Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network.

Most tissues develop from stem cells and precursors that undergo differentiation as their proliferative potential decreases. Mature differentiated cells rarely proliferate and are replaced at the end of their life by new cells derived from precursors. Langerhans cells (LCs) of the epidermis, although of myeloid origin, were shown to renew in tissues independently from the bone marrow, suggesting the existence of a dermal or epidermal progenitor. We investigated the mechanisms involved in LC development and homeostasis. We observed that a single wave of LC precursors was recruited in the epidermis of mice around embryonic day 18 and acquired a dendritic morphology, major histocompatibility complex II, CD11c, and langerin expression immediately after birth. Langerin+ cells then undergo a massive burst of proliferation between postnatal day 2 (P2) and P7, expanding their numbers by 10–20-fold. After the first week of life, we observed low-level proliferation of langerin+ cells within the epidermis. However, in a mouse model of atopic dermatitis (AD), a keratinocyte signal triggered increased epidermal LC proliferation. Similar findings were observed in epidermis from human patients with AD. Therefore, proliferation of differentiated resident cells represents an alternative pathway for development in the newborn, homeostasis, and expansion in adults of selected myeloid cell populations such as LCs. This mechanism may be relevant in locations where leukocyte trafficking is limited.

Kinematics of the ring-like nebula SuWt 2

We present the first detailed spatio-kinematical analysis and modelling of the southern planetary nebula SuWt 2. This object presents a problem for current theories of planetary nebula formation and evolution, as it is not known to contain a central post-main-sequence star. Deep narrow-band [NII]6584Å images reveal the presence of faint bipolar lobes emanating from the edges of the nebular ring. Long-slit observations of the Ha and [NII]6584Å emission lines were obtained using the ESO (European Southern Observatory) Multi-Mode Instrument on the 3.6-m ESO New Technology Telescope. The spectra reveal the nebular morphology as a bright torus encircling the waist of an extended bipolar structure. By deprojection, the inclination of the ring is found to be 68° +/- 2° (cf. ~90° for the double A-type binary believed to lie at the centre of the nebula), and the ring expansion velocity is found to be 28 kms-1. Our findings are discussed with relation to possible formation scenarios for SuWt 2. Through comparison of the nebular heliocentric systemic velocity, found here to be -25 +/- 5km s-1, and the heliocentric systemic velocity of the double A-type binary, we conclude that neither component of the binary could have been the nebular progenitor. However, we are unable to rule out the presence of a third component to the system, which would have been the nebula progenitor.

Dust and the Type II-Plateau Supernova 2004et

We present mid-infrared (MIR) observations of the Type II-plateau supernova (SN) 2004et, obtained with the Spitzer Space Telescope between 64 and 1406 days past explosion. Late-time optical spectra are also presented. For the period 300-795 days past explosion, we argue that the spectral energy distribution (SED) of SN 2004et comprises (1) a hot component due to emission from optically thick gas, as well as free-bound radiation; (2) a warm component due to newly formed, radioactively heated dust in the ejecta; and (3) a cold component due to an IR echo from the interstellar-medium dust of the host galaxy, NGC 6946. There may also have been a small contribution to the IR SED due to free-free emission from ionized gas in the ejecta. We reveal the first-ever spectroscopic evidence for silicate dust formed in the ejecta of a supernova. This is supported by our detection of a large, but progressively declining, mass of SiO. However, we conclude that the mass of directly detected ejecta dust grew to no more than a few times 10(-4) M-circle dot. We also provide evidence that the ejecta dust formed in comoving clumps of fixed size. We argue that, after about two years past explosion, the appearance of wide, box-shaped optical line profiles was due to the impact of the ejecta on the progenitor circumstellar medium and that the subsequent formation of a cool, dense shell was responsible for a later rise in the MIR flux. This study demonstrates the rich, multifaceted ways in which a typical core-collapse supernova and its progenitor can produce and/or interact with dust grains. The work presented here adds to the growing number of studies that do not support the contention that SNe are responsible for the large mass of observed dust in high-redshift galaxies.

Extensive optical and near-infrared observations of the nearby, narrow-lined type Ic SN 2007gr: days 5 to 415

We present photometric and spectroscopic observations at optical and near-infrared wavelengths of the nearby type Ic supernova 2007gr. These represent the most extensive data-set to date of any supernova of this sub-type, with frequent coverage from shortly after discovery to more than one year post-explosion. We deduce a rise time to B-band maximum of 11.5 +/- 2.7 d. We find a peak B-band magnitude of M-B = -16.8, and light curves which are remarkably similar to the so-called "hypernova" SN 2002ap. In contrast, the spectra of SNe 2007gr and 2002ap show marked differences, not least in their respective expansion velocities. We attribute these differences primarily to the density profiles of their progenitor stars at the time of explosion i.e. a more compact star for SN 2007gr compared to SN 2002ap. From the quasi-bolometric light curve of SN 2007gr, we estimate that 0.076 +/- 0.010 M-circle dot of Ni-56 was produced in the explosion. Our near-infrared (IR) spectra clearly show the onset and disappearance of the first overtone of carbon monoxide (CO) between similar to 70 to 175 d relative to B-band maximum. The detection of the CO molecule implies that ionised He was not microscopically mixed within the carbon/oxygen layers. From the optical spectra, near-IR light curves, and colour evolution, we find no evidence for dust condensation in the ejecta out to about +400 d. Given the combination of unprecedented temporal coverage, and high signal-to-noise data, we suggest that SN 2007gr could be used as a template object for supernovae of this sub-class.

SN 2005 gj: evidence for LBV supernovae progenitors?

There is mounting observational evidence in favour of Luminous Blue Variables (LBVs) being the direct progenitors of supernovae. Here we present possibly the most convincing evidence yet for such progenitors. We find multiple absorption component P-Cygni profiles of hydrogen and helium in the spectrum of SN 2005gj, which we interpret as being an imprint of the progenitor's mass-loss history. Such profiles have previously only been detected in Luminous Blue Variables. This striking resemblance of the profiles, along with wind velocities and periods consistent with those of LBVs leads us to connect SN 2005gj to an LBV progenitor.

GALEX AND PAN-STARRS1 DISCOVERY OF SN IIP 2010aq: THE FIRST FEW DAYS AFTER SHOCK BREAKOUT IN A RED SUPERGIANT STAR

We present the early UV and optical light curve of Type IIP supernova (SN) 2010aq at z = 0.0862, and compare it to analytical models for thermal emission following SN shock breakout in a red supergiant star. SN 2010aq was discovered in joint monitoring between the Galaxy Evolution Explorer (GALEX) Time Domain Survey (TDS) in the NUV and the Pan-STARRS1 Medium Deep Survey (PS1 MDS) in the g, r, i, and z bands. The GALEX and Pan-STARRS1 observations detect the SN less than 1 day after the shock breakout, measure a diluted blackbody temperature of 31,000 +/- 6000 K 1 day later, and follow the rise in the UV/optical light curve over the next 2 days caused by the expansion and cooling of the SN ejecta. The high signal-to-noise ratio of the simultaneous UV and optical photometry allows us to fit for a progenitor star radius of 700 +/- 200R(circle dot), the size of a red supergiant star. An excess in UV emission two weeks after shock breakout compared with SNe well fitted by model atmosphere-code synthetic spectra with solar metallicity is best explained by suppressed line blanketing due to a lower metallicity progenitor star in SN 2010aq. Continued monitoring of PS1 MDS fields by the GALEX TDS will increase the sample of early UV detections of Type II SNe by an order of magnitude and probe the diversity of SN progenitor star properties.

The death of massive stars - I. Observational constraints on the progenitors of Type II-P supernovae

We present the results of a 10.5-yr, volume-limited (28-Mpc) search for supernova (SN) progenitor stars. In doing so we compile all SNe discovered within this volume (132, of which 27 per cent are Type Ia) and determine the relative rates of each subtype from literature studies. The core-collapse SNe break down into 59 per cent II-P and 29 per cent Ib/c, with the remainder being IIb (5 per cent), IIn (4 per cent) and II-L (3 per cent). There have been 20 II-P SNe with high-quality optical or near-infrared pre-explosion images that allow a meaningful search for the progenitor stars. In five cases they are clearly red supergiants, one case is unconstrained, two fall on compact coeval star clusters and the other twelve have no progenitor detected. We review and update all the available data for the host galaxies and SN environments (distance, metallicity and extinction) and determine masses and upper mass estimates for these 20 progenitor stars using the STARS stellar evolutionary code and a single consistent homogeneous method. A maximum likelihood calculation suggests that the minimum stellar mass for a Type II-P to form is m(min) = 8.5(-1.5)(+1) M-circle dot and the maximum mass for II-P progenitors is m(max) = 16.5 +/- 1.5 M-circle dot, assuming a Salpeter initial mass function holds for the progenitor population (in the range Gamma = -1.35(-0.7)(+0.3)). The minimum mass is consistent with current estimates for the upper limit to white dwarf progenitor masses, but the maximum mass does not appear consistent with massive star populations in Local Group galaxies. Red supergiants in the Local Group have masses up to 25 M-circle dot and the minimum mass to produce a Wolf-Rayet star in single star evolution (between solar and LMC metallicity) is similarly 25-30 M-circle dot. The reason we have not detected any high-mass red supergiant progenitors above 17 M-circle dot is unclear, but we estimate that it is statistically significant at 2.4 sigma confidence. Two simple reasons for this could be that we have systematically underestimated the progenitor masses due to dust extinction or that stars between 17-25 M-circle dot produce other kinds of SNe which are not II-P. We discuss these possibilities and find that neither provides a satisfactory solution. We term this discrepancy the 'red supergiant problem' and speculate that these stars could have core masses high enough to form black holes and SNe which are too faint to have been detected. We compare the Ni-56 masses ejected in the SNe to the progenitor mass estimates and find that low-luminosity SNe with low Ni-56 production are most likely to arise from explosions of low-mass progenitors near the mass threshold that can produce a core-collapse.

The Disappearance of the Progenitors of Supernovae 1993J and 2003gd

Using images from the Hubble Space Telescope and the Gemini Telescope, we confirmed the disappearance of the progenitors of two type II supernovae (SNe) and evaluated the presence of other stars associated with them. We found that the progenitor of SN 2003gd, an M-supergiant star, is no longer observed at the SN location and determined its intrinsic brightness using image subtraction techniques. The progenitor of SN 1993J, a K-supergiant star, is also no longer present, but its B-supergiant binary companion is still observed. The disappearance of the progenitors confirms that these two supernovae were produced by red supergiants.

Ultra-bright Optical Transients are Linked with Type Ic Supernovae

Recent searches by unbiased, wide-field surveys have uncovered a group of extremely luminous optical transients. The initial discoveries of SN 2005ap by the Texas Supernova Search and SCP-06F6 in a deep Hubble pencil beam survey were followed by the Palomar Transient Factory confirmation of host redshifts for other similar transients. The transients share the common properties of high optical luminosities (peak magnitudes similar to -21 to -23), blue colors, and a lack of H or He spectral features. The physical mechanism that produces the luminosity is uncertain, with suggestions ranging from jet-driven explosion to pulsational pair instability. Here, we report the most detailed photometric and spectral coverage of an ultra-bright transient (SN 2010gx) detected in the Pan-STARRS 1 sky survey. In common with other transients in this family, early-time spectra show a blue continuum and prominent broad absorption lines of O II. However, about 25 days after discovery, the spectra developed type Ic supernova features, showing the characteristic broad Fe II and Si II absorption lines. Detailed, post-maximum follow-up may show that all SN 2005ap and SCP-06F6 type transients are linked to supernovae Ic. This poses problems in understanding the physics of the explosions: there is no indication from late-time photometry that the luminosity is powered by Ni-56, the broad light curves suggest very large ejected masses, and the slow spectral evolution is quite different from typical Ic timescales. The nature of the progenitor stars and the origin of the luminosity are intriguing and open questions.

Outgrowth Endothelial Cells: Characterization and Their Potential for Reversing Ischemic Retinopathy

Purpose. Endothelial progenitor cells (EPCs) have potential for promoting vascular repair and revascularization of ischemic retina. However, the highly heterogeneous nature of these cells causes confusion when assessing their biological functions. The purpose of this study was to provide a comprehensive comparison between the two main EPC subtypes, early EPCs (eEPCs) and outgrowth endothelial cells (OECs), and to establish the potential of OECs as a novel cell therapy for ischemic retinopathy.

Methods. Two types of human blood-derived EPCs were isolated and compared using immunophenotyping and multiple in vitro functional assays to assess interaction with retinal capillary endothelial cells and angiogenic activity. OECs were delivered intravitreally in a mouse model of ischemic retinopathy, and flat mounted retinas were examined using confocal microscopy.

Results. These data indicate that eEPCs are hematopoietic cells with minimal proliferative capacity that lack tube-forming capacity. By contrast, OECs are committed to an endothelial lineage and have significant proliferative and de novo tubulogenic potential. Furthermore, only OECs are able to closely interact with endothelial cells through adherens and tight junctions and to integrate into retinal vascular networks in vitro. The authors subsequently chose OECs to test a novel cell therapy approach for ischemic retinopathy. Using a murine model of retinal ischemia, they demonstrated that OECs directly incorporate into the resident vasculature, significantly decreasing avascular areas, concomitantly increasing normovascular areas, and preventing pathologic preretinal neovascularization.

Conclusions. As a distinct EPC population, OECs have potential as therapeutic cells to vascularize the ischemic retina.

Thrombopoietin, flt3-ligand and c-kit-ligand modulate HOX gene expression in expanding cord blood CD133(+) cells

Haemopoietic stem/progenitor cell (HSPC) development is regulated by extrinsic and intrinsic stimuli. Extrinsic modulators include growth factors and cell adhesion molecules, whereas intrinsic regulation is achieved with many transcription factor families, of which the HOX gene products are known to be important in haemopoiesis. Umbilical cord blood CD133(+) HSPC proliferation potential was tested in liquid culture with 'TPOFLK' (thrombopoietin, flt-3 ligand and c-kit ligand, promoting HSPC survival and self-renewal), in comparison to 'K36EG' (c-kit-ligand, interleukins-3 and -6, erythropoietin and granulocyte colony-stimulating factor, inducing haemopoietic differentiation). TPOFLK induced a higher CD133(+) HSPC proliferation (up to 60-fold more, at week 8) and maintained a higher frequency of the primitive colony-forming cells than K36EG. Quantitative polymerase chain reaction analysis revealed opposite expression patterns for specific HOX genes in expanding cord blood CD133(+) HSPC. After 8 weeks in liquid culture, TPOFLK increased the expression of HOX B3, B4 and A9 (associated with uncommitted HSPC) and reduced the expression of HOX B8 and A10 (expressed in committed myeloid cells) when compared to K36EG. These results suggest that TPOFLK induces CD133(+) HSPC proliferation, self-renewal and maintenance, up-regulation of HOX B3, B4 and A9 and down-regulation of HOX B8 and A10 gene expression.

Vascular stem cells and ischaemic retinopathies

Retinal ischaemic disorders such as diabetic retinopathy and retinal vein occlusion are common. The hypoxia-related stimuli from oxygen-deprived neural and glial networks can drive expression of growth factors and cytokines which induce leakage from the surviving vasculature and/or pre-retinal and papillary neovascularisation. If left untreated, retinal vascular stasis, hypoxia or ischaemia can lead to macular oedema or fibro-vascular scar formation which are associated with severe visual impairment, and even blindness. Current therapies for ischaemic retinopathies include laser photocoagulation, injection of corticosteroids or VEGF-antibodies and vitreoretinal surgery, however they carry significant side effects. As an alternative approach, we propose that if reparative intra-retinal angiogenesis can be harnessed at the appropriate stage, ischaemia could be contained or reversed. This review provides evidence that reperfusion of ischaemic retina and suppression of sight-threatening sequelae is possible in both experimental and clinical settings. In particular, there is emphasis on the clinical potential for endothelial progenitor cells (EPCs) to promote vascular repair and reversal of ischaemic injury in various tissues including retina. Gathering evidence from an extensive published literature, we outline the molecular and phenotypic nature of EPCs, how they are altered in disease and provide a rationale for harnessing the vascular reparative properties of various cell sub-types. When some of the remaining questions surrounding the clinical use of EPCs are addressed, they may provide an exciting new therapeutic option for treating ischaemic retinopathies. (C) 2011 Elsevier Ltd. All rights reserved.

The Delta Np63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer

Little is known about the origin of basal-like breast cancers, an aggressive disease that is highly similar to BRCA1-mutant breast cancers. p63 family proteins that are structurally related to the p53 suppressor protein are known to function in stem cell regulation and stratified epithelia development in multiple tissues, and p63 expression may be a marker of basal-like breast cancers. Here we report that Delta Np63 isoforms of p63 are transcriptional targets for positive regulation by BRCA1. Our analyses of breast cancer tissue microarrays and BRCA1-modulated breast cancer cell lines do not support earlier reports that p63 is a marker of basal-like or BRCA1 mutant cancers. Nevertheless, we found that BRCA1 interacts with the specific p63 isoform Delta Np63 gamma along with transcription factor isoforms AP-2 alpha and AP-2 gamma. BRCA1 required Delta Np63 gamma and AP-2 gamma to localize to an intronic enhancer region within the p63 gene to upregulate transcription of the Delta Np63 isoforms. In mammary stem/progenitor cells, siRNA- mediated knockdown of Delta Np63 expression resulted in genomic instability, increased cell proliferation, loss of DNA damage checkpoint control, and impaired growth control. Together, our findings establish that transcriptional upregulation of Delta Np63 proteins is critical for BRCA1 suppressor function and that defects in BRCA1-Delta Np63 signaling are key events in the pathogenesis of basal-like breast cancer. Cancer Res; 71( 5); 1933-44. (c) 2011 AACR.

Adiponectin is produced by lymphocytes and is a negative regulator of granulopoiesis

Lymphocytes have long been established to play an important role in the regulation of hematopoiesis and produce many cytokines that act on hematopoietic progenitor cells. Previous studies by our group have shown that normal, unstimulated lymphocytes produce a protein that inhibits normal bone marrow GM colony formation. Adiponectin is an adipokine that has been demonstrated to act as a negative regulator of hematopoiesis and immune function. This study aimed to determine if the inhibitory molecule that we described previously was adiponectin. Here, we show transcription, translation, and secretion of adiponectin from lymphocytes and demonstrate that its receptors, AdipoR1 and AdipoR2, are expressed by bone marrow MNCs. We show that although the adiponectin expression is low in lymphocytes, it is sufficient to induce a significant inhibitory effect on GM precursors (CFU-GM) and activate the AMPK pathway in these cells. The regulation of adiponectin production by lymphocytes and its detailed function in suppressing GM colony formation need to be elucidated now. Our findings suggest a functional role for adiponectin as a negative regulator of granulopoiesis. J. Leukoc. Biol. 88: 807-811; 2010.

Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells

Chronic myeloid leukemia (CML) is treated effectively with tyrosine kinase inhibitors (TKIs); however, 2 key problems remain-the insensitivity of CML stem and progenitor cells to TKIs and the emergence of TKI-resistant BCR-ABL mutations. BCR-ABL activity is associated with increased proteasome activity and proteasome inhibitors (PIs) are cytotoxic against CML cell lines. We demonstrate that bortezomib is antiproliferative and induces apoptosis in chronic phase (CP) CD34(+) CML cells at clinically achievable concentrations. We also show that bortezomib targets primitive CML cells, with effects on CD34(+)38(-), long-term culture-initiating (LTC-IC) and nonobese diabetic/severe combined immunodeficient (NOD/SCID) repopulating cells. Bortezomib is not selective for CML cells and induces apoptosis in normal CD34(+)38(-) cells. The effects against CML cells are seen when bortezomib is used alone and in combination with dasatinib. Bortezomib causes proteasome but not BCR-ABL inhibition and is also effective in inhibiting proteasome activity and inducing apoptosis in cell lines expressing BCR-ABL mutations, including T315I. By targeting both TKI-insensitive stem and progenitor cells and TKI-resistant BCR-ABL mutations, we believe that bortezomib offers a potential therapeutic option in CML. Because of known toxicities, including myelosuppression, the likely initial clinical application of bortezomib in CML would be in resistant and advanced disease. (Blood. 2010;115:2241-2250)