Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy

It is generally believed that increase in adult contractile cardiac mass can be accomplished only by hypertrophy of existing myocytes. Documentation of myocardial regeneration in acute stress has challenged this dogma and led to the proposition that myocyte renewal is fundamental to cardiac homeostasis. Here we report that in human aortic stenosis, increased cardiac mass results from a combination of myocyte hypertrophy and hyperplasia. Intense new myocyte formation results from the differentiation of stem-like cells committed to the myocyte lineage. These cells express stem cell markers and telomerase. Their number increased >13-fold in aortic stenosis. The finding of cell clusters with stem cells making the transition to cardiogenic and myocyte precursors, as well as very primitive myocytes that turn into terminally differentiated myocytes, provides a link between cardiac stem cells and myocyte differentiation. Growth and differentiation of these primitive cells was markedly enhanced in hypertrophy, consistent with activation of a restricted number of stem cells that, through symmetrical cell division, generate asynchronously differentiating progeny. These clusters strongly support the existence of cardiac stem cells that amplify and commit to the myocyte lineage in response to increased workload. Their presence is consistent with the notion that myocyte hyperplasia significantly contributes to cardiac hypertrophy and accounts for the subpopulation of cycling myocytes

Cardiac adaptations from 4 weeks of intensity-controlled vigorous exercise are lost after a similar period of detraining

Intensity‐controlled (relative to VO2max) treadmill exercise training in adult rats results in the activation and ensuing differentiation of endogenous c‐kitpos cardiac stem/progenitor cells (eCSCs) into newly formed cardiomyocytes and capillaries. Whether these training‐induced adaptations persist following detraining is undetermined. Twelve male Wistar rats (~230 g) were exercised at 80–85% of their VO2max for 30 min day−1, 4 days week−1 for 4 weeks (TR; n = 6), followed by 4 weeks of detraining (DTR; n = 6). Twelve untrained rats acted as controls (CTRL). Exercise training significantly enhanced VO2max (11.34 mL kg−1 min−1) and wet heart weight (29%) above CTRL (P < 0.05). Echocardiography revealed that exercise training increased LV mass (~32%), posterior and septal wall thickness (~15%), ejection fraction and fractional shortening (~10%) compared to CTRL (P < 0.05). Cardiomyocyte diameter (17.9 ± 0.1 μm vs. 14.9 ± 0.6 μm), newly formed (BrdUpos/Ki67pos) cardiomyocytes (7.2 ± 1.3%/1.9 ± 0.7% vs. 0.2 ± 0.1%/0.1 ± 0.1%), total cardiomyocyte number (45.6 ± 0.6 × 106 vs. 42.5 ± 0.4 × 106), c‐kitpos eCSC number (884 ± 112 per 106 cardiomyocytes vs. 482 ± 132 per 106 cardiomyocytes), and capillary density (4123 ± 227 per mm2 vs. 2117 ± 118 per mm2) were significantly greater in the LV of trained animals (P < 0.05) than CTRL. Detraining removed the stimulus for c‐kitpos eCSC activation (640 ± 98 per 106 cardiomyocytes) and resultant cardiomyocyte hyperplasia (0.4 ± 0.3% BrdUpos/0.2 ± 0.2% Ki67pos cardiomyocytes). Capillary density (3673 ± 374 per mm2) and total myocyte number (44.7 ± 0.5 × 106) remained elevated following detraining, but cardiomyocyte hypertrophy (15.0 ± 0.4 μm) was lost, resulting in a reduction of anatomical (wall thickness ~4%; LV mass ~10% and cardiac mass ~8%, above CTRL) and functional (EF & FS ~2% above CTRL) parameters gained through exercise training. These findings demonstrate that cardiac adaptations, produced by 4 weeks of intensity‐controlled exercise training are lost after a similar period of detraining

Large Eddy simulations of isolated and installed jet noise using the high-order discontinuous Galerkin method

A recently developed computational framework for jet noise is used to compute the noise generated by an isolated and installed jet. The framework consists of two parts. In the first part, the spectral/hp element framework Nektar++ is used to compute the near-field flow. Nektar++ solves the unfiltered Navier-Stokes equations on unstructured grids using the high-order discontinuous Galerkin method. The discrete equations are integrated in time using an implicit scheme based on the matrix-free Newton-GMRES method. In the second part, the Antares library is used to compute the far-field noise. Antares solves the Ffowcs Williams - Hawkings equation for a permeable integration surface in the time domain using a source-time dominant algorithm. The simulations are validated against experimental data obtained in the Doak Laboratory Flight Jet Rig, located at the University of Southampton. For the isolated jet, good agreement is achieved, both in terms of the flow statistics and the far-field noise. The discrepancies observed for the isolated jet are believed to be caused by an under-resolved boundary layer in the simulations. For the installed jet, the flow statistics are also well predicted. In the far-field, very good agreement is achieved for downstream observers. For upstream observers, some discrepancies are observed for very high and very low frequencies

The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation

Aims It is a dogma of cardiovascular pathophysiology that the increased cardiac mass in response to increased workload is produced by the hypertrophy of the pre-existing myocytes. The role, if any, of adult-resident endogenous cardiac stem/progenitor cells (eCSCs) and new cardiomyocyte formation in physiological cardiac remodelling remains unexplored. Methods and results In response to regular, intensity-controlled exercise training, adult rats respond with hypertrophy of the pre-existing myocytes. In addition, a significant number (∼7%) of smaller newly formed BrdU-positive cardiomyocytes are produced by the exercised animals. Capillary density significantly increased in exercised animals, balancing cardiomyogenesis with neo-angiogenesis. c-kitpos eCSCs increased their number and activated state in exercising vs. sedentary animals. c-kitpos eCSCs in exercised hearts showed an increased expression of transcription factors, indicative of their commitment to either the cardiomyocyte (Nkx2.5pos) or capillary (Ets-1pos) lineages. These adaptations were dependent on exercise duration and intensity. Insulin-like growth factor-1, transforming growth factor-β1, neuregulin-1, bone morphogenetic protein-10, and periostin were significantly up-regulated in cardiomyocytes of exercised vs. sedentary animals. These factors differentially stimulated c-kitpos eCSC proliferation and commitment in vitro, pointing to a similar role in vivo. Conclusion Intensity-controlled exercise training initiates myocardial remodelling through increased cardiomyocyte growth factor expression leading to cardiomyocyte hypertrophy and to activation and ensuing differentiation of c-kitpos eCSCs. This leads to the generation of new myocardial cells. These findings highlight the endogenous regenerative capacity of the adult heart, represented by the eCSCs, and the fact that the physiological cardiac adaptation to exercise stress is a combination of cardiomyocyte hypertrophy and hyperplasia (cardiomyocytes and capillaries)

Deuteration around the ultracompact HII region Mon R2

The massive star-forming region Mon R2 hosts the closest ultra-compact HII region that can be spatially resolved with current single-dish telescopes. We used the IRAM-30m telescope to carry out an unbiased spectral survey toward two important positions (namely IF and MP2), in order to studying the chemistry of deuterated molecules toward Mon R2. We found a rich chemistry of deuterated species at both positions, with detections of C2D, DCN, DNC, DCO+, D2CO, HDCO, NH2D, and N2D+ and their corresponding hydrogenated species and isotopologs. Our high spectral resolution observations allowed us to resolve three velocity components: the component at 10 km/s is detected at both positions and seems associated with the layer most exposed to the UV radiation from IRS 1; the component at 12 km/s is found toward the IF position and seems related to the molecular gas; finally, a component at 8.5 km/s is only detected toward the MP2 position, most likely related to a low-UV irradiated PDR. We derived the column density of all the species, and determined the deuterium fractions (Dfrac). The values of Dfrac are around 0.01 for all the observed species, except for HCO+ and N2H+ which have values 10 times lower. The values found in Mon R2 are well explained with pseudo-time-dependent gas-phase model in which deuteration occurs mainly via ion-molecule reactions with H2D+, CH2D+ and C2HD+. Finally, the [H13CN]/[HN13C] ratio is very high (~11) for the 10 km/s component, which also agree with our model predictions for an age of ~0.01-0.1 Myr. The deuterium chemistry is a good tool for studying star-forming regions. The low-mass star-forming regions seem well characterized with Dfrac(N2H+) or Dfrac(HCO+), but it is required a complete chemical modeling to date massive star-forming regions, because the higher gas temperature together with the rapid evolution of massive protostars.Comment: 14 pages of manuscript, 17 pages of apendix, 7 figures in the main text, accepted for publication in A&

Unraveling UBC 274: a morphological, kinematical and chemical analysis of a disrupting open cluster

We do a morphological, kinematic and chemical analysis of the disrupting cluster UBC 274 (2.5 Gyr, $d=1778$ pc) to study its global properties. We use HDBSCAN to obtain a new membership list up to 50 pc from its centre and up to magnitude $G=19$ using Gaia EDR3 data. We use high resolution and high signal-to-noise spectra to obtain atmospheric parameters of 6 giants and subgiants, and individual abundances of 18 chemical species. The cluster has a highly eccentric (0.93) component, tilted $\sim$10 deg with respect to the plane of the Galaxy, which is morphologically compatible with the result of a test-particle simulation of a disrupting cluster. Our abundance analysis shows that the cluster has a subsolar metallicity of [Fe/H]$=-0.08\pm0.02$. Its chemical pattern is compatible with that of Ruprecht 147, of similar age but located closer to the Sun, with the remarkable exception of neutron-capture elements, which present an overabundance of $[n\mathrm{/Fe]}\sim0.1$. The cluster's elongated morphology is associated with the internal part of its tidal tail, following the expected dynamical process of disruption. We find a significant sign of mass segregation where the most massive stars appear 1.5 times more concentrated than other stars. The cluster's overabundance of neutron-capture elements can be related to the metallicity dependence of the neutron-capture yields due to the secondary nature of these elements, predicted by some models. UBC 274 presents a high chemical homogeneity at the level of $0.03$ dex in the sampled region of its tidal tails.Comment: Accepted by A&

Aeroacoustic analysis of a closely installed chevron nozzle jet using the high-order discontinuous Galerkin method

In this paper, we use Large Eddy Simulations (LES) in combination with the Ffowcs Williams - Hawkings method to study the influence of chevrons on the flow field as well as the noise produced by a closely installed M = 0.6 jet. The LES simulations are performed with the spectral/hp element framework Nektar++. Nektar++ uses the high-order discontinuous Galerkin method and an implicit scheme based on the matrix-free Newton-GMRES method to discretize the unfiltered Navier-Stokes equations in space and time, respectively. The far-field noise is computed using Antares. Antares solves the Ffowcs Williams - Hawkings equation for a permeable integration surface in the time-domain using a source-time dominant algorithm. The aerodynamic results show good agreement with experimental data obtained in the Doak Laboratory Flight Jet Rig, located at the University of Southampton. Some discrepancies are observed in terms of the far-field noise levels, especially for higher polar observer angles relative to the downstream jet axis. In terms of noise reduction potential, the simulations predict that the chevrons reduce the OASPL by 1dB compared to an installed round nozzle for all observers located on the unshielded side of the wing. This should be compared to the experiments, which predict a 1.5dB noise reduction for the same chevron nozzle

Massive young disks around Herbig Ae stars

Herbig Ae stars (HAe) are the precursors of Vega-type systems and, therefore, crucial objects in planet formation studies. Thus far, only a few disks associated with HAe stars have been studied using millimetre interferometers. Our aim is to determine the dust evolution and the lifetime of the disks associated with Herbig Ae stars. We imaged the continuum emission at 3 mm and 1.3 mm of the Herbig Ae/Be stars BD+61154, RR Tau, VY Mon and LkHa 198 using the Plateau de Bure Interferometer (PdBI). These stars are in the upper end of the stellar mass range of the Herbig Ae stars (stellar mass greater than 3 solar masses). Our measurements were used to complete the Spectral Energy Distribution (SED). The modelling of the SED, in particular the FIR-mm part, allow us to determine the masses and dust properties of these disks. We detected the disks associated with BD+61154, RR Tau and VY Mon with disk masses of 0.35 Msun, 0.05 Msun and 0.40 Msun respectively. The disk around LkHa 198 was not detected with an upper limit to the disk mass of 0.004 Msun. We detected, however, the disks associated with the younger stellar objects LkHa 198--IR and LkHa 198-mm that are located in the vicinity of LkHa 198. The fitting of the mm part of the SED reveal that the grains in the mid-plane of the disks around BD+61154, RR Tau and VY Mon have sizes of 1--1000 microns. Therefore, grains have not grown to centimetre sizes in these disks yet. These massive (M>3 Msun) and young (about 1 Myr) HAe stars are surrounded by massive (>0.04 Msun) disks with grains of micron-millimetre sizes. Although grain growth is proceeding in these disks, their evolutionary stage is prior to the formation of planetesimals. These disks are less evolved than those detected around T Tauri and Herbig Be stars

Adult cardiac stem cells are multipotent and robustly myogenic: c-kit expression is necessary but not sufficient for their identification

Multipotent adult resident cardiac stem cells (CSCs) were first identified by the expression of c-kit, the stem cell factor receptor. However, in the adult myocardium c-kit alone cannot distinguish CSCs from other c-kit-expressing (c-kitpos) cells. The adult heart indeed contains a heterogeneous mixture of c-kitpos cells, mainly composed of mast and endothelial/progenitor cells. This heterogeneity of cardiac c-kitpos cells has generated confusion and controversy about the existence and role of CSCs in the adult heart. Here, to unravel CSC identity within the heterogeneous c-kit-expressing cardiac cell population, c-kitpos cardiac cells were separated through CD45-positive or -negative sorting followed by c-kitpos sorting. The blood/endothelial lineage-committed (Lineagepos) CD45posc-kitpos cardiac cells were compared to CD45neg(Lineageneg/Linneg) c-kitpos cardiac cells for stemness and myogenic properties in vitro and in vivo. The majority (~90%) of the resident c-kitpos cardiac cells are blood/endothelial lineage-committed CD45posCD31posc-kitpos cells. In contrast, the LinnegCD45negc-kitpos cardiac cell cohort, which represents 10% of the total c-kitpos cells, contain all the cardiac cells with the properties of adult multipotent CSCs. These characteristics are absent from the c-kitneg and the blood/endothelial lineage-committed c-kitpos cardiac cells. Single Linnegc-kitpos cell-derived clones, which represent only 1–2% of total c-kitpos myocardial cells, when stimulated with TGF-β/Wnt molecules, acquire full transcriptome and protein expression, sarcomere organisation, spontaneous contraction and electrophysiological properties of differentiated cardiomyocytes (CMs). Genetically tagged cloned progeny of one Linnegc-kitpos cell when injected into the infarcted myocardium, results in significant regeneration of new CMs, arterioles and capillaries, derived from the injected cells. The CSC’s myogenic regenerative capacity is dependent on commitment to the CM lineage through activation of the SMAD2 pathway. Such regeneration was not apparent when blood/endothelial lineage-committed c-kitpos cardiac cells were injected. Thus, among the cardiac c-kitpos cell cohort only a very small fraction has the phenotype and the differentiation/regenerative potential characteristics of true multipotent CSCs