Angiogenesis in tissue engineering : Breathing life into constructed tissue substitutes

Long-term function of three-dimensional (3D) tissue constructs depends on adequate vascularization after implantation. Accordingly, research in tissue engineering has focused on the analysis of angiogenesis. For this purpose, 2 sophisticated in vivo models (the chorioallantoic membrane and the dorsal skinfold chamber) have recently been introduced in tissue engineering research, allowing a more detailed analysis of angiogenic dysfunction and engraftment failure. To achieve vascularization of tissue constructs, several approaches are currently under investigation. These include the modification of biomaterial properties of scaffolds and the stimulation of blood vessel development and maturation by different growth factors using slow-release devices through pre-encapsulated microspheres. Moreover, new microvascular networks in tissue substitutes can be engineered by using endothelial cells and stem cells or by creating arteriovenous shunt loops. Nonetheless, the currently used techniques are not sufficient to induce the rapid vascularization necessary for an adequate cellular oxygen supply. Thus, future directions of research should focus on the creation of microvascular networks within 3D tissue constructs in vitro before implantation or by co-stimulation of angiogenesis and parenchymal cell proliferation to engineer the vascularized tissue substitute in situ

Postnatal expression profiles of atypical cadherin FAT1 suggest its role in autism

Genetic studies have linked FAT1 (FAT atypical cadherin 1) with autism spectrum disorder (ASD); however, the role that FAT1 plays in ASD remains unknown. In mice, the function of Fat1 has been primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and soma of granule neurons, as well as being present in the synaptic plasma membrane and postsynaptic densities. Interestingly, FAT1 expression was decreased in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) from individuals with ASD. These findings suggest a novel role for FAT1 in postnatal development and may be particularly important for cerebellum function. As the cerebellum is one of the vulnerable brain regions in ASD, our study warrants further investigation of FAT1 in the disease etiology

A Time Course Analysis of the Electrophysiological Properties of Neurons Differentiated from Human Induced Pluripotent Stem Cells (iPSCs)

Many protocols have been designed to differentiate human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs) into neurons. Despite the relevance of electrophysiological properties for proper neuronal function, little is known about the evolution over time of important neuronal electrophysiological parameters in iPSC-derived neurons. Yet, understanding the development of basic electrophysiological characteristics of iPSC-derived neurons is critical for evaluating their usefulness in basic and translational research. Therefore, we analyzed the basic electrophysiological parameters of forebrain neurons differentiated from human iPSCs, from day 31 to day 55 after the initiation of neuronal differentiation. We assayed the developmental progression of various properties, including resting membrane potential, action potential, sodium and potassium channel currents, somatic calcium transients and synaptic activity. During the maturation of iPSC-derived neurons, the resting membrane potential became more negative, the expression of voltage-gated sodium channels increased, the membrane became capable of generating action potentials following adequate depolarization and, at day 48–55, 50% of the cells were capable of firing action potentials in response to a prolonged depolarizing current step, of which 30% produced multiple action potentials. The percentage of cells exhibiting miniature excitatory post-synaptic currents increased over time with a significant increase in their frequency and amplitude. These changes were associated with an increase of Ca2+ transient frequency. Co-culturing iPSC-derived neurons with mouse glial cells enhanced the development of electrophysiological parameters as compared to pure iPSC-derived neuronal cultures. This study demonstrates the importance of properly evaluating the electrophysiological status of the newly generated neurons when using stem cell technology, as electrophysiological properties of iPSC-derived neurons mature over time

Galaxy Group at z=0.3 Associated with the Damped Lyman Alpha System Towards Quasar Q1127-145

(Abridged) We performed a spectroscopic galaxy survey, complete to m<20.3 (L_B>0.15L_B* at z=0.3), within 100x100" of the quasar Q1127-145 (z=1.18). The VLT/UVES quasar spectrum contains three z<0.33 MgII absorption systems. We obtained eight new galaxy redshifts, adding to the four previously known, and galaxy star formation rates and metallicities were computed where possible. A strong MgII system [W_r(2796)=1.8A], which is a known DLA, had three previously identified galaxies; we found two additional galaxies associated with this system. These five galaxies form a group with diverse properties, such as a luminosity range of 0.04<L_B<0.63L_B*, an impact parameter range of 17<D<241kpc and velocity dispersion of 115km/s. The DLA group galaxy redshifts span beyond the 350km/s velocity spread of the metallic absorption lines of the DLA itself. The two brightest group galaxies have SFRs of a few Msun/yr and should not have strong winds. We have sufficient spectroscopic information to directly compare three of the five group galaxies' (emission-line) metallicities with the DLA (absorption) metallicity: the DLA metallicity is 1/10th solar, substantially lower than the three galaxies' which range between less than 1/2 solar to solar metallicity. HST/WFPC-2 imaging shows perturbed morphologies for the three brightest group galaxies, with tidal tails extending 25kpc. We favor a scenario where the DLA absorption originates from tidal debris in the group environment. Another absorber exhibits weak MgII absorption [W_r(2796)=0.03A] and had a previously identified galaxy at a similar redshift. We have identified a second galaxy associated with this system. Both galaxies have solar metallicities and unperturbed morphologies. The SFR of one galaxy is much lower than expected for strong outflows. Finally, we have identified five galaxies at large impact parameters with no associated MgII absorption.Comment: 15 pages, 7 figures, 5 tables. Accepted for publication in MNRAS

The Sixth Annual Translational Stem Cell Research Conference of the New York Stem Cell Foundation

The New York Stem Cell Foundation's "Sixth Annual Translational Stem Cell Research Conference" convened on October 11-12, 2011 at the Rockefeller University in New York City. Over 450 scientists, patient advocates, and stem cell research supporters from 14 countries registered for the conference. In addition to poster and platform presentations, the conference featured panels entitled "Road to the Clinic" and "The Future of Regenerative Medicine". © 2012 New York Academy of Sciences

Morphological Properties of z~0.5 Absorption-Selected Galaxies: The Role of Galaxy Inclination

We have used GIM2D to quantify the morphological properties of 40 intermediate redshift MgII absorption-selected galaxies (0.03<Wr(2796)<2.9 Ang), imaged with WFPC-2/HST, and compared them to the halo gas properties measured form HIRES/Keck and UVES/VLT quasar spectra. We find that as the quasar-galaxy separation, D, increases the MgII equivalent decreases with large scatter, implying that D is not the only physical parameter affecting the distribution and quantity of halo gas. Our main result shows that inclination correlates with MgII absorption properties after normalizing out the relationship (and scatter) between the absorption properties and D. We find a 4.3 sigma correlation between Wr(2796) and galaxy inclination, normalized by impact parameter, i/D. Other measures of absorption optical depth also correlate with i/D at greater than 3.2 sigma significance. Overall, this result suggests that MgII gas has a co-planer geometry, not necessarily disk-like, that is coupled to the galaxy inclination. It is plausible that the absorbing gas arises from tidal streams, satellites, filaments, etc., which tend to have somewhat co-planer distributions. This result does not support a picture in which MgII absorbers with Wr(2796)<1A are predominantly produced by star-formation driven winds. We further find that; (1) MgII host galaxies have quantitatively similar bulge and disk scale length distribution to field galaxies at similar redshifts and have a mean disk and bulge scale length of 3.8kpc and 2.5kpc, respectively; (2) Galaxy color and luminosity do not correlate strongly with absorption properties, implying a lack of a connection between host galaxy star formation rates and absorption strength; (3) Parameters such as scale lengths and bulge-to-total ratios do not significantly correlate with the absorption parameters, suggesting that the absorption is independent of galaxy size or mass.Comment: 21 pages, 7 figures, 7 tables. Accepted for publication in MNRAS. Revised v3 updates Table 5 columns 8 and 11. ArXiv copy includes full version of Fig. 1 (additional 6 pages

Logopenic and nonfluent variants of primary progressive aphasia are differentiated by acoustic measures of speech production

Differentiation of logopenic (lvPPA) and nonfluent/agrammatic (nfvPPA) variants of Primary Progressive Aphasia is important yet remains challenging since it hinges on expert based evaluation of speech and language production. In this study acoustic measures of speech in conjunction with voxel-based morphometry were used to determine the success of the measures as an adjunct to diagnosis and to explore the neural basis of apraxia of speech in nfvPPA. Forty-one patients (21 lvPPA, 20 nfvPPA) were recruited from a consecutive sample with suspected frontotemporal dementia. Patients were diagnosed using the current gold-standard of expert perceptual judgment, based on presence/absence of particular speech features during speaking tasks. Seventeen healthy age-matched adults served as controls. MRI scans were available for 11 control and 37 PPA cases; 23 of the PPA cases underwent amyloid ligand PET imaging. Measures, corresponding to perceptual features of apraxia of speech, were periods of silence during reading and relative vowel duration and intensity in polysyllable word repetition. Discriminant function analyses revealed that a measure of relative vowel duration differentiated nfvPPA cases from both control and lvPPA cases (r2 = 0.47) with 88% agreement with expert judgment of presence of apraxia of speech in nfvPPA cases. VBM analysis showed that relative vowel duration covaried with grey matter intensity in areas critical for speech motor planning and programming: precentral gyrus, supplementary motor area and inferior frontal gyrus bilaterally, only affected in the nfvPPA group. This bilateral involvement of frontal speech networks in nfvPPA potentially affects access to compensatory mechanisms involving right hemisphere homologues. Measures of silences during reading also discriminated the PPA and control groups, but did not increase predictive accuracy. Findings suggest that a measure of relative vowel duration from of a polysyllable word repetition task may be sufficient for detecting most cases of apraxia of speech and distinguishing between nfvPPA and lvPPA

iPSC-Derived Dopamine Neurons Reveal Differences between Monozygotic Twins Discordant for Parkinson’s Disease

SummaryParkinson’s disease (PD) has been attributed to a combination of genetic and nongenetic factors. We studied a set of monozygotic twins harboring the heterozygous glucocerebrosidase mutation (GBA N370S) but clinically discordant for PD. We applied induced pluripotent stem cell (iPSC) technology for PD disease modeling using the twins’ fibroblasts to evaluate and dissect the genetic and nongenetic contributions. Utilizing fluorescence-activated cell sorting, we obtained a homogenous population of “footprint-free” iPSC-derived midbrain dopaminergic (mDA) neurons. The mDA neurons from both twins had ∼50% GBA enzymatic activity, ∼3-fold elevated α-synuclein protein levels, and a reduced capacity to synthesize and release dopamine. Interestingly, the affected twin’s neurons showed an even lower dopamine level, increased monoamine oxidase B (MAO-B) expression, and impaired intrinsic network activity. Overexpression of wild-type GBA and treatment with MAO-B inhibitors normalized α-synuclein and dopamine levels, suggesting a combination therapy for the affected twin

Progress report no. 1

Statement of responsibility on title-page reads: Editors: I.A. Forbes, M.J. Driscoll, D.D. Lanning, I. Kaplan, N.C. Rasmussen; Contributors: S.A. Ali, S.T. Brewer, D.K. Choi, F.M. Clikeman, W.R. Corcoran, M.J. Driscoll, I.A. Forbes, C.W. Forsberg, S.L. Ho, C.S. Kang, I. Kaplan, J.L. Klucar, D.D. Lanning, T.C. Leung, E.L. McFarland P.G. Mertens, N.R. Ortiz, A. Pant, N.A. Passman, N.C. Rasmussen, M.K. Sheaffer, D.A. Shupe, G.E. Sullivan, A.T. Supple, J.W. Synan, C.P. Tzanos, W.J. Westlake"MIT-4105-3."Includes bibliographical referencesProgress report; June 30, 1970U.S. Atomic Energy Commission contracts: AT(30-1)410

Task-Specific Codes for Face Recognition: How they Shape the Neural Representation of Features for Detection and Individuation

The variety of ways in which faces are categorized makes face recognition challenging for both synthetic and biological vision systems. Here we focus on two face processing tasks, detection and individuation, and explore whether differences in task demands lead to differences both in the features most effective for automatic recognition and in the featural codes recruited by neural processing.Our study appeals to a computational framework characterizing the features representing object categories as sets of overlapping image fragments. Within this framework, we assess the extent to which task-relevant information differs across image fragments. Based on objective differences we find among task-specific representations, we test the sensitivity of the human visual system to these different face descriptions independently of one another. Both behavior and functional magnetic resonance imaging reveal effects elicited by objective task-specific levels of information. Behaviorally, recognition performance with image fragments improves with increasing task-specific information carried by different face fragments. Neurally, this sensitivity to the two tasks manifests as differential localization of neural responses across the ventral visual pathway. Fragments diagnostic for detection evoke larger neural responses than non-diagnostic ones in the right posterior fusiform gyrus and bilaterally in the inferior occipital gyrus. In contrast, fragments diagnostic for individuation evoke larger responses than non-diagnostic ones in the anterior inferior temporal gyrus. Finally, for individuation only, pattern analysis reveals sensitivity to task-specific information within the right "fusiform face area".OUR RESULTS DEMONSTRATE: 1) information diagnostic for face detection and individuation is roughly separable; 2) the human visual system is independently sensitive to both types of information; 3) neural responses differ according to the type of task-relevant information considered. More generally, these findings provide evidence for the computational utility and the neural validity of fragment-based visual representation and recognition