Megakaryocytes possess a STING pathway that is transferred to platelets to potentiate activation.

Platelets display unexpected roles in immune and coagulation responses. Emerging evidence suggests that STING is implicated in hypercoagulation. STING is an adaptor protein downstream of the DNA sensor cyclic GMP-AMP synthase (cGAS) that is activated by cytosolic microbial and self-DNA during infections, and in the context of loss of cellular integrity, to instigate the production of type-I IFN and pro-inflammatory cytokines. To date, whether the cGAS-STING pathway is present in platelets and contributes to platelet functions is not defined. Using a combination of pharmacological and genetic approaches, we demonstrate here that megakaryocytes and platelets possess a functional cGAS-STING pathway. Our results suggest that in megakaryocytes, STING stimulation activates a type-I IFN response, and during thrombopoiesis, cGAS and STING are transferred to proplatelets. Finally, we show that both murine and human platelets contain cGAS and STING proteins, and the cGAS-STING pathway contributes to potentiation of platelet activation and aggregation. Taken together, these observations establish for the first time a novel role of the cGAS-STING DNA sensing axis in the megakaryocyte and platelet lineage.

Undersampled Diffusion-Weighted 129Xe MRI Morphometry of Airspace Enlargement: Feasibility in Chronic Obstructive Pulmonary Disease.

Multi-b diffusion-weighted hyperpolarized gas MRI measures pulmonary airspace enlargement using apparent diffusion coefficients (ADC) and mean linear intercepts (Lm). Rapid single-breath acquisitions may facilitate clinical translation, and, hence, we aimed to develop single-breath three-dimensional multi-b diffusion-weighted 129Xe MRI using k-space undersampling. We evaluated multi-b (0, 12, 20, 30 s/cm2) diffusion-weighted 129Xe ADC/morphometry estimates using a fully sampled and retrospectively undersampled k-space with two acceleration-factors (AF = 2 and 3) in never-smokers and ex-smokers with chronic obstructive pulmonary disease (COPD) or alpha-one anti-trypsin deficiency (AATD). For the three sampling cases, mean ADC/Lm values were not significantly different (all p > 0.5); ADC/Lm values were significantly different for the COPD subgroup (0.08 cm2s-1/580 µm, AF = 3; all p < 0.001) as compared to never-smokers (0.05 cm2s-1/300 µm, AF = 3). For never-smokers, mean differences of 7%/7% and 10%/7% were observed between fully sampled and retrospectively undersampled (AF = 2/AF = 3) ADC and Lm values, respectively. For the COPD subgroup, mean differences of 3%/4% and 11%/10% were observed between fully sampled and retrospectively undersampled (AF = 2/AF = 3) ADC and Lm, respectively. There was no relationship between acceleration factor with ADC or Lm (p = 0.9); voxel-wise ADC/Lm measured using AF = 2 and AF = 3 were significantly and strongly related to fully-sampled values (all p < 0.0001). Multi-b diffusion-weighted 129Xe MRI is feasible using two different acceleration methods to measure pulmonary airspace enlargement using Lm and ADC in COPD participants and never-smokers.

Hyperpolarized 129Xe MRI at low field: Current status and future directions.

Magnetic Resonance Imaging (MRI) is dictated by the magnetization of the sample, and is thus a low-sensitivity imaging method. Inhalation of hyperpolarized (HP) noble gases, such as helium-3 and xenon-129, is a non-invasive, radiation-risk free imaging technique permitting high resolution imaging of the lungs and pulmonary functions, such as the lung microstructure, diffusion, perfusion, gas exchange, and dynamic ventilation. Instead of increasing the magnetic field strength, the higher spin polarization achievable from this method results in significantly higher net MR signal independent of tissue/water concentration. Moreover, the significantly longer apparent transverse relaxation time T2* of these HP gases at low magnetic field strengths results in fewer necessary radiofrequency (RF) pulses, permitting larger flip angles; this allows for high-sensitivity imaging of in vivo animal and human lungs at conventionally low (<0.5 T) field strengths and suggests that the low field regime is optimal for pulmonary MRI using hyperpolarized gases. In this review, theory on the common spin-exchange optical-pumping method of hyperpolarization and the field dependence of the MR signal of HP gases are presented, in the context of human lung imaging. The current state-of-the-art is explored, with emphasis on both MRI hardware (low field scanners, RF coils, and polarizers) and image acquisition techniques (pulse sequences) advancements. Common challenges surrounding imaging of HP gases and possible solutions are discussed, and the future of low field hyperpolarized gas MRI is posed as being a clinically-accessible and versatile imaging method, circumventing the siting restrictions of conventional high field scanners and bringing point-of-care pulmonary imaging to global facilities.

Application of a 2D frequency encoding sectoral approach to hyperpolarized 129Xe MRI at low field.

Inhaled hyperpolarized 129Xe MRI is a non-invasive and radiation risk free lung imaging method, which can directly measure the business unit of the lung where gas exchange occurs: the alveoli and acinar ducts (lung function). Currently, three imaging approaches have been demonstrated to be useful for hyperpolarized 129Xe MR in lungs: Fast Gradient Recalled Echo (FGRE), Radial Projection Reconstruction (PR), and spiral/cones. Typically, non-Cartesian acquisitions such as PR and spiral/cones require specific data post-processing, such as interpolating, regridding, and density-weighting procedures for image reconstruction, which often leads to smoothing effects and resolution degradation. On the other hand, Cartesian methods such as FGRE are not short-echo time (TE) methods; they suffer from imaging gradient-induced diffusion-weighting of the k-space center, and employ a significant number of radio-frequency (RF) pulses. Due to the non-renewable magnetization of the hyperpolarized media, the use of a large number of RF pulses (FGRE/PR) required for full k-space coverage is a significant limitation, especially for low field (<0.5 T) hyperpolarized gas MRI. We demonstrate an ultra-fast, purely frequency-encoded, Cartesian pulse sequence called Frequency-Encoding Sectoral (FES), which takes advantage of the long T2* of hyperpolarized 129Xe gas at low field strength (0.074 T). In contrast to PR/FGRE, it uses a much smaller number of RF pulses, and consequently maximizes image Signal-to-Noise Ratio (SNR) while shortening acquisition time. Additionally, FES does not suffer from non-uniform T2* decay leading to image blurring; a common issue with interleaved spirals/cones. The Cartesian k-space coverage of the proposed FES method does not require specific k-space data post-processing, unlike PR/FGRE and spiral/cones methods. Proton scans were used to compare the FES sequence to both FGRE and Phase Encoding Sectoral, in terms of their SNR values and imaging efficiency estimates. Using FES, proton and hyperpolarized 129Xe images were acquired from a custom hollow acrylic phantom (0.04L) and two normal rats (129Xe only), utilizing both single-breath and multiple-breath schemes. For the 129Xe phantom images, the apparent diffusion coefficient, T1, and T2* relaxation maps were acquired and generated. Blurring due to the T2* decay and B0 field variation were simulated to estimate dependence of the image resolution on the duration of the data acquisition windows (i.e. sector length), and temperature-induced resonance frequency shift from the low field magnet hardware.