Intravascular Application of Labelled Cell Spheroids: An Approach for Ischemic Peripheral Artery Disease.

Mesenchymal stem cells (MSC) are known for their vascular regeneration capacity by neoangiogenesis. Even though, several delivery approaches exist, particularly in the case of intravascular delivery, only limited number of cells reach the targeted tissue and are not able to remain on site. Applicated cells exhibit poor survival accompanied with a loss of functionality. Moreover, cell application techniques lead to cell death and impede the overall MSC function and survival. 3D cell spheroids mimic the physiological microenvironment, thus, overcoming these limitations. Therefore, in this study we aimed to evaluate and assess the feasibility of 3D MSCs spheroids for endovascular application, for treatment of ischemic peripheral vascular pathologies. Multicellular 3D MSC spheroids were generated at different cell seeding densities, labelled with ultra-small particles of iron oxide (USPIO) and investigated in vitro in terms of morphology, size distribution, mechanical stability as well as ex vivo with magnetic resonance imaging (MRI) to assess their trackability and distribution. Generated 3D spheroids were stable, viable, maintained stem cell phenotype and were easily trackable and visualized via MRI. MSC 3D spheroids are suitable candidates for endovascular delivery approaches in the context of ischemic peripheral vascular pathologies.

Magnetic Resonance Imaging of Diverticular Disease and its Association with Adipose Tissue Compartments and Constitutional Risk Factors in Subjects from a Western General Population.

PURPOSE: To determine the association of asymptomatic diverticular disease as assessed by magnetic resonance imaging (MRI) with adipose tissue compartments, hepatic steatosis and constitutional risk factors within a cohort drawn from a Western general population. MATERIALS AND METHODS: Asymptomatic subjects enrolled in a prospective case-control study underwent a 3 Tesla MRI scan, including an isotropic VIBE-Dixon sequence of the entire trunk. The presence and extent of diverticular disease were categorized according to the number of diverticula in each colonic segment in a blinded fashion. The amount of visceral, subcutaneous, and total adipose tissue (VAT, SAT, and TAT) was quantified by MRI. Additionally, the degree of hepatic steatosis, indicated as hepatic proton density fat fraction (hepatic PDFF) was determined using a multi-echo T1w sequence. Constitutional cardiometabolic risk factors were obtained and univariate and multivariate associations were calculated. RESULTS: A total of 371 subjects were included in the analysis (58.2 % male, 56.2 ±â€Š9.2 years). Based on MRI, 154 participants (41.5 %) had diverticular disease with 62 cases (17 %) being advanced diverticular disease. Subjects with advanced diverticular disease had a significantly higher body mass index (BMI) (BMI: 29.9 ±â€Š5.1 vs. 27.5 ±â€Š4.6, p < 0.001; respectively). Furthermore, all adipose tissue compartments were increased in subjects with advanced diverticular disease (e. g. VAT: 6.0 ±â€Š2.8 vs. 4.2 ±â€Š2.6 and SAT: 9.2 ±â€Š3.6 vs. 7.8 ±â€Š3.6, all p < 0.001, respectively). Similarly, subjects with advanced diverticular disease had significantly higher hepatic PDFF (4.9 [2.7, 11.4] vs. 6.1 [5.5, 14.6], p = 0.002). CONCLUSION: Advanced diverticular disease is associated with an increased volume of adipose tissue compartments and BMI, which may suggest a metabolic role in disease development. KEY POINTS: · Diverticular disease is associated with constitutional risk factors such as BMI.. · Excess of adipose tissue compartments and hepatic steatosis are associated with the prevalence of diverticular disease.. · Our results suggest a shared pathological pathway of cardiometabolic alterations and the prevalence of diverticular disease.. · MRI is feasible for the assessment of adipose tissue compartments, hepatic steatosis, and diverticular disease and allows identification of patients who are at risk but in an asymptomatic disease state.. CITATION FORMAT: · Storz C, Rospleszcz S, Askani E et al. Magnetic Resonance Imaging of Diverticular Disease and its Association with Adipose Tissue Compartments and Constitutional Risk Factors in Subjects from a Western General Population. Fortschr Röntgenstr 2021; 193: 33 - 41.

Modulating endothelial adhesion and migration impacts stem cell therapies efficacy.

BACKGROUND: Limited knowledge of stem cell therapies` mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated. We tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with the host endothelium. METHODS: We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s pathologies in vivo. FINDINGS: PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in the brain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke. INTERPRETATION: Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy. FUNDING: Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Health.

Transarterial Chemoembolization of Hepatocellular Carcinoma Using Radiopaque Drug-Eluting Embolics: How to Pursue Periprocedural Cross-Sectional Imaging?

PURPOSE: To compare different imaging techniques (volume perfusion CT, cone-beam CT, and dynamic gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced dynamic contrast-enhanced MR imaging with golden-angle radial sparse parallel MR imaging) in evaluation of transarterial chemoembolization of hepatocellular carcinoma (HCC) using radiopaque drug-eluting embolics (DEE). MATERIALS AND METHODS: MR imaging and CT phantom investigation of radiopaque DEE was performed. In the clinical portion of the study, 13 patients (22 HCCs) were prospectively enrolled. All patients underwent cross-sectional imaging before and after transarterial chemoembolization using 100-300 µm radiopaque DEE. Qualitative assessment of images using a Likert scale was performed. RESULTS: In the phantom study, CT-related beam-hardening artifacts were markedly visible at a concentration of 12% (v/v) radiopaque DEE; MR imaging demonstrated no significant detectable signal intensity changes. Imaging obtained before transarterial chemoembolization showed no significant difference regarding tumor depiction. Visualization of tumor feeding arteries was significantly improved with volume perfusion CT (P < .001) and cone-beam CT (P = .002) compared with MR imaging. Radiopaque DEE led to significant decrease in tumor depiction (P = .001) and significant increase of beam-hardening artifacts (P = .012) using volume perfusion CT before versus after transarterial chemoembolization. Greater residual arterial tumor enhancement was detected with MR imaging (10 HCCs) compared with volume perfusion CT (8 HCCs) and cone-beam CT (6 HCCs). CONCLUSIONS: Using radiopaque DEE, the imaging modalities provided comparable early treatment assessment. In HCCs with dense accumulation of radiopaque DEE, treatment assessment using volume perfusion CT or cone-beam CT may be impaired owing to resulting beam-hardening artifacts and contrast stasis. Dynamic contrast-enhanced MR imaging may add value in detection of residual arterial tumor enhancement.

Characteristics and associated risk factors of diverticular disease assessed by magnetic resonance imaging in subjects from a Western general population.

OBJECTIVES: Diverticular disease represents an increasing pathology and healthcare burden worldwide. Our aim was to study the prevalence, extent and distribution of asymptomatic diverticular disease assessed by magnetic resonance imaging (MRI) in a sample of a Western population. METHODS: Subjects from a population-based cohort study who underwent 3-T MRI were analyzed for the prevalence and extent of diverticula of the colon using an isotropic VIBE-Dixon gradient-echo sequence. The extent of diverticular disease was categorized according to the number of diverticula in each colonic segment. Univariate and adjusted analyses were performed to assess associated characteristics and risk factors. RESULTS: Among 393 subjects included in the analysis (56.4 ± 9.2 years, 57.5% males), 164 (42%) had diverticular disease, with the highest prevalence in the left-sided colonic segments (93% diverticular disease in the descending and sigmoid segment). Subjects with advanced diverticular disease were older (62.1 vs. 54.4 years) and had a higher body mass index (BMI), LDL cholesterol levels and systolic blood pressure (30.2 ± 5.1 vs. 27.8 ± 4.9 kg/m2, 149.8 ± 29.3 vs. 135.2 ± 32.9 mg/dl and 128.2 ± 14.1 vs. 118.4 ± 16.1 mmHg, respectively; all p > 0.003) compared with subjects without diverticular disease. In contrast, no significant correlation could be found for gender, physical activity, smoking status and alcohol consumption (all p > 0.31). Intra-rater reliability was excellent for all colonic segments (intra-class correlation [ICC] = 0.99-1.00), and inter-rater reliability was excellent for left- and right-sided colonic segments (ICC = 0.84-0.97). CONCLUSIONS: These findings provide insights into the disease mechanism of asymptomatic diverticular disease and may help to improve prevention of diverticulosis and its associated complications. KEY POINTS: • Overall prevalence of asymptomatic diverticular disease assessed by MRI was 42%, affecting predominantly the left-sided colon. • Asymptomatic diverticular disease was associated with age and cardiometabolic risk factors. • Magnetic resonance imaging reveals insights into the pathophysiologic mechanism of asymptomatic diverticular disease.

The role of visceral and subcutaneous adipose tissue measurements and their ratio by magnetic resonance imaging in subjects with prediabetes, diabetes and healthy controls from a general population without cardiovascular disease.

OBJECTIVE: To study the relationship of area- and volumetric-based visceral and subcutaneous adipose tissue (VAT and SAT) by MRI and their ratio in subjects with impaired glucose metabolism from the general population. METHODS: Subjects from a population-based cohort with established prediabetes, diabetes and healthy controls without prior cardiovascular diseases underwent 3 T MRI. VAT and SAT were assessed as total volume and area on a single slice, and their ratio (VAT/SAT) was calculated. Clinical covariates and cardiovascular risk factors, such as hypertension and glycemic state were assessed in standardized fashion. Univariate and adjusted analyses were conducted. RESULTS: Among 384 subjects (age: 56.2 ± 9.2 years, 58.1% male) with complete MRI data available, volumetric and single-slice VAT, SAT and VAT/SAT ratio were strongly correlated (all >r = 0.89). Similarly, VAT/SATvolume ratio was strongly correlated with VATvolume but not with SAT (r = 0.72 and r = -0.21, respectively). Significant higher levels of VAT, SAT and VAT/SAT ratio were found in subjects with impaired glucose metabolism (all p ≤ 0.01). After adjustment for potential cardiovascular confounders, VATvolume and VAT/SATvolume ratio remained significantly higher in subjects with impaired glucose metabolism (VATvolume = 6.9 ± 2.5 l and 3.4 ± 2.3 l; VAT/SATvolume ratio = 0.82 ± 0.34 l and 0.49 ± 0.29 l in patients with diabetes and controls, respectively, all p < 0.02), whereas the association for SATvolume attenuated. Additionally, there was a decreasing effect of glycemic status on VAT/SATvolume ratio with increasing body mass index and waist circumference (p < 0.05). CONCLUSIONS: VATvolume and VAT/SATvolume ratio are associated with impaired glucose metabolism, independent of cardiovascular risk factors or MRI-based quantification technique, with a decreasing effect of VAT/SATvolume ratio in obese subjects. Advances in knowledge: Quantification of VATvolume and VAT/SATvolume ratio by MRI represents a reproducable biomarker associated with cardiometabolic risk factors in subjects with impaired glucose metabolism, while the association of VAT/SATvolume ratio with glycemic state is attenuated in obese subjects.

Manufacture of endothelial colony-forming progenitor cells from steady-state peripheral blood leukapheresis using pooled human platelet lysate.

BACKGROUND: Endothelial colony-forming progenitor cells (ECFCs) are promising candidates for cell therapies. However, ECFC translation to the clinic requires optimized isolation and manufacture technologies according to good manufacturing practice (GMP). STUDY DESIGN AND METHODS: ECFCs were manufactured from steady-state peripheral blood (PB) leukapheresis (11 donors), using GMP-compliant technologies including pooled human platelet (PLT) lysate, and compared to human umbilical cord endothelial cells, human aortic endothelial cells, and human cerebral microvascular endothelial cells. Specific variables assessed were growth kinetics, phenotype, trophic factors production, stimulation of tube formation, and Dil-AcLDL uptake. RESULTS: ECFCs could be isolated from PB leukapheresis units with mean processed volume of 5411 mL and mean white blood cell (WBC) concentration factor of 8.74. The mean frequency was 1.44 × 10-8 ECFCs per WBC, corresponding to a mean of 177.8 ECFCs per apheresis unit. Expandable for up to 12 cumulative population doublings, calculated projection showed that approximately 730 × 103 ECFCs could be manufactured from 1 apheresis unit. ECFCs produced epidermal growth factor, hepatocyte growth factor, vascular endothelial growth factor (VEGF)-A, PLT-derived growth factor-B, interleukin-8, and monocyte chemoattractant protein-1, featured high potential for capillary-like tubes formation, and showed no telomerase activity. They were characterized by CD29, CD31, CD44, CD105, CD117, CD133, CD144, CD146, and VEGF-R2 expression, with the most common subpopulation CD34+CD117-CD133-. Compared to controls, ECFCs featured greater Dil-AcLDL uptake and higher expression of CD29, CD31, CD34, CD44, CD144, and VEGF-R2. CONCLUSIONS: Here we show that isolation of ECFCs with proangiogenic profile from steady-state PB leukapheresis is feasible, marking a first step toward ECFC product manufacture according to GMP.

Quantitative Assessment of Iron-Labeled Stem-Cell Adhesion at the Vessel Wall in a Vascular Flow Model: Correlation of T2*-Weighted Imaging at 3 T and Histology.

PURPOSE: To evaluate the distribution of superparamagnetic iron oxide (SPIO)-labeled cells in a perfused segment of a porcine artery and to estimate the number of adherent cells by means of magnetic resonance (MR) imaging. MATERIALS AND METHODS: Six vessel specimens (diameters between 0.8 and 1.2 cm) were placed in a bioreactor system, and 2 × 10(4) to 1 × 10(6) SPIO-labeled endothelial colony-forming cells were injected into the artery within the perfused reactor. The area of resulting signal extinctions at the inner wall of the vessels was quantified on MR images by using a high-resolution T2*-weighted sequence with a slice-by-slice approach. After imaging, the labeled cells were quantified histologically. RESULTS: The total iron load of each cell was 56.5 pg ± 14.4. In the applied range of 2 × 10(4) to 1 × 10(6) cells per vessel, the area of iron-induced signal extinction at the vessel wall on T2*-weighted imaging corresponded to the histologically detected cell number (r = 0.98, P < .001). CONCLUSIONS: A correlation between the area of signal extinction and the number of labeled cells at the vessel wall was found. This might help to evaluate dose rates in further clinical applications of intravascular cell-based therapies.