Initiation of cyst formation in autosomal dominant polycystic kidney disease (ADPKD) occurs when kidney tubule cells are rendered null for either PKD1 or PKD2 by somatic 'second hit' mutations. ...Subsequent cyst progression remodels the organ through changes in tubule cell shape, proliferation and secretion. The kidney develops inflammation and fibrosis. We constructed a mouse model in which adult inactivation of either Pkd gene can be followed by reactivation of the gene at a later time. Using this model, we show that re-expression of Pkd genes in cystic kidneys results in rapid reversal of ADPKD. Cyst cell proliferation is reduced, autophagy is activated and cystic tubules with expanded lumina lined by squamoid cells revert to normal lumina lined by cuboidal cells. Increases in inflammation, extracellular matrix deposition and myofibroblast activation are reversed, and the kidneys become smaller. We conclude that phenotypic features of ADPKD are reversible and that the kidney has an unexpected capacity for plasticity controlled at least in part by ADPKD gene function.
The continuous need for ion gradient restoration across the cell membrane, a prerequisite for synaptic transmission and conduction, is believed to be a major factor for brain's high oxidative demand. ...However, do energy requirements of signaling and nonsignaling components of cortical neurons and astrocytes vary with activity levels and across species? We derived oxidative ATP demand associated with signaling (Ps) and nonsignaling (Pns) components in the cerebral cortex using species-specific physiologic and anatomic data. In rat, we calculated glucose oxidation rates from layer-specific neuronal activity measured across different states, spanning from isoelectricity to awake and sensory stimulation. We then compared these calculated glucose oxidation rates with measured glucose metabolic data for the same states a% reported by 2-deoxy-glucose autoradiography. Fixed values for Ps and Pns were able to predict the entire range of states in the rat. We then calculated glucose oxidation rates from human EEG data acquired under various conditions using fixed Ps and Pns values derived for the rat. These calculated metabolic data in human cerebral cortex compared well with glucose metabolism measured by PET. Independent of species, linear relationship was established between neuronal activity and neuronal oxidative demand beyond isoelectricity. Cortical signaling requirements dominated energy demand in the awake state, whereas nonsignaling requirements were ~20% of awake value. These predictions are supported by ¹³C magnetic resonance spectroscopy results. We conclude that mitochondrial energy support for signaling and nonsignaling components in cerebral cortex are conserved across activity levels in mammalian species.
Advances in Imaging Brain Metabolism Hyder, Fahmeed; Rothman, Douglas L
Annual review of biomedical engineering,
06/2017, Letnik:
19, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Metabolism is central to neuroimaging because it can reveal pathways by which neuronal and glial cells use nutrients to fuel their growth and function. We focus on advanced magnetic resonance imaging ...(MRI) and magnetic resonance spectroscopy (MRS) methods used in brain metabolic studies.
17
O-MRS and
31
P-MRS, respectively, provide rates of oxygen use and ATP synthesis inside mitochondria, whereas
19
F-MRS enables measurement of cytosolic glucose metabolism. Calibrated functional MRI (fMRI), an advanced form of fMRI that uses contrast generated by deoxyhemoglobin, provides maps of oxygen use that track neuronal firing across brain regions.
13
C-MRS is the only noninvasive method of measuring both glutamatergic neurotransmission and cell-specific energetics with signaling and nonsignaling purposes. Novel MRI contrasts, arising from endogenous diamagnetic agents and exogenous paramagnetic agents, permit pH imaging of glioma. Overall, these magnetic resonance methods for imaging brain metabolism demonstrate translational potential to better understand brain disorders and guide diagnosis and treatment.
Magnetic resonance imaging (MRI)-based quantification of the blood-oxygenation-level-dependent (BOLD) effect allows oxygen extraction fraction (OEF) mapping. The multi-parametric quantitative BOLD ...(mq-BOLD) technique facilitates relative OEF (rOEF) measurements with whole brain coverage in clinically applicable scan times. Mq-BOLD requires three separate scans of cerebral blood volume and transverse relaxation rates measured by gradient-echo (1/T2∗) and spin-echo (1/T2). Although the current method is of clinical merit in patients with stroke, glioma and internal carotid artery stenosis (ICAS), there are relaxation measurement artefacts that impede the sensitivity of mq-BOLD and artificially elevate reported rOEF values.
We posited that T2-related biases caused by slice refocusing imperfections during rapid 2D-GraSE (Gradient and Spin Echo) imaging can be reduced by applying 3D-GraSE imaging sequences, because the latter requires no slice selective pulses. The removal of T2-related biases would decrease overestimated rOEF values measured by mq-BOLD. We characterized effects of T2-related bias in mq-BOLD by comparing the initially employed 2D-GraSE and two proposed 3D-GraSE sequences to multiple single spin-echo reference measurements, both in vitro and in vivo. A phantom and 25 participants, including young and elderly healthy controls as well as ICAS-patients, were scanned. We additionally proposed a procedure to reliably identify and exclude artefact affected voxels. In the phantom, 3D-GraSE derived T2 values had 57% lower deviation from the reference. For in vivo scans, the formerly overestimated rOEF was reduced by −27% (p < 0.001). We obtained rOEF = 0.51, which is much closer to literature values from positron emission tomography (PET) measurements. Furthermore, increased sensitivity to a focal rOEF elevation in an ICAS-patient was demonstrated.
In summary, the application of 3D-GraSE improves the mq-BOLD-based rOEF quantification while maintaining clinically feasible scan times. Thus, mq-BOLD with non-slice selective T2 imaging is highly promising to improve clinical diagnostics of cerebrovascular diseases such as ICAS.
•MRI-based mq-BOLD can quantify the cerebral relative oxygen extraction fraction.•It allows rOEF mapping with full brain coverage within clinically feasible scan time.•T2 mapping by 3D-GraSE for mq-BOLD improves previous rOEF overestimations.•T2 and OEF in young and elderly participants correlate well with the literature.•Improved mq-BOLD is sensitive to focal rOEF increases in carotid artery stenosis.
We synthesized manganese ferrite (MnFe2O4) nanoparticles of different sizes by varying pH during chemical co-precipitation procedure and modified their surfaces with polysaccharide chitosan (CS) to ...investigate characteristics of hyperthermia and magnetic resonance imaging (MRI). Structural features were analyzed by X-ray diffraction (XRD), high-resolution transmission electron microscopy (TEM), selected area diffraction (SAED) patterns, and Mössbauer spectroscopy to confirm the formation of superparamagnetic MnFe2O4 nanoparticles with a size range of 5–15 nm for pH of 9–12. The hydrodynamic sizes of nanoparticles were less than 250 nm with a polydispersity index of 0.3, whereas the zeta potentials were higher than 30 mV to ensure electrostatic repulsion for stable colloidal suspension. MRI properties at 7T demonstrated that transverse relaxation (T2) doubled as the size of CS-coated MnFe2O4 nanoparticles tripled in vitro. However, longitudinal relaxation (T1) was strongest for the smallest CS-coated MnFe2O4 nanoparticles, as revealed by in vivo positive contrast MRI angiography. Cytotoxicity assay on HeLa cells showed CS-coated MnFe2O4 nanoparticles is viable regardless of ambient pH, whereas hyperthermia studies revealed that both the maximum temperature and specific loss power obtained by alternating magnetic field exposure depended on nanoparticle size and concentration. Overall, these results reveal the exciting potential of CS-coated MnFe2O4 nanoparticles in MRI and hyperthermia studies for biomedical research.
There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white ...matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.
Macrophages are a source of both proinflammatory and restorative functions in damaged tissue through complex dynamic phenotypic changes. Here, we sought to determine whether monocyte-derived ...macrophages (MDMs) contribute to recovery after acute sterile brain injury. By profiling the transcriptional dynamics of MDMs in the murine brain after experimental intracerebral hemorrhage (ICH), we found robust phenotypic changes in the infiltrating MDMs over time and demonstrated that MDMs are essential for optimal hematoma clearance and neurological recovery. Next, we identified the mechanism by which the engulfment of erythrocytes with exposed phosphatidylserine directly modulated the phenotype of both murine and human MDMs. In mice, loss of receptor tyrosine kinases AXL and MERTK reduced efferocytosis of eryptotic erythrocytes and hematoma clearance, worsened neurological recovery, exacerbated iron deposition, and decreased alternative activation of macrophages after ICH. Patients with higher circulating soluble AXL had poor 1-year outcomes after ICH onset, suggesting that therapeutically augmenting efferocytosis may improve functional outcomes by both reducing tissue injury and promoting the development of reparative macrophage responses. Thus, our results identify the efferocytosis of eryptotic erythrocytes through AXL/MERTK as a critical mechanism modulating macrophage phenotype and contributing to recovery from ICH.
Under normal conditions, high sodium (Na
) in extracellular (Na
) and blood (Na
) compartments and low Na
in intracellular milieu (Na
) produce strong transmembrane (ΔNa
) and weak transendothelial ...(ΔNa
) gradients respectively, and these manifest the cell membrane potential (V
) as well as blood-brain barrier (BBB) integrity. We developed a sodium (
Na) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic polyanionic agent to measure ΔNa
and ΔNa
. In vitro
Na-MRSI established that the
Na signal is intensely shifted by the agent compared to other biological factors (e.g., pH and temperature). In vivo
Na-MRSI showed Na
remained unshifted and Na
was more shifted than Na
, and these together revealed weakened ΔNa
and enhanced ΔNa
in rat gliomas (vs. normal tissue). Compared to normal tissue, RG2 and U87 tumors maintained weakened ΔNa
(i.e., depolarized V
) implying an aggressive state for proliferation, whereas RG2 tumors displayed elevated ∆Na
suggesting altered BBB integrity. We anticipate that
Na-MRSI will allow biomedical explorations of perturbed Na
homeostasis in vivo.
Previous ¹³C magnetic resonance spectroscopy experiments have shown that over a wide range of neuronal activity, approximately one molecule of glucose is oxidized for every molecule of glutamate ...released by neurons and recycled through astrocytic glutamine. The measured kinetics were shown to agree with the stoichiometry of a hypothetical astrocyte-to-neuron lactate shuttle model, which predicted negligible functional neuronal uptake of glucose. To test this model, we measured the uptake and phosphorylation of glucose in nerve terminals isolated from rats infused with the glucose analog, 2-fluoro-2-deoxy- d -glucose (FDG) in vivo. The concentrations of phosphorylated FDG (FDG ₆P), normalized with respect to known neuronal metabolites, were compared in nerve terminals, homogenate, and cortex of anesthetized rats with and without bicuculline-induced seizures. The increase in FDG ₆P in nerve terminals agreed well with the increase in cortical neuronal glucose oxidation measured previously under the same conditions in vivo , indicating that direct uptake and oxidation of glucose in nerve terminals is substantial under resting and activated conditions. These results suggest that neuronal glucose-derived pyruvate is the major oxidative fuel for activated neurons, not lactate-derived from astrocytes, contradicting predictions of the original astrocyte-to-neuron lactate shuttle model under the range of study conditions.
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