Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity

A crucial factor in improving cellular therapy effectiveness for myocardial regeneration is to safely and efficiently increase the cell engraftment rate. ...

Establishment of a Murine Pulp Exposure Model with a Novel Mouth-Gag for Pulpitis Research

Pulpitis, a common cause of natural tooth loss, leads to necrosis and loss of bioactivity in the inflamed dental pulp. Unraveling the mechanisms ...

University of Alabama at Birmingham

Sichuan University

Exercise has been shown to be the best intervention in the treatment of many diseases. Many of the benefits of exercise are mediated by adaptions induced in skeletal muscle. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators has emerged as being key mediators of the exercise response and is considered to be essential for many of the adaptions seen in skeletal muscle. However, the contribution of the PGC-1s in skeletal muscle has been evaluated by the use of either whole body or congenital skeletal muscle-specific deletion. In these models, PGC-1s were never present, thereby opening the possibility to developmental compensation. Therefore, we generated an inducible muscle-specific deletion of PGC-1α and -1β (iMyo-PGC-1DKO), in which both PGC-1α and -β can be deleted specifically in adult skeletal muscle. These iMyo-PGC-1DKO animals were used to assess the role of both PGC-1α and -1β in adult skeletal muscle and their contribution to the exercise training response. Untrained iMyo-PGC-1DKO animals exhibited a time-dependent decrease in exercise performance 8 wk postdeletion, similar to what was observed in the congenital muscle-specific PGC-1DKOs. However, after 4 wk of voluntary training, the iMyo-PGC-1DKOs exhibited an increase in exercise performance with a similar adaptive response compared with control animals. This increase was associated with an increase in electron transport complex (ETC) expression and activity in the absence of PGC-1α and -1β expression. Taken together these data suggest that PGC-1α and -1β expression are not required for training-induced exercise performance, highlighting the contribution of PGC-1-independent mechanisms.

Adult expression of PGC-1α and -1β in skeletal muscle is not required for endurance exercise-induced enhancement of exercise capacity.

The broadly expressed transcriptional coregulator LDB1 is essential for β-cell development and glucose homeostasis. However, it is unclear whether LDB1 has metabolic roles beyond the β-cell, especially under metabolic stress. Global Ldb1 deletion results in early embryonic lethality; thus, we used global heterozygous Ldb1+/- and inducible β-cell-specific Ldb1-deficient (Ldb1Δβ-cell) mice. We assessed glucose and insulin tolerance, body composition, feeding, and energy expenditure during high-fat diet exposure. Brown adipose tissue (BAT) biology was evaluated by thermogenic gene expression and LDB1 chromatin immunoprecipitation analysis. We found that partial loss of Ldb1 does not impair the maintenance of glucose homeostasis; rather, we observed improved insulin sensitivity in these mice. Partial loss of Ldb1 also uncovered defects in energy expenditure in lean and diet-induced obese (DIO) mice. This decreased energy expenditure during DIO was associated with significantly altered BAT gene expression, specifically Cidea, Elovl3, Cox7a1, and Dio2. Remarkably, the observed changes in energy balance during DIO were absent in Ldb1Δβ-cell mice, despite a similar reduction in plasma insulin, suggesting a role for LDB1 in BAT. Indeed, LDB1 is expressed in brown adipocytes and occupies a regulatory domain of Elovl3, a gene crucial to normal BAT function. We conclude that LDB1 regulates energy homeostasis, in part through transcriptional modulation of critical regulators in BAT function.

LDB1 Regulates Energy Homeostasis During Diet-Induced Obesity.

Cardiovascular physiology exhibits time-of-day-dependent oscillations, which are mediated by both extrinsic (e.g., environment/behavior) and intrinsic (e.g., circadian clock) factors. Disruption of circadian rhythms negatively affects multiple cardiometabolic parameters. Recent studies suggest that the cardiomyocyte circadian clock directly modulates responsiveness of the heart to metabolic stimuli (e.g., fatty acids) and stresses (e.g., ischemia/reperfusion). The aim of this study was to determine whether genetic disruption of the cardiomyocyte circadian clock impacts insulin-regulated pathways in the heart. Genetic disruption of the circadian clock in cardiomyocyte-specific Bmal1 knockout (CBK) and cardiomyocyte-specific Clock mutant (CCM) mice altered expression (gene and protein) of multiple insulin signaling components in the heart, including p85α and Akt. Both baseline and insulin-mediated Akt activation was augmented in CBK and CCM hearts (relative to littermate controls). However, insulin-mediated glucose utilization (both oxidative and non-oxidative) and AS160 phosphorylation were attenuated in CBK hearts, potentially secondary to decreased Inhibitor-1. Consistent with increased Akt activation in CBK hearts, mTOR signaling was persistently increased, which was associated with attenuation of autophagy, augmented rates of protein synthesis, and hypertrophy. Importantly, pharmacological inhibition of mTOR (rapamycin; 10days) normalized cardiac size in CBK mice. These data suggest that disruption of cardiomyocyte circadian clock differentially influences insulin-regulated processes, and provide new insights into potential pathologic mediators following circadian disruption.

Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart.

Rodent hearts can regenerate myocardium lost to apical resection or myocardial infarction for up to 7 days after birth, but whether a similar window for myocardial regeneration also exists in large mammals is unknown.

Regenerative Potential of Neonatal Porcine Hearts.

The effectiveness of cell-based treatments for regenerative myocardial therapy is limited by low rates of cell engraftment. Y-27632 inhibits Rho-associated protein kinase (ROCK), which regulates the cytoskeletal changes associated with cell adhesion, and has been used to protect cultured cells during their passaging. Here, we investigated whether preconditioning of cardiomyocytes, derived from human-induced pluripotent stem cells (hiPSC-CM), with Y-27632 improves their survival and engraftment in a murine model of acute myocardial infarction (MI).

Y-27632 preconditioning enhances transplantation of human-induced pluripotent stem cell-derived cardiomyocytes in myocardial infarction mice.

The adoptive transfer of human T cells or genetically-engineered T cells with cancer-targeting receptors has shown tremendous promise for eradicating tumors in clinical trials. The objective of this study was to develop a novel T cell biomanufacturing platform using stirred-tank bioreactor for large-scale and high-quality cellular production. First, various factors, such as bioreactor parameters, media, supplements, stimulation, seed age, and donors, were investigated. A serum-free fed-batch bioproduction process was developed to achieve 1000-fold expansion within 8 days after first stimulation and another 500-fold expansion with second stimulation. Second, this biomanufacturing process was successfully scaled up in bioreactor with dilution factor of 10, and the robustness and reproducibility of the process was confirmed by the inclusion of different donors' T cells of various qualities. Finally, T cell quality was monitored using 12 surface markers and 3 intracellular cytokines as the critical quality assessment criteria in early, middle and late stages of cell production. In this study, a new biomanufacturing platform was created to produce reliable, reproducible, high-quality, and large-quantity (i.e. > 5 billion) human T cells in stirred-tank bioreactor. This platform is compatible with the production systems of monoclonal antibodies, vaccines, and other therapeutic cells, which provides not only the proof-of-concept but also the ready-to-use new approach of T cell expansion for clinical immune therapy.

Novel biomanufacturing platform for large-scale and high-quality human T cells production.

A universal sacrificial template-based synthesis strategy was reported to prepare three dimensional (3D) reduced oxide graphene supported PtM (M=Fe, Co, Ni) hollow nanospheres (PtM/RGO HNSs). The inner 3D wrinkle-free graphene skeleton can promote electron and ion kinetics, resulting in enhancement for the permeation of small organic molecule in fuel cells. As inspired by this, the 3D PtM (M=Fe, Co, Ni)/RGO HNSs exhibit clearly enhanced electrocatalytic activity and durability towards the methanol oxidation reaction (MOR) in acidic medium compared with a commercial Pt/C catalyst. This study provides a versatile approach of realizing controlled synthesis of 3D graphene-metal hybrid nanostructures irrespective of the components of the metal domains, and will pave the way for the design of hetero-nanostructures with optimized morphologies and functions.

A General Strategy for the Synthesis of PtM (M=Fe, Co, Ni) Decorated Three-Dimensional Hollow Graphene Nanospheres for Efficient Methanol Electrooxidation.

The development of high-efficiency electrocatalysts with low costs for the oxygen evolution reaction (OER) is essential, but remains challenging. Herein, a new synthetic process is proposed to prepare Ni S particles embedded in N,P-codoped honeycomb porous carbon aerogels (Ni S /N,P-HPC) through a hydrogel approach. The preparation of Ni S /N,P-HPC begins with the sol-gel polymerization of tripolyphosphate, chitosan, and guanidine polymer that contains metal-binding sites, allowing for the uniform incorporation of Ni ions into the gel matrix, freeze-drying, and subsequent carbonization under an inert atmosphere. This synthesis resolves difficulties in synthesizing the pure Ni S phase caused by the instability of Ni S at high temperature, while affording good control of the porous structure and N,P-doping of carbon aerogels. The synergy between the structural advantages of N,P-carbon aerogels (such as easily accessible active sites, high specific surface area, and excellent electron transport) and the intrinsic electrochemical properties of Ni S result in the outstanding OER performance of Ni S /N,P-HPC, with overpotentials as low as 0.37 V at 10 mA cm . The work outlined herein offers a simple and effective method for the development of carbon-based electrocatalysts for renewable energy conversion.

Hydrogel-Derived Honeycomb Ni S /N,P-C as an Efficient Oxygen Evolution Catalyst.

Atomically ordered RhP nanoclusters encapsulated within a high-surface-area hollow mesoporous carbon nanoreactor are catalytically active for hydrogen production  the electrocatalytic hydrogen evolution reaction and the room-temperature dehydrogenation of ammonia borane.

Yawen Tang

Department of Biomedical Engineering,
School of Medicine,
School of Engineering,
Department of Biomedical Engineering, School of Medicine, School of Engineering

University of Alabama at Birmingham

Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity

Establishment of a Murine Pulp Exposure Model with a Novel Mouth-Gag for Pulpitis Research

Yawen Tang

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Biomedical Engineering,School of Medicine,School of Engineering,Department of Biomedical Engineering, School of Medicine, School of Engineering

University of Alabama at Birmingham

Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity

Establishment of a Murine Pulp Exposure Model with a Novel Mouth-Gag for Pulpitis Research

Department of Biomedical Engineering,
School of Medicine,
School of Engineering,
Department of Biomedical Engineering, School of Medicine, School of Engineering