Advances in 3D Organoid Models for Stem Cell-Based Cardiac Regeneration

The adult human heart cannot regain complete cardiac function following tissue injury, making cardiac regeneration a current clinical unmet need. There are a number of clinical procedures aimed at reducing ischemic damage following injury; however, it has not yet been possible to stimulate adult cardiomyocytes to recover and proliferate. The emergence of pluripotent stem cell technologies and 3D culture systems has revolutionized the field. Specifically, 3D culture systems have enhanced precision medicine through obtaining a more accurate human microenvironmental condition to model disease and/or drug interactions in vitro. In this study, we cover current advances and limitations in stem cell-based cardiac regenerative medicine. Specifically, we discuss the clinical implementation and limitations of stem cell-based technologies and ongoing clinical trials. We then address the advent of 3D culture systems to produce cardiac organoids that may better represent the human heart microenvironment for disease modeling and genetic screening. Finally, we delve into the insights gained from cardiac organoids in relation to cardiac regeneration and further discuss the implications for clinical translation

Human iPSCs and Genome Editing Technologies for Precision Cardiovascular Tissue Engineering

Induced pluripotent stem cells (iPSCs) originate from the reprogramming of adult somatic cells using four Yamanaka transcription factors. Since their discovery, the stem cell (SC) field achieved significant milestones and opened several gateways in the area of disease modeling, drug discovery, and regenerative medicine. In parallel, the emergence of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) revolutionized the field of genome engineering, allowing the generation of genetically modified cell lines and achieving a precise genome recombination or random insertions/deletions, usefully translated for wider applications. Cardiovascular diseases represent a constantly increasing societal concern, with limited understanding of the underlying cellular and molecular mechanisms. The ability of iPSCs to differentiate into multiple cell types combined with CRISPR-Cas9 technology could enable the systematic investigation of pathophysiological mechanisms or drug screening for potential therapeutics. Furthermore, these technologies can provide a cellular platform for cardiovascular tissue engineering (TE) approaches by modulating the expression or inhibition of targeted proteins, thereby creating the possibility to engineer new cell lines and/or fine-tune biomimetic scaffolds. This review will focus on the application of iPSCs, CRISPR-Cas9, and a combination thereof to the field of cardiovascular TE. In particular, the clinical translatability of such technologies will be discussed ranging from disease modeling to drug screening and TE applications

Combining Cell Technologies With Biomimetic Tissue Engineering Applications: A New Paradigm for Translational Cardiovascular Therapies

Cardiovascular disease is a major cause of morbidity and mortality worldwide and, to date, the clinically available prostheses still present several limitations. The design of next-generation regenerative replacements either based on cellular or extracellular matrix technologies can address these shortcomings. Therefore, tissue engineered constructs could potentially become a promising alterative to the current therapeutic options for patients with cardiovascular diseases. In this review, we selectively present an overview of the current tissue engineering tools such as induced pluripotent stem cells, biomimetic materials, computational modeling, and additive manufacturing technologies, with a focus on their application to translational cardiovascular therapies. We discuss how these advanced technologies can help the development of biomimetic tissue engineered constructs and we finally summarize the latest clinical evidence for their use, and their potential therapeutic outcome

The homotopy theory of simplicial props

The category of (colored) props is an enhancement of the category of colored operads, and thus of the category of small categories. In this paper, the second in a series on "higher props," we show that the category of all small colored simplicial props admits a cofibrantly generated model category structure. With this model structure, the forgetful functor from props to operads is a right Quillen functor.Comment: Final version, to appear in Israel J. Mat

As-yet-uncultivated oral bacteria: breadth and association with oral and extra-oral diseases

It has been shown that 40–60% of the bacteria found in different healthy and diseased oral sites still remain to be grown in vitro, phenotypically characterized, and formally named as species. The possibility exists that these as-yet-uncultivated bacteria play important ecological roles in oral bacterial communities and may participate in the pathogenesis of several oral infectious diseases. There is also a potential for these as-yet-uncultivated oral bacteria to take part in extra-oral infections. For a comprehensive characterization of physiological and pathogenic properties as well as antimicrobial susceptibility of individual bacterial species, strains need to be grown in pure culture. Advances in culturing techniques have allowed the cultivation of several oral bacterial taxa only previously known by a 16S rRNA gene sequence signature, and novel species have been proposed. There is a growing need for developing improved methods to cultivate and characterize the as-yet-uncultivated portion of the oral microbiome so as to unravel its role in health and disease

Nanoliter Reactors Improve Multiple Displacement Amplification of Genomes from Single Cells

Since only a small fraction of environmental bacteria are amenable to laboratory culture, there is great interest in genomic sequencing directly from single cells. Sufficient DNA for sequencing can be obtained from one cell by the Multiple Displacement Amplification (MDA) method, thereby eliminating the need to develop culture methods. Here we used a microfluidic device to isolate individual Escherichia coli and amplify genomic DNA by MDA in 60-nl reactions. Our results confirm a report that reduced MDA reaction volume lowers nonspecific synthesis that can result from contaminant DNA templates and unfavourable interaction between primers. The quality of the genome amplification was assessed by qPCR and compared favourably to single-cell amplifications performed in standard 50-μl volumes. Amplification bias was greatly reduced in nanoliter volumes, thereby providing a more even representation of all sequences. Single-cell amplicons from both microliter and nanoliter volumes provided high-quality sequence data by high-throughput pyrosequencing, thereby demonstrating a straightforward route to sequencing genomes from single cells

Gravitational Microlensing Evidence for a Planet Orbiting a Binary Star System

The study of extra-solar planetary systems has emerged as a new discipline of observational astronomy in the past few years with the discovery of a number of extra-solar planets. The properties of most of these extra-solar planets were not anticipated by theoretical work on the formation of planetary systems. Here we report observations and light curve modeling of gravitational microlensing event MACHO-97-BLG-41, which indicates that the lens system consists of a planet orbiting a binary star system. According to this model, the mass ratio of the binary star system is 3.8:1 and the stars are most likely to be a late K dwarf and an M dwarf with a separation of about 1.8 AU. A planet of about 3 Jupiter masses orbits this system at a distance of about 7 AU. If our interpretation of this light curve is correct, it represents the first discovery of a planet orbiting a binary star system and the first detection of a Jovian planet via the gravitational microlensing technique. It suggests that giant planets may be common in short period binary star systems.Comment: 11 pages, with 1 color and 2 b/w Figures included (published version

New Debris Disks Around Nearby Main Sequence Stars: Impact on The Direct Detection of Planets

Using the MIPS instrument on the Spitzer telescope, we have searched for infrared excesses around a sample of 82 stars, mostly F, G, and K main-sequence field stars, along with a small number of nearby M stars. These stars were selected for their suitability for future observations by a variety of planet-finding techniques. These observations provide information on the asteroidal and cometary material orbiting these stars - data that can be correlated with any planets that may eventually be found. We have found significant excess 70um emission toward 12 stars. Combined with an earlier study, we find an overall 70um excess detection rate of $13 \pm 3$% for mature cool stars. Unlike the trend for planets to be found preferentially toward stars with high metallicity, the incidence of debris disks is uncorrelated with metallicity. By newly identifying 4 of these stars as having weak 24um excesses (fluxes $\sim$10% above the stellar photosphere), we confirm a trend found in earlier studies wherein a weak 24um excess is associated with a strong 70um excess. Interestingly, we find no evidence for debris disks around 23 stars cooler than K1, a result that is bolstered by a lack of excess around any of the 38 K1-M6 stars in 2 companion surveys. One motivation for this study is the fact that strong zodiacal emission can make it hard or impossible to detect planets directly with future observatories like the {\it Terrestrial Planet Finder (TPF)}. The observations reported here exclude a few stars with very high levels of emission, $>$1,000 times the emission of our zodiacal cloud, from direct planet searches. For the remainder of the sample, we set relatively high limits on dust emission from asteroid belt counterparts

PTF11kx: A Type-Ia Supernova with a Symbiotic Nova Progenitor

There is a consensus that Type-Ia supernovae (SNe Ia) arise from the thermonuclear explosion of white dwarf stars that accrete matter from a binary companion. However, direct observation of SN Ia progenitors is lacking, and the precise nature of the binary companion remains uncertain. A temporal series of high-resolution optical spectra of the SN Ia PTF 11kx reveals a complex circumstellar environment that provides an unprecedentedly detailed view of the progenitor system. Multiple shells of circumsteller are detected and the SN ejecta are seen to interact with circumstellar material (CSM) starting 59 days after the explosion. These features are best described by a symbiotic nova progenitor, similar to RS Ophiuchi.Comment: 27 pages, 5 figures. In pres