scholarly journals SWI and phase imaging reveal intracranial calcifications in the P301L mouse model of human tauopathy

2020 ◽  
Vol 33 (6) ◽  
pp. 769-781 ◽  
Author(s):  
Ruiqing Ni ◽  
Yvette Zarb ◽  
Gisela A. Kuhn ◽  
Ralph Müller ◽  
Yankey Yundung ◽  
...  
Keyword(s):  
Mouse Model ◽  
Diamagnetic Susceptibility ◽  
Ex Vivo ◽  
Phase Imaging ◽  
Phosphorylated Tau ◽  
Gradient Echo ◽  
Micro Computed Tomography ◽  
Intracranial Calcifications ◽  
Phase Images

Abstract Objective Brain calcifications are associated with several neurodegenerative diseases. Here, we describe the occurrence of intracranial calcifications as a new phenotype in transgenic P301L mice overexpressing four repeat tau, a model of human tauopathy. Materials and methods Thirty-six P301L mice (Thy1.2) and ten age-matched non-transgenic littermates of different ages were assessed. Gradient echo data were acquired in vivo and ex vivo at 7 T and 9.4 T for susceptibility-weighted imaging (SWI) and phase imaging. In addition, ex vivo micro-computed tomography (μCT) was performed. Histochemistry and immunohistochemistry were used to investigate the nature of the imaging lesions. Results SW images revealed regional hypointensities in the hippocampus, cortex, caudate nucleus, and thalamus of P301L mice, which in corresponding phase images indicated diamagnetic lesions. Concomitantly, µCT detected hyperdense lesions, though fewer lesions were observed compared to MRI. Diamagnetic susceptibility lesions in the hippocampus increased with age. The immunochemical staining of brain sections revealed osteocalcin-positive deposits. Furthermore, intra-neuronal and vessel-associated osteocalcin-containing nodules co-localized with phosphorylated-tau (AT8 and AT100) in the hippocampus, while vascular osteocalcin-containing nodules were detected in the thalamus in the absence of phosphorylated-tau deposition. Discussion SWI and phase imaging sensitively detected intracranial calcifications in the P301L mouse model of human tauopathy.

scholarly journals Tau deposition is associated with imaging patterns of tissue calcification in the P301L mouse model of human tauopathy

2019 ◽  
Author(s):  
Ruiqing Ni ◽  
Yvette Zarb ◽  
Gisela A. Kuhn ◽  
Ralph Müller ◽  
Yankey Yundung ◽  
...  
Keyword(s):  
Mouse Model ◽  
Ex Vivo ◽  
Intracranial Calcification ◽  
Phosphorylated Tau ◽  
Micro Computed Tomography ◽  
Brain Calcification ◽  
Phase Images ◽  
Magnetic Resonance Imaging Mri ◽  
Immunohistochemical Evidence

AbstractBrain calcification is associated with several neurodegenerative proteinopathies. Here, we report a new phenotype of intracranial calcification in transgenic P301L mice overexpressing 4 repeat tau. P301L mice (Thy1.2) of 3, 5, 9 and 18-25 months-of-age and age-matched non-transgenic littermates were assessed using in vivo/ex vivo magnetic resonance imaging (MRI) with a gradient recalled echo sequence and micro computed tomography (μCT). Susceptibility weighted images computed from the gradient recalled echo data revealed regional hypointensities in the hippocampus, cortex, caudate nucleus and thalamus of P301L mice, which in corresponding phase images indicated diamagnetic lesions. Concomitantly, µCT detected hyperdense lesions. Occurrence of diamagnetic susceptibility lesions in the hippocampus, increased with age. Immunochemical staining of brain sections revealed bone protein-positive deposits. Furthermore, intra-neuronal and vessel-associated protein-containing nodules co-localized with phosphorylated-tau (AT8 and AT100) in the hippocampus. Protein-containing nodules were detected also in the thalamus in the absence of phosphorylated-tau deposition. In contrast, osteocalcin-containing nodules were vessel-associated, indicating ossified vessels, in the thalamus in absence of phosphorylated-tau. In summary, MRI and µCT demonstrated imaging pattern of intracranial calcification, concomitant with immunohistochemical evidence of formation of protein deposits containing bone proteins along with phosphorylated-tau in the P301L mouse model of human tauopathy. The P301L mouse model may thus serve as a future model to study the pathogenesis of brain calcifications in tauopathies.

A novel mouse model based on intersectional genetics enables unambiguous in vivo discrimination between plasmacytoid and other dendritic cells and their comparative characterization

2022 ◽  
Author(s):  
Michael Valente ◽  
Nils Collinet ◽  
Thien-Phong Vu Manh ◽  
Karima Naciri ◽  
Gilles Bessou ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Steady State ◽  
Mouse Model ◽  
Single Cell ◽  
Ex Vivo ◽  
High Specificity ◽  
Type I ◽  
Specific Expression ◽  
Physiological Functions

Plasmacytoid dendritic cells (pDC) were identified about 20 years ago, based on their unique ability to rapidly produce copious amounts of all subsets of type I and type III interferon (IFN-I/III) upon virus sensing, while being refractory to infection. Yet, the identity and physiological functions of pDC are still a matter of debate, in a large part due to their lack of specific expression of any single cell surface marker or gene that would allow to track them in tissues and to target them in vivo with high specificity and penetrance. Indeed, recent studies showed that previous methods that were used to identify or deplete pDC also targeted other cell types, including pDC-like cells and transitional DC (tDC) that were proposed to be responsible for all the antigen presentation ability previously attributed to steady state pDC. Hence, improving our understanding of the nature and in vivo choreography of pDC physiological functions requires the development of novel tools to unambiguously identify and track these cells, including in comparison to pDC-like cells and tDC. Here, we report successful generation of a pDC-reporter mouse model, by using an intersectional genetic strategy based on the unique co-expression of Siglech and Pacsin1 in pDC. This pDC-Tomato mouse strain allows specific ex vivo and in situ detection of pDC. Breeding them with Zbtb46GFP mice allowed side-by-side purification and transcriptional profiling by single cell RNA sequencing of bona fide pDC, pDC-like cells and tDC, in comparison to type 1 and 2 conventional DC (cDC1 and cDC2), both at steady state and during a viral infection, revealing diverging activation patterns of pDC-like cells and tDC. Finally, by breeding pDC-Tomato mice with Ifnb1EYFP mice, we determined the choreography of pDC recruitment to the micro-anatomical sites of viral replication in the spleen, with initially similar but later divergent behaviors of the pDC that engaged or not into IFN-I production. Our novel pDC-Tomato mouse model, and newly identified gene modules specific to combinations of DC types and activations states, will constitute valuable resources for a deeper understanding of the functional division of labor between DC types and its molecular regulation at homeostasis and during viral infections.

scholarly journals Comparison of In Vivo and Ex Vivo MRI for the Detection of Structural Abnormalities in a Mouse Model of Tauopathy

2017 ◽  
Vol 11 ◽  
Author(s):  
Holly E. Holmes ◽  
Nick M. Powell ◽  
Da Ma ◽  
Ozama Ismail ◽  
Ian F. Harrison ◽  
...  
Keyword(s):  
Mouse Model ◽  
Ex Vivo ◽  
Structural Abnormalities

scholarly journals Predilection for developing a hematogenous orthopaedic implant-associated infection in older versus younger mice

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
John M. Thompson ◽  
Alyssa G. Ashbaugh ◽  
Yu Wang ◽  
Robert J. Miller ◽  
Julie E. Pickett ◽  
...  
Keyword(s):  
At Risk ◽  
Staphylococcus Aureus ◽  
Mouse Model ◽  
Ex Vivo ◽  
Kirschner Wire ◽  
Age Groups ◽  
Orthopaedic Implant ◽  
X Ray ◽  
Risk Patients

Abstract Background The pathogenesis of hematogenous orthopaedic implant-associated infections (HOIAI) remains largely unknown, with little understanding of the influence of the physis on bacterial seeding. Since the growth velocity in the physis of long bones decreases during aging, we sought to evaluate the role of the physis on influencing the development of Staphylococcus aureus HOIAI in a mouse model comparing younger versus older mice. Methods In a mouse model of HOIAI, a sterile Kirschner wire was inserted retrograde into the distal femur of younger (5–8-week-old) and older (14–21-week-old) mice. After a 3-week convalescent period, a bioluminescent Staphylococcus aureus strain was inoculated intravenously. Bacterial dissemination to operative and non-operative legs was monitored longitudinally in vivo for 4 weeks, followed by ex vivo bacterial enumeration and X-ray analysis. Results In vivo bioluminescence imaging and ex vivo CFU enumeration of the bone/joint tissue demonstrated that older mice had a strong predilection for developing a hematogenous infection in the operative legs but not the non-operative legs. In contrast, this predilection was less apparent in younger mice as the infection occurred at a similar rate in both the operative and non-operative legs. X-ray imaging revealed that the operative legs of younger mice had decreased femoral length, likely due to the surgical and/or infectious insult to the more active physis, which was not observed in older mice. Both age groups demonstrated substantial reactive bone changes in the operative leg due to infection. Conclusions The presence of an implant was an important determinant for developing a hematogenous orthopaedic infection in older but not younger mice, whereas younger mice had a similar predilection for developing periarticular infection whether or not an implant was present. On a clinical scale, diagnosing HOIAI may be difficult particularly in at-risk patients with limited examination or other data points. Understanding the influence of age on developing HOIAI may guide clinical surveillance and decision-making in at-risk patients.

scholarly journals Mitochondrial augmentation of CD34+ cells from healthy donors and patients with mitochondrial DNA disorders confers functional benefit

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Elad Jacoby ◽  
Moriya Ben Yakir-Blumkin ◽  
Shiri Blumenfeld-Kan ◽  
Yehuda Brody ◽  
Amilia Meir ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mouse Model ◽  
Ex Vivo ◽  
Hematopoietic Stem ◽  
Functional Benefit ◽  
Syngeneic Mouse Model ◽  
Multisystemic Disease ◽  
Stem And Progenitor Cells ◽  
Disease Modifying

AbstractMitochondria are cellular organelles critical for numerous cellular processes and harboring their own circular mitochondrial DNA (mtDNA). Most mtDNA associated disorders (either deletions, mutations, or depletion) lead to multisystemic disease, often severe at a young age, with no disease-modifying therapies. Mitochondria have a capacity to enter eukaryotic cells and to be transported between cells. We describe a method of ex vivo augmentation of hematopoietic stem and progenitor cells (HSPCs) with normal exogenous mitochondria, termed mitochondrial augmentation therapy (MAT). Here, we show that MAT is feasible and dose dependent, and improves mitochondrial content and oxygen consumption of healthy and diseased HSPCs. Ex vivo mitochondrial augmentation of HSPCs from a patient with a mtDNA disorder leads to superior human engraftment in a non-conditioned NSGS mouse model. Using a syngeneic mouse model of accumulating mitochondrial dysfunction (Polg), we show durable engraftment in non-conditioned animals, with in vivo transfer of mitochondria to recipient hematopoietic cells. Taken together, this study supports MAT as a potential disease-modifying therapy for mtDNA disorders.

scholarly journals Ultrasonography validation for early alteration of diaphragm echodensity and function in the mdx mouse model of Duchenne muscular dystrophy

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245397
Author(s):  
Antonietta Mele ◽  
Paola Mantuano ◽  
Adriano Fonzino ◽  
Francesco Rana ◽  
Roberta Francesca Capogrosso ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Ex Vivo ◽  
Eccentric Contraction ◽  
Invasive Technique ◽  
Mdx Mouse ◽  
Early Stages ◽  
Over Time

The mdx mouse model of Duchenne muscular dystrophy is characterized by functional and structural alterations of the diaphragm since early stages of pathology, closely resembling patients’ condition. In recent years, ultrasonography has been proposed as a useful longitudinal non-invasive technique to assess mdx diaphragm dysfunction and evaluate drug efficacy over time. To date, only a few preclinical studies have been conducted. Therefore, an independent validation of this method by different laboratories is needed to increase results reliability and reduce biases. Here, we performed diaphragm ultrasonography in 3- and 6-month-old mdx mice, the preferred age-window for pharmacology studies. The alteration of diaphragm function over time was measured as diaphragm ultrasound movement amplitude. At the same time points, a first-time assessment of diaphragm echodensity was performed, as an experimental index of progressive loss of contractile tissue. A parallel evaluation of other in vivo and ex vivo dystrophy-relevant readouts was carried out. Both 3- and 6-month-old mdx mice showed a significant decrease in diaphragm amplitude compared to wild type (wt) mice. This index was well-correlated either with in vivo running performance or ex vivo isometric tetanic force of isolated diaphragm. In addition, diaphragms from 6-month-old dystrophic mice were also highly susceptible to eccentric contraction ex vivo. Importantly, we disclosed an age-dependent increase in echodensity in mdx mice not observed in wt animals, which was independent from abdominal wall thickness. This was accompanied by a notable increase of pro-fibrotic TGF-β1 levels in the mdx diaphragm and of non-muscle tissue amount in diaphragm sections stained by hematoxylin & eosin. Our findings corroborate the usefulness of diaphragm ultrasonography in preclinical drug studies as a powerful tool to monitor mdx pathology progression since early stages.

Dual in vivo PET ex vivo FACS cell tracking of neutrophils – first results in a mouse model of Alzheimer disease

2019 ◽  
Author(s):  
M Poxleitner ◽  
SH Hoffmann ◽  
A Maurer ◽  
G Reischl ◽  
AM Wild ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Mouse Model ◽  
Cell Tracking ◽  
Ex Vivo ◽  
First Results

scholarly journals Lipoteichoic Acid Accelerates Bone Healing by Enhancing Osteoblast Differentiation and Inhibiting Osteoclast Activation in a Mouse Model of Femoral Defects

2020 ◽  
Vol 21 (15) ◽  
pp. 5550
Author(s):  
Chih-Chien Hu ◽  
Chih-Hsiang Chang ◽  
Yi-min Hsiao ◽  
Yuhan Chang ◽  
Ying-Yu Wu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Bone Formation ◽  
Bone Regeneration ◽  
Bone Healing ◽  
Lipoteichoic Acid ◽  
Calcium Deposition ◽  
Micro Computed Tomography ◽  
Osteoclast Activation

Lipoteichoic acid (LTA) is a cell wall component of Gram-positive bacteria. Limited data suggest that LTA is beneficial for bone regeneration in vitro. Thus, we used a mouse model of femoral defects to explore the effects of LTA on bone healing in vivo. Micro-computed tomography analysis and double-fluorochrome labeling were utilized to examine whether LTA can accelerate dynamic bone formation in vivo. The effects of LTA on osteoblastogenesis and osteoclastogenesis were also studied in vitro. LTA treatment induced prompt bone bridge formation, rapid endochondral ossification, and accelerated healing of fractures in mice with femoral bone defects. In vitro, LTA directly enhanced indicators of osteogenic factor-induced MC3T3-E1 cell differentiation, including alkaline phosphatase activity, calcium deposition and osteopontin expression. LTA also inhibited osteoclast activation induced by receptor activator of nuclear factor-kappa B ligand. We identified six molecules that may be associated with LTA-accelerated bone healing: monocyte chemoattractant protein 1, chemokine (C-X-C motif) ligand 1, cystatin C, growth/differentiation factor 15, endostatin and neutrophil gelatinase-associated lipocalin. Finally, double-fluorochrome, dynamic-labeling data indicated that LTA significantly enhanced bone-formation rates in vivo. In conclusion, our findings suggest that LTA has promising bone-regeneration properties.

Advances in imaging feto-placental vasculature: new tools to elucidate the early life origins of health and disease

2020 ◽  
pp. 1-11
Author(s):  
Yutthapong Tongpob ◽  
Caitlin Wyrwoll
Keyword(s):  
Ex Vivo ◽  
Light Sheet ◽  
Experimental Models ◽  
Cardiovascular Development ◽  
Micro Computed Tomography ◽  
Placental Function ◽  
Light Sheet Microscopy ◽  
Health And Disease ◽  
Insight Into

Abstract Optimal placental function is critical for fetal development, and therefore a crucial consideration for understanding the developmental origins of health and disease (DOHaD). The structure of the fetal side of the placental vasculature is an important determinant of fetal growth and cardiovascular development. There are several imaging modalities for assessing feto-placental structure including stereology, electron microscopy, confocal microscopy, micro-computed tomography, light-sheet microscopy, ultrasonography and magnetic resonance imaging. In this review, we present current methodologies for imaging feto-placental vasculature morphology ex vivo and in vivo in human and experimental models, their advantages and limitations and how these provide insight into placental function and fetal outcomes. These imaging approaches add important perspective to our understanding of placental biology and have potential to be new tools to elucidate a deeper understanding of DOHaD.

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