Background— Recent results from animal studies suggest that stem cells may be able to home to sites of myocardial injury to assist in tissue regeneration. However, the histological interpretation of postmortem tissue, on which many of these studies are based, has recently been widely debated. Methods and Results— With the use of the high sensitivity of a combined single-photon emission CT (SPECT)/CT scanner, the in vivo trafficking of allogeneic mesenchymal stem cells (MSCs) colabeled with a radiotracer and MR contrast agent to acute myocardial infarction was dynamically determined. Redistribution of the labeled MSCs after intravenous injection from initial localization in the lungs to nontarget organs such as the liver, kidney, and spleen was observed within 24 to 48 hours after injection. Focal and diffuse uptake of MSCs in the infarcted myocardium was already visible in SPECT/CT images in the first 24 hours after injection and persisted until 7 days after injection and was validated by tissue counts of radioactivity. In contrast, MRI was unable to demonstrate targeted cardiac localization of MSCs in part because of the lower sensitivity of MRI. Conclusions— Noninvasive radionuclide imaging is well suited to dynamically track the biodistribution and trafficking of mesenchymal stem cells to both target and nontarget organs.

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Background and Purpose-In animal models of stroke, functional improvement has been obtained after stem cell transplantation. Successful therapy depends largely on achieving a robust and targeted cell engraftment, with intraarterial (IA) injection being a potentially attractive route of administration. We assessed the suitability of laser Doppler flow (LDF) signal measurements and magnetic resonance (MR) imaging for noninvasive dual monitoring of targeted IA cell delivery. Methods-Transient cerebral ischemia was induced in adult Wistar rats (nϭ25) followed by IA or intravenous (IV) injection of mesenchymal stem cells (MSCs) labeled with superparamagnetic iron oxide. Cell infusion was monitored in real time with transcranial laser Doppler flowmetry while cellular delivery was assessed with MRI in vivo (4.7T) and ex vivo (9.4T). Results-Successful delivery of magnetically labeled MSCs could be readily visualized with MRI after IA but not IV injection. IA stem cell injection during acute stroke resulted in a high variability of cerebral engraftment. The amount of LDF reduction during cell infusion (up to 80%) was found to correlate well with the degree of intracerebral engraftment, with low LDF values being associated with significant morbidity. Key Words: laser Doppler flow Ⅲ MRI Ⅲ stroke Ⅲ stem cells Ⅲ transplantation R ecent discoveries in the field of stem cell research have opened new avenues for the therapy of complex diseases, particularly those of the central nervous system. It has been shown repeatedly in animal models that neurological deficits can be diminished by the introduction of therapeutic cells. 1,2 These observations in animal models provided the basis for the first clinical trials in Parkinson disease 3 and stroke patients. 4 -6 Stroke is a leading cause of serious, long-term disability, and survivors of ischemic insults have little effective treatment available. Although evidence of the beneficial effects of stem cells in animal stroke models is growing, the mechanisms behind the improvements are still unclear. 7 Some investigators have postulated that functional improvement is related to trophic support, which promotes survival of challenged neurons in the penumbra, 8 inducing myelination and neural plasticity, 9 or is attributable to other factors, such as neoangiogenesis. 10 Other researchers suggest that functional improvement is related to both neuronal differentiation and integration. 11 In any case, demonstration of therapeutic effects have been modest to date, and clearly, optimization of robust engraftment and detailed characterization of basic cellular events, such as migration, differentiation, and grafthost interactions, remains essential. Conclusions-HighOne obstacle that has hampered the advancement of stem cell transplantation is inadequate methodology to allow stem cell characterization in living organisms. Several techniques for noninvasive in vivo cellular imaging have been developed, including intravital multi-photon microscopy, 12,13 bioluminescence, 14 PET, 15 and MRI. 1...

Stem cell therapies offer great promise for many diseases, especially those without current effective treatments. It is believed that noninvasive imaging techniques, which offer the ability to track the status of cells after transplantation, will expedite progress in this field and help to achieve maximized therapeutic effect. Today’s biomedical imaging technology allows for real-time, noninvasive monitoring of grafted stem cells including their biodistribution, migration, survival, and differentiation, with magnetic resonance imaging (MRI) of nanoparticle-labeled cells being one of the most commonly used techniques. Among the advantages of MR cell tracking are its high spatial resolution, no exposure to ionizing radiation, and clinical applicability. In order to track cells by MRI, the cells need to be labeled with magnetic nanoparticles, for which many types exist. There are several cellular labeling techniques available, including simple incubation, use of transfection agents, magnetoelectroporation, and magnetosonoporation. In this overview article, we will review the use of different magnetic nanoparticles and discuss how these particles can be used to track the distribution of transplanted cells in different organ systems. Caveats and limitations inherent to the tracking of nanoparticle-labeled stem cells are also discussed.

We report optical fiber experiments allowing to investigate integrable turbulence in the focusing regime of the one dimensional nonlinear Schrödinger equation (1D-NLSE). Our experiments are very similar in their principle to water tank experiments with random initial conditions (see M. Onorato et al. Phys. Rev. E 70 067302 (2004)). Using an original optical sampling setup, we measure precisely the probability density function (PDF) of optical power of partially coherent waves rapidly fluctuating with time. The PDF is found to evolve from the normal law to a strong heavy-tailed distribution, thus revealing the formation of rogue waves in integrable turbulence. Numerical simulations of 1D-NLSE with stochastic initial conditions reproduce quantitatively the experiments. Our investigations suggest that the statistical features experimentally observed rely on the stochastic generation of coherent analytic solutions of 1D-NLSE such as Peregrine solitons.The field of nonlinear optics has recently grown as a favorable laboratory to investigate both statistical properties of nonlinear random waves and hydrodynamic-like phenomena [1][2][3]. In particular, several recent works point out analogies between hydrodynamics and nonlinear fiber optics in the observation of supercontinuum generation [4], undular bores [2], optical turbulence, laminarturbulent transition [1] or oceanographic rogue waves (RW) [5,6].Rogue waves (RW), also called freak waves, are extremely large amplitude waves occurring more frequently than expected from the normal law [7,8] As stressed out in the recent review [6], there is no obvious analogy between most of the optical experiments on extreme events and oceanography. However a direct correspondence between nonlinear optics and hydrodynamics is provided by the one-dimensional nonlinear Schrödinger equation (1D-NLSE) (see Eq. (1)) that describes various wave systems [6,18]. In particular, the focusing 1D-NLSE describes at leading order the physics of deep-water wave trains and it plays a central role in the study of RW [6-8, 18, 19].Modulational instability (MI) is believed to be a fundamental mechanism for the formation of RW [8,20]. Moreover, analytical solutions of the integrable 1D-NLSE such a Akhmediev breathers (AB), Peregrine solitons or Kuznetsov-Ma solitons (KMs) are now considered as possible prototypes of RW [19,[21][22][23]. These coherent structures have been generated from very specific, carefullydesigned coherent initial conditions in optical fiber experiments [21,23,24].On the contrary, oceanic RW emerge from the interplay of incoherent waves in turbulent systems. The occurrence of RW in wave turbulence has been theoretically studied in optics [25,26] and in hydrodynamics [27]. In hydrodynamical experiments made with one-dimensional water tanks, non gaussian statistics of the wave height has been found to emerge from random initial conditions [20,28].The appropriate theoretical framework combining a statistical approach of random waves together with the 1D-NLSE is integrable turbulence...

Microvessels of the blood-brain barrier (BBB) regulate transport into the brain. The highly specialized brain microvascular endothelial cells, a major component of the BBB, express tight junctions and efflux transporters which regulate paracellular and transcellular permeability. However, most existing models of BBB microvessels fail to exhibit physiological barrier function. Here, using (iPSC)-derived human brain microvascular endothelial cells (dhBMECs) within templated type I collagen channels we mimic the cylindrical geometry, cell-extracellular matrix interactions, and shear flow typical of human brain post-capillary venules. We characterize the structure and barrier function in comparison to non-brain-specific microvessels, and show that dhBMEC microvessels recapitulate physiologically low solute permeability and quiescent endothelial cell behavior. Transcellular permeability is increased two-fold using a clinically relevant dose of a p-glycoprotein inhibitor tariquidar, while paracellular permeability is increased using a bolus dose of hyperosmolar agent mannitol. Lastly, we show that our human BBB microvessels are responsive to inflammatory cytokines via upregulation of surface adhesion molecules and increased leukocyte adhesion, but no changes in permeability. Human iPSC-derived blood-brain barrier microvessels support quantitative analysis of barrier function and endothelial cell dynamics in quiescence and in response to biologically- and clinicallyrelevant perturbations.

In type I diabetes mellitus, islet transplantation provides a moment-to-moment fine regulation of insulin. Success rates vary widely, however, necessitating suitable methods to monitor islet delivery, engraftment and survival. Here magnetic resonance-trackable magnetocapsules have been used simultaneously to immunoprotect pancreatic beta-cells and to monitor, non-invasively in real-time, hepatic delivery and engraftment by magnetic resonance imaging (MRI). Magnetocapsules were detected as single capsules with an altered magnetic resonance appearance on capsule rupture. Magnetocapsules were functional in vivo because mouse beta-cells restored normal glycemia in streptozotocin-induced diabetic mice and human islets induced sustained C-peptide levels in swine. In this large-animal model, magnetocapsules could be precisely targeted for infusion by using magnetic resonance fluoroscopy, whereas MRI facilitated monitoring of liver engraftment over time. These findings are directly applicable to ongoing improvements in islet cell transplantation for human diabetes, particularly because our magnetocapsules comprise clinically applicable materials.

Purpose Chemical exchange saturation transfer (CEST) imaging is a new MRI technology allowing the detection of low concentration endogenous cellular proteins and metabolites indirectly through their exchangeable protons. A new technique, variable delay multi-pulse CEST (VDMP-CEST), is proposed to eliminate the need for recording full Z-spectra and performing asymmetry analysis to obtain CEST contrast. Methods The VDMP-CEST scheme involves acquiring images with two (or more) delays between radiofrequency saturation pulses in pulsed CEST, producing a series of CEST images sensitive to the speed of saturation transfer. Subtracting two images or fitting a time series produces CEST and relayed-nuclear Overhauser enhancement CEST maps without effects of direct water saturation and, when using low radiofrequency power, minimal magnetization transfer contrast interference. Results When applied to several model systems (bovine serum albumin, crosslinked bovine serum albumin, l-glutamic acid) and in vivo on healthy rat brain, VDMP-CEST showed sensitivity to slow to intermediate range magnetization transfer processes (rate < 100–150 Hz), such as amide proton transfer and relayed nuclear Overhauser enhancement-CEST. Images for these contrasts could be acquired in short scan times by using a single radiofrequency frequency. Conclusions VDMP-CEST provides an approach to detect CEST effect by sensitizing saturation experiments to slower exchange processes without interference of direct water saturation and without need to acquire Z-spectra and perform asymmetry analysis.