardef@1b8baf3org.highwire.dtl.DTLVardef@f9b3af_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2020

Diffusion tensor imaging and arterial tissue: establishing the influence of arterial tissue microstructure on fractional anisotropy, mean diffusivity and tractography

In this study we investigated the potential of diffusion tensor imaging (DTI) for providing insight into microstructural changes in arterial tissue by exploring the influence that cell, collagen and elastin content have on fractional anisotropy (FA), mean diffusivity (MD) and tractography. Five ex vivo porcine carotid artery models (n = 6 vessels each) - native, fixed native, collagen degraded, elastin degraded and decellularised - were developed to selectively remove components of arterial microstructure. Intact vessels were imaged at 7 T using a DTI protocol with b = 0 and 800 s/mm2 and 10 isotopically distributed directions. FA and MD values were evaluated in the medial layer of vessels and compared across tissue models. FA values measured in native and fixed native vessels were significantly higher (p<0.0001) than those in the elastin degraded and decellularised arteries. Collagen degraded vessels had a significantly higher (p<0.01) FA than elastin degraded and decellularised vessels. Native and fixed vessels had significantly lower (p<0.0001) MD values than elastin degraded, while the MD in decellularised arteries was significantly higher than that in both native (p<0.01) and fixed (p<0.005) tissue. Significantly lower (p<0.005) MD was measured in collagen degraded compared with the elastin degraded model. Tractography results yielded similar helically arranged tracts for native and collagen degraded vessels, whilst elastin degraded and decellularised vessels showed no consistent tracts. FA, MD and tractography were found to be highly sensitive to changes in the microstructural composition of arterial tissue, with cell content being a dominant source of the measured anisotropy in the vessel wall.

bioengineering↗

bioRxiv2020

The calcium binding protein S100β marks Hedgehog-responsive perivascular stem cells that contribute to intimal thickening following iatrogenic flow restriction

A hallmark of subclinical atherosclerosis is the accumulation of vascular smooth muscle cell (SMC)-like cells leading to intimal thickening. While medial SMCs contribute, the participation of hedgehog responsive resident vascular stem cells (vSCs) to lesion formation remains unclear. Using transgenic eGFP mice and genetic lineage tracing of S100{beta} vSCs in vivo, we identified S100{beta}/Sca1 cells derived from a S100{beta} non-SMC parent population within lesions that co-localise with smooth muscle -actin (SMA) cells following iatrogenic flow restriction, an effect attenuated following hedgehog inhibition with the smoothened inhibitor, cyclopamine. In vitro, S100{beta}/Sca1 cells isolated from atheroprone regions of the mouse aorta expressed hedgehog signalling components, acquired the di-methylation of histone 3 lysine 4 (H3K4me2) stable SMC epigenetic mark at the Myh11 locus and underwent myogenic differentiation in response to recombinant sonic hedgehog (SHh). Both S100{beta} and PTCH1 cells were present in human vessels while S100{beta} cells were enriched in arteriosclerotic lesions. Recombinant SHh promoted myogenic differentiation of human induced pluripotent stem cell-derived S100{beta} neuroectoderm progenitors In vitro. We conclude that hedgehog responsive S100{beta} vSCs contribute to lesion formation and support targeting hedgehog signalling to treat subclinical arteriosclerosis.

cell biology↗