Macrophages Control Vascular Stem/Progenitor Cell Plasticity Through Tumor Necrosis Factor-α-Mediated Nuclear Factor-κB Activation

Objective: Vascular lineage differentiation of stem/progenitor cells can contribute to both tissue repair and exacerbation of vascular diseases such as in vein grafts. The role of macrophages in controlling vascular progenitor differentiation is largely unknown and may play an important role in graft development. This study aims to identify the role of macrophages in vascular stem/progenitor cell differentiation and thereafter elucidate the mechanisms that are involved in the macrophage- mediated process.

Approach and Results: We provide in vitro evidence that macrophages can induce endothelial cell (EC) differentiation of the stem/progenitor cells while simultaneously inhibiting their smooth muscle cell differentiation. Mechanistically, both effects were mediated by macrophage-derived tumor necrosis factor-α (TNF-α) via TNF-α receptor 1 and canonical nuclear factor-κB activation. Although the overexpression of p65 enhanced EC (or attenuated smooth muscle cell) differentiation, p65 or TNF-α receptor 1 knockdown using lentiviral short hairpin RNA inhibited EC (or rescued smooth muscle cell) differentiation in response to TNF-α. Furthermore, TNF-α–mediated EC differentiation was driven by direct binding of nuclear factor-κB (p65) to specific VE-cadherin promoter sequences. Subsequent experiments using an ex vivo decellularized vessel scaffold confirmed an increase in the number of ECs and reduction in smooth muscle cell marker expression in the presence of TNF-α. The lack of TNF-α in a knockout mouse model of vein graft decreased endothelialization and significantly increased thrombosis formation.

Conclusions: Our study highlights the role of macrophages in directing vascular stem/progenitor cell lineage commitment through TNF-α–mediated TNF-α receptor 1 and nuclear factor-κB activation that is likely required for endothelial repair in vascular diseases such as vein graft.

Endothelial progenitor cells in diabetic retinopathy

Diabetic retinopathy (DR) is a leading cause of visual impairment worldwide. Patients with DR may irreversibly lose sight as a result of the development of diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR); retinal blood vessel dysfunction and degeneration plays an essential role in their pathogenesis. Although new treatments have been recently introduced for DME, including intravitreal vascular endothelial growth factor inhibitors (anti-VEGFs) and steroids, a high proportion of patients (~40-50%) do not respond to these therapies. Furthermore, for people with PDR, laser photocoagulation remains a mainstay therapy despite this being an inherently destructive procedure. Endothelial progenitor cells (EPCs) are a low-frequency population of circulating cells known to be recruited to sites of vessel damage and tissue ischemia where they promote vascular healing and re-perfusion. A growing body of evidence suggests that the number and function of EPCs are altered in patients with varying degrees of diabetes duration, metabolic control, and in the presence or absence of DR. Although there are no clear-cut outcomes from these clinical studies, there is mounting evidence that some EPC sub-types may be involved in the pathogenesis of DR and may also serve as biomarkers for disease progression and stratification. Moreover, some EPC sub-types have considerable potential as therapeutic modalities for DME and PDR in the context of cell therapy. This study presents basic clinical concepts of DR and combines this with a general insight on EPCs and their relation to future directions in understanding and treating this important diabetic complication.

The progenitor mass of the Type IIP supernova SN 2004et from late-time spectral modeling

SN 2004et is one of the nearest and best-observed Type IIP supernovae, with a progenitor detection as well as good photometric and spectroscopic observational coverage well into the nebular phase. Based on nucleosynthesis from stellar evolution/explosion models we apply spectral modeling to analyze its 140-700 day evolution from ultraviolet to mid-infrared. We find a M_ZAMS= 15 Msun progenitor star (with an oxygen mass of 0.8 Msun) to satisfactorily reproduce [O I] 6300, 6364 {\AA} and other emission lines of carbon, sodium, magnesium, and silicon, while 12 Msun and 19 Msun models under- and overproduce most of these lines, respectively. This result is in fair agreement with the mass derived from the progenitor detection, but in disagreement with hydrodynamical modeling of the early-time light curve. From modeling of the mid-infrared iron-group emission lines, we determine the density of the "Ni-bubble" to rho(t) = 7E-14*(t/100d)^-3 g cm^-3, corresponding to a filling factor of f = 0.15 in the metal core region (V = 1800 km/s). We also confirm that silicate dust, CO, and SiO emission are all present in the spectra.

Toward Characterization Of The Type IIP Supernova Progenitor Population: A Statistical Sample Of Light Curves From Pan-STARRS1

In recent years, wide-field sky surveys providing deep multi-band imaging have presented a new path for indirectly characterizing the progenitor populations of core-collapse supernovae (SN): systematic light curve studies. We assemble a set of 76 grizy-band Type IIP SN light curves from Pan-STARRS1, obtained over a constant survey program of 4 years and classified using both spectroscopy and machine learning-based photometric techniques. We develop and apply a new Bayesian model for the full multi-band evolution of each light curve in the sample. We find no evidence of a sub-population of fast-declining explosions (historically referred to as "Type IIL" SNe). However, we identify a highly significant relation between the plateau phase decay rate and peak luminosity among our SNe IIP. These results argue in favor of a single parameter, likely determined by initial stellar mass, predominantly controlling the explosions of red supergiants. This relation could also be applied for supernova cosmology, offering a standardizable candle good to an intrinsic scatter of 0.2 mag. We compare each light curve to physical models from hydrodynamic simulations to estimate progenitor initial masses and other properties of the Pan-STARRS1 Type IIP SN sample. We show that correction of systematic discrepancies between modeled and observed SN IIP light curve properties and an expanded grid of progenitor properties, are needed to enable robust progenitor inferences from multi-band light curve samples of this kind. This work will serve as a pathfinder for photometric studies of core-collapse SNe to be conducted through future wide field transient searches.

Controlling Surface Topology and Functionality of Electrospun Fibers on the Nanoscale using Amphiphilic Block Copolymers To Direct Mesenchymal Progenitor Cell Adhesion

Surface patterning in three dimensions is of great importance in biomaterials design for controlling cell behavior. A facile one-step functionalization of biodegradable PDLLA fibers using amphiphilic diblock copolymers is demonstrated here to systematically vary the fiber surface composition. The copolymers comprise a hydrophilic poly[oligo(ethylene glycol) methacrylate] (POEGMA), poly[(2-methacryloyloxy)ethyl phosphorylcholine] (PMPC), or poly[2-(dimethylamino)ethyl methacrylate)] (PDMAEMA) block and a hydrophobic poly(l-lactide) (PLA) block. The block copolymer-modified fibers have increased surface hydrophilicity compared to that of PDLLA fibers. Mixtures of PLAPMPC and PLAPOEGMA copolymers are utilized to exploit microphase separation of the incompatible hydrophilic PMPC and POEGMA blocks at the fiber surface. Conjugation of an RGD cell-adhesive peptide to one hydrophilic block (POEGMA) using thiol-ene chemistry produces fibers with domains of cell-adhesive (POEGMA) and cell-inert (PMPC) sites, mimicking the adhesive properties of the extracellular matrix (ECM). Human mesenchymal progenitor cells (hES-MPs) showed much better adhesion to the fibers with surface-adhesive heterogeneity compared to that to fibers with only adhesive or only inert surface chemistries.

SN 2012ec: mass of the progenitor from PESSTO follow-up of the photospheric phase

We present the results of a photometric and spectroscopic monitoring campaign of SN 2012ec, which exploded in the spiral galaxy NGC 1084, during the photospheric phase. The photometric light curve exhibits a plateau with luminosity L = 0.9 x 10(42) erg s(-1) and duration similar to 90 d, which is somewhat shorter than standard Type II-P supernovae (SNe). We estimate the nickel mass M(Ni-56) = 0.040 +/- 0.015 M-circle dot from the luminosity at the beginning of the radioactive tail of the light curve. The explosion parameters of SN 2012ec were estimated from the comparison of the bolometric light curve and the observed temperature and velocity evolution of the ejecta with predictions from hydrodynamical models. We derived an envelope mass of 12.6 M-circle dot, an initial progenitor radius of 1.6 x 10(13) cm and an explosion energy of 1.2 foe. These estimates agree with an independent study of the progenitor star identified in pre-explosion images, for which an initial mass of M = 14-22 M-circle dot was determined. We have applied the same analysis to two other Type II-P SNe (SNe 2012aw and 2012A), and carried out a comparison with the properties of SN 2012ec derived in this paper. We find a reasonable agreement between the masses of the progenitors obtained from pre-explosion images and masses derived from hydrodynamical models. We estimate the distance to SN 2012ec with the standardized candle method (SCM) and compare it with other estimates based on other primary and secondary indicators. SNe 2012A, 2012aw and 2012ec all follow the standard relations for the SCM for the use of Type II-P SNe as distance indicators.

Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells

The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34 + cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript andor exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicingprocessing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expressionsplicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34 + cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processespathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

GALEX Detection of Shock Breakout in Type IIP Supernova PS1-13arp: Implications for the Progenitor Star Wind

We present the GALEX detection of a UV burst at the time of explosion of an optically normal supernova (SN) IIP (PS1-13arp) from the Pan-STARRS1 survey at z = 0.1665. The temperature and luminosity of the UV burst match the theoretical predictions for shock breakout in a red supergiant (RSG), but with a duration a factor of similar to 50 longer than expected. We compare the NUV light curve of PS1-13arp to previous GALEX detections of SNe IIP and find clear distinctions that indicate that the UV emission is powered by shock breakout, and not by the subsequent cooling envelope emission previously detected in these systems. We interpret the similar to 1 day duration of the UV signal with a shock breakout in the wind of an RSG with a pre-explosion mass-loss rate of similar to 10(-3) M-circle dot yr(-1). This mass-loss rate is enough to prolong the duration of the shock breakout signal, but not enough to produce an excess in the optical plateau light curve or narrow emission lines powered by circumstellar interaction. This detection of nonstandard, potentially episodic high mass loss in an RSG SN progenitor has favorable consequences for the prospects of future wide-field UV surveys to detect shock breakout directly in these systems, and provide a sensitive probe of the pre-explosion conditions of SN progenitors.

On the progenitor of the Type Ic SN 2013dk in the Antennae galaxies

We report the results of our search for the progenitor candidate of SN 2013dk, a Type Ic supernova (SN) that exploded in the Antennae galaxy system. We compare pre-explosion Hubble Space Telescope (HST) archival images with SN images obtained using adaptive optics at the ESO Very Large Telescope. We isolate the SN position to within 3σ uncertainty radius of 0.02 arcsec and show that there is no detectable point source in any of the HST filter images within the error circle. We set an upper limit to the absolute magnitude of the progenitor to be MF555W ≳ -5.7, which does not allow Wolf-Rayet (WR) star progenitors to be ruled out. A bright source appears 0.17 arcsec away, which is either a single bright supergiant or compact cluster, given its absolute magnitude of MF555W = -9.02 ± 0.28 extended wings and complex environment. However, even if this is a cluster, the spatial displacement of SN 2013dk means that its membership is not assured. The strongest statement that we can make is that in the immediate environment of SN 2013dk (within 10 pc or so), we find no clear evidence of either a point source coincident with the SN or a young stellar cluster that could host a massive WR progenitor.