Search

Simple Summary: This study aimed to estimate genetic parameters for serum insulin-like growth factor I concentrations and their correlations with performance traits in beef cattle. A divergent selection experiment for this important hormone began in 1989. From the 2009 through to the 2017 breeding season, the selection criterion in the two lines was changed to high vs. low maintenance energy expected progeny differences. Estimates of direct heritability were moderate, ranging from 0.34 ± 0.07 to 0.46 ± 0.07 for insulin-like growth factor I concentrations and from 0.32 ± 0.05 to 0.39 ± 0.07 for the growth traits. The heritability of maternal genetic effects for insulin-like growth factor I concentration ranged from 0.02 ± 0.11 to 0.17 ± 0.05 and was similarly low for the weight traits. Maternal permanent environmental effects were negligible for insulin-like growth factor I but were somewhat larger for the weight traits. Direct maternal correlations for postweaning insulin-like growth factor I concentrations were approximately −0.90. The genetic correlations of insulin-like growth factor I with weight traits were generally positive but small. Environmental and phenotypic correlations between insulin-like growth factor I concentrations and growth traits were generally low, indicating that shared environmental influences are minimal, and that this hormone has a modest impact on growth traits. These findings suggest that while IGF-I concentration has some influence, it is not the primary determinant of weight gain or hip height. This study investigated the genetic parameters for serum IGF-I concentrations and growth traits in beef cattle. A divergent selection experiment for serum IGF-I concentration was initiated in 1989. One hundred spring-calving (50 high line and 50 low line) and 100 fall-calving (50 high line and 50 low line) black Angus cows with unknown IGF-I concentrations were randomly assigned to the two divergent selection lines. For the 2009 through 2017 breeding seasons, the selection criterion in the two lines was changed from serum IGF-I concentration to high vs. low maintenance energy expected progeny differences (ME EPDs). The number of records available for analysis varied from 2056 for IGF-I concentration on day 42 of the postweaning performance test to 2988 for birth weight, with the exception that only 617 records were available for IGF-I concentration at weaning. (Co)variance components were estimated for direct and maternal additive genetic effects using an animal model and multiple-trait, derivative-free, restricted maximum likelihood (MTDFREML) computer programs. Direct heritability estimates for serum IGF-I concentrations ranged from 0.34 ± 0.07 to 0.46 ± 0.07, whereas direct heritability estimates for weight traits ranged from 0.32 ± 0.05 to 0.39 ± 0.07. Maternal genetic effects on IGF-I were low, with estimates ranging from 0.02 ± 0.11 to 0.17 ± 0.05, and were similarly low for weight traits. Maternal permanent environmental effects were negligible for IGF-I but were larger for weight traits, especially for weaning weight (0.22 ± 0.04). Direct maternal correlations for postweaning IGF-I concentrations were approximately −0.90. The genetic correlations of IGF-I with weight traits were generally low, with negative correlations observed for birth weight and small positive correlations for the other weight traits. Environmental and phenotypic correlations between IGF-I concentrations and growth traits were generally small, indicating circulating IGF-I has a modest impact on growth traits in beef cattle. [ABSTRACT FROM AUTHOR]

On March 1 and 2, 2018, the National Institutes of Health 2018 Progenitor Cell Translational Consortium, Cardiovascular Bioengineering Symposium, was held at the University of Alabama at Birmingham. Convergence of life sciences and engineering to advance the understanding and treatment of heart failure was the theme of the meeting. Over 150 attendees were present, and >40 scientists presented their latest work on engineering human functional myocardium for disease modeling, drug development, and heart failure research. The scientists, engineers, and physicians in the field of cardiovascular sciences met and discussed the most recent advances in their work and proposed future strategies for overcoming the major roadblocks of cardiovascular bioengineering and therapy. Particular emphasis was given for manipulation and using of stem/progenitor cells, biomaterials, and methods to provide molecular, chemical, and mechanical cues to cells to influence their identity and fate in vitro and in vivo. Collectively, these works are profoundly impacting and progressing toward deciphering the mechanisms and developing novel treatments for left ventricular dysfunction of failing hearts. Here, we present some important perspectives that emerged from this meeting.

Cardiomyocyte ploidy has been described but remains obscure in cardiac interstitial cells. Ploidy of c-kit+ cardiac interstitial cells was assessed using confocal, karyotypic, and flow cytometric technique. Notable differences were found between rodent (rat, mouse) c-kit+ cardiac interstitial cells possessing mononuclear tetraploid (4n) content, compared to large mammals (human, swine) with mononuclear diploid (2n) content. In-situ analysis, confirmed with fresh isolates, revealed diploid content in human c-kit+ cardiac interstitial cells and a mixture of diploid and tetraploid content in mouse. Downregulation of the p53 signaling pathway provides evidence why rodent, but not human, c-kit+ cardiac interstitial cells escape replicative senescence. Single cell transcriptional profiling reveals distinctions between diploid versus tetraploid populations in mouse c-kit+ cardiac interstitial cells, alluding to functional divergences. Collectively, these data reveal notable species-specific biological differences in c-kit+ cardiac interstitial cells, which could account for challenges in extrapolation of myocardial from preclinical studies to clinical trials.

Notch signaling, an important signaling pathway in cardiac development, has been shown to mediate the reparative functions of c-kit+ progenitor cells (CPCs). However, it is unclear how each of the four canonical Notch-activating ligands affects intracellular processes in c-kit+ cells when used as an external stimulus. Neonatal c-kit+ CPCs were stimulated using four different chimeric Notch-activating ligands tethered to Dynabeads, and the resulting changes were assessed using TaqMan gene expression arrays, with subsequent analysis by principal component analysis (PCA). Additionally, functional outcomes were measured using an endothelial cell tube formation assay and MSC migration assay to assess the paracrine capacity to stimulate new vessel formation and recruit other reparative cell types to the site of injury. Gene expression data showed that stimulation with Jagged-1 is associated with the greatest pro-angiogenic gene response, including the expression of VEGF and basement membrane proteins, while the other canonical ligands, Jagged-2, Dll-1, and Dll-4, are more associated with regulatory and epigenetic changes. The functional assay showed differential responses to the four ligands in terms of angiogenesis, while none of the ligands produced a robust change in migration. These data demonstrate how the four Notch-activating ligands differentially regulate CPC gene expression and function. [ABSTRACT FROM AUTHOR]

Cardiac progenitor cells (CPCs) have rapidly advanced to clinical trials, yet little is known regarding their interaction with the microenvironment. Signaling cues present in the microenvironment change with development and disease. This work aims to assess the influence of two distinct signaling moieties on CPCs: cyclic biaxial strain and extracellular matrix. We evaluate four endpoints for improving CPC therapy: paracrine signaling, proliferation, connexin43 expression, and alignment. Vascular endothelial growth factor A (about 900 pg/mL) was secreted by CPCs cultured on fibronectin and collagen I. The application of mechanical strain increased vascular endothelial growth factor A secretion 2-4-fold for CPCs cultured on poly-L-lysine, laminin, or a naturally derived cardiac extracellular matrix. CPC proliferation was at least 25% higher on fibronectin than that on other matrices, especially for lower strain magnitudes. At 5% strain, connexin43 expression was highest on fibronectin. With increasing strain magnitude, connexin43 expression decreased by as much as 60% in CPCs cultured on collagen I and a naturally derived cardiac extracellular matrix. Cyclic mechanical strain induced the strongest CPC alignment when cultured on fibronectin or collagen I. This study demonstrates that culturing CPCs on fibronectin with 5% strain magnitude is optimal for their vascular endothelial growth factor A secretion, proliferation, connexin43 expression, and alignment.

AimsTo evaluate the ability of N-acetylglucosamine (GlcNAc) decorated nanoparticles and their cargo to modulate calcium handling in failing cardiac myocytes (CMs).Materials & methodsPrimary CMs isolated from normal and failing hearts were treated with GlcNAc nanoparticles in order to assess the ability of the nanoparticles and their cargo to correct dysfunctional calcium handling in failing myocytes.Results & conclusionGlcNAc particles reduced aberrant calcium release in failing CMs and restored sarcomere function. Additionally, encapsulation of a small calcium-modulating protein, S100A1, in GlcNAc nanoparticles also showed improved calcium regulation. Thus, the development of our bioactive nanoparticle allows for a 'two-hit' treatment, by which the cargo and also the nanoparticle itself can modulate intracellular protein activity.

There is a great need for the development of therapeutic strategies that can target biomolecules to damaged myocardium. Necrosis of myocardium during a myocardial infarction (MI) is characterized by extracellular release of DNA, which can serve as a potential target for ischemic tissue. Hoechst, a histological stain that binds to double-stranded DNA can be conjugated to a variety of molecules. Insulin-like growth factor-1 (IGF-1), a small protein/polypeptide with a short circulating-half life is cardioprotective following MI but its clinical use is limited by poor delivery, as intra-myocardial injections have poor retention and chronic systemic presence has adverse side effects. Here, we present a novel delivery vehicle for IGF-1, via its conjugation to Hoechst for targeting infarcted tissue. Using a mouse model of ischemia-reperfusion, we demonstrate that intravenous delivery of Hoechst-IGF-1 results in activation of Akt, a downstream target of IGF-1 and protects from cardiac fibrosis and dysfunction following MI.

Cell therapies involving c‐kit+ progenitor cells (CPCs) and mesenchymal stem cells (MSCs) have been actively studied for cardiac repair. The benefits of such therapies have more recently been attributed to the release of small extracellular vesicles (sEVs) from the parent cells. These sEVs are 30−180 nm vesicles containing protein/nucleic acid cargo encapsulated within an amphiphilic bilayer membrane. Despite their pro‐reparative effects, sEV composition and cargo loading is highly variable, making it challenging to develop robust therapies with sEVs. Synthetic alternatives have been developed to allow cargo modulation, including prior work from the laboratory, to design sEV‐like vehicles (ELVs). ELVs are synthesized from the sEV membrane but allow controlled cargo loading. It is previously shown that loading pro‐angiogenic miR‐126 into CPC‐derived ELVs significantly increases endothelial cell angiogenesis compared to CPC‐sEVs alone. Here, they expand on this work to design MSC‐derived ELVs and study the role of the parent cell type on ELV composition and function. It is found that ELV origin does affect the ELV potency and that ELV membrane composition can affect outcomes. This study showcases the versatility of ELVs to be synthesized from different parent cells and highlights the importance of selecting ELV source cells based on the desired functional outcomes. [ABSTRACT FROM AUTHOR]