Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for biomedical research. However, they are immature, which is a barrier to modeling adult-onset cardiovascular disease. Here, we sought to develop a simple method that could drive cultured hiPSC-CMs toward maturity across a number of phenotypes, with the aim of utilizing mature hiPSC-CMs to model human cardiovascular disease. hiPSC-CMs were cultured in fatty acid-based medium and plated on micropatterned surfaces. These cells display many characteristics of adult human cardiomyocytes, including elongated cell morphology, sarcomeric maturity, and increased myofibril contractile force. In addition, mature hiPSC-CMs develop pathological hypertrophy, with associated myofibril relaxation defects, in response to either a pro-hypertrophic agent or genetic mutations. The more mature hiPSC-CMs produced by these methods could serve as a useful in vitro platform for characterizing cardiovascular disease.Naive pluripotency can be maintained in medium with two inhibitors plus leukemia inhibitory factor (2i/LIF) supplementation, which primarily affects canonical WNT, FGF/ERK, and JAK/STAT3 signaling. However, whether one of these three supplements alone is sufficient to maintain naive self-renewal remains unclear. Here we show that LIF alone in medium is sufficient for adaptation of 2i/L-ESCs to embryonic stem cells (ESCs) in a hypermethylated state (L-ESCs). Global transcriptomic analysis shows that L-ESCs are close to 2i/L-ESCs and in a stable state between naive and primed pluripotency. Notably, our results demonstrate that DNA methyltransferases (DNMTs) play an important role in LIF-dependent mouse ESC adaptation and self-renewal. LIF-dependent ESC adaptation efficiency is significantly increased in serum treatment and reduced in Dnmt3a or Dnmt3l knockout ESCs. Importantly, unlike epiblast stem cells, L-ESCs contribute to somatic tissues and germ cells in chimeras. L-ESCs cultured under such simple conditions as in this study would provide a more conducive platform to clarify the molecular mechanism of ESCs in in vitro culture.Cognitive deficits associated with Alzheimer's disease (AD) severely impact daily life for the millions of affected individuals. Progressive memory impairment in AD patients is associated with degeneration of the hippocampus. The dentate gyrus of the hippocampus, a region critical for learning and memory functions, is a site of adult neurogenesis in mammals. Recent evidence in humans indicates that hippocampal neurogenesis likely persists throughout life, but declines with age and is strikingly impaired in AD. https://www.selleckchem.com/products/AT7867.html Our understanding of how neurogenesis supports learning and memory in healthy adults is only beginning to emerge. The extent to which decreased neurogenesis contributes to cognitive decline in aging and AD remains poorly understood. However, studies in rodent models of AD and other neurodegenerative diseases raise the possibility that targeting neurogenesis may ameliorate cognitive dysfunction in AD. Here, we review recent progress in understanding how adult neurogenesis is impacted in the context of aging and AD.Human mesenchymal stem/stromal cell (hMSC)-based cell therapies are promising for treating a variety of diseases. The unique immunomodulatory properties of hMSCs have extended their therapeutic potential beyond tissue regeneration. However, extensive pre-clinical culture expansion inevitably drives cells toward replicative "aging" and a consequent decline in quality. These "in vitro-aged" hMSCs resemble biologically aged cells, which have been reported to show senescence signatures, diminished immunosuppressive capacity, and weakened regenerative potential as well as pro-inflammatory features. In this review, we have surveyed the literature to explore the intimate relationship between the inflammatory status of hMSCs and their in vitro aging process. We posit that a shift from an anti-inflammatory to a pro-inflammatory phenotype of culture-expanded hMSCs contributes to a deterioration in their therapeutic efficacy. Potential molecular and cellular mechanisms underpinning this phenomenon have been discussed. We have also highlighted studies that leverage these mechanisms to make culture-expanded hMSCs more amenable for clinical use.A small subgroup of embryonic stem cells (ESCs) exhibit molecular features similar to those of two-cell embryos (2C). However, it remains elusive whether 2C-like cells and 2C embryos share similar epigenetic features. Here, we map the genome-wide profiles of histone H3K4me3 and H3K27me3 in 2C-like cells. We found that the majority of genes in 2C-like cells inherit their histone status from ESCs. Among the genes showing a switch in their histone methylation status during 2C-like transitions, only a small number acquire 2C-embryo epigenetic signatures. In contrast, broad H3K4me3 domains display extensive loss in 2C-like cells. Most of the differentially expressed genes display decreased H3K4me3 and H3K27me3 levels in 2C-like cells, whereas de novo H3K4me3 deposition is closely linked with the expression levels of upregulated 2C-specific genes. Taken together, our study reveals the unique epigenetic profiles of 2C-like cells, facilitating the further exploration of totipotency in the future.Chondrodysplasias are hereditary diseases caused by mutations in the components of growth cartilage. Although the unfolded protein response (UPR) has been identified as a key disease mechanism in mouse models, no suitable in vitro system has been reported to analyze the pathology in humans. Here, we developed a three-dimensional culture protocol to differentiate hypertrophic chondrocytes from induced pluripotent stem cells (iPSCs) and examine the phenotype caused by MATN3 and COL10A1 mutations. Intracellular MATN3 or COL10 retention resulted in increased ER stress markers and ER size in most mutants, but activation of the UPR was dependent on the mutation. Transcriptome analysis confirmed a UPR with wide-ranging changes in bone homeostasis, extracellular matrix composition, and lipid metabolism in the MATN3 T120M mutant, which further showed altered cellular morphology in iPSC-derived growth-plate-like structures in vivo. We then applied our in vitro model to drug testing, whereby trimethylamine N-oxide led to a reduction of ER stress and intracellular MATN3.