Nicotinamide promotes cardiomyocyte derivation and survival through kinase inhibition in human pluripotent stem cells

Nicotinamide, the amide form of Vitamin B3, is a common nutrient supplement that plays important role in human fetal development. Nicotinamide has been widely used in clinical treatments, including the treatment of diseases during pregnancy. However, its impacts during embryogenesis have not been fully understood. In this study, we show that nicotinamide plays multiplex roles in mesoderm differentiation of human embryonic stem cells (hESCs). Nicotinamide promotes cardiomyocyte fate from mesoderm progenitor cells, and suppresses the emergence of other cell types. Independent of its functions in PARP and Sirtuin pathways, nicotinamide modulates differentiation through kinase inhibition. A KINOMEscan assay identifies 14 novel nicotinamide targets among 468 kinase candidates. We demonstrate that nicotinamide promotes cardiomyocyte differentiation through p38 MAP kinase inhibition. Furthermore, we show that nicotinamide enhances cardiomyocyte survival as a Rho-associated protein kinase (ROCK) inhibitor. This study reveals nicotinamide as a pleiotropic molecule that promotes the derivation and survival of cardiomyocytes, and it could become a useful tool for cardiomyocyte production for regenerative medicine. It also provides a theoretical foundation for physicians when nicotinamide is considered for treatments for pregnant women.

DNA methylation dynamics of long noncoding RNA during human fetal development

Aim: To determine whether the promoters of long noncoding RNAs (lncRNAs) undergo dynamic changes in DNA methylation during fetal development. Methods: ANOVA and the tissue specificity index were used to identify and validate tissue-specific methylation sites. Age-associated DNA methylation signatures were identified by applying the elastic net method. Results: The lncRNA methylome landscape was characterized in four types of fetal tissue and at three gestational time points, and specific characteristics relative to the tissue of origin and developmental age were identified. Higher levels of lncRNA methylation might be involved in tissue differentiation. LncRNAs harboring age-associated methylation signatures may participate in the fetal developmental process. Conclusion: This study provides novel insights into the role of lncRNA methylomes in fetal tissue specification and development.

Six Decades of Research on Human Fetal Gonadal Steroids

Human fetal gonads acquire endocrine steroidogenic capabilities early during their differentiation. Genetic studies show that this endocrine function plays a central role in the sexually dimorphic development of the external genitalia during fetal development. When this endocrine function is dysregulated, congenital malformations and pathologies are the result. In this review, we explain how the current knowledge of steroidogenesis in human fetal gonads has benefited from both the technological advances in steroid measurements and the assembly of detailed knowledge of steroidogenesis machinery and its expression in human fetal gonads. We summarise how the conversion of radiolabelled steroid precursors, antibody-based assays, mass spectrometry, ultrastructural studies, and the in situ labelling of proteins and mRNA have all provided complementary information. In this review, our discussion goes beyond the debate on recommendations concerning the best choice between the different available technologies, and their degrees of reproducibility and sensitivity. The available technologies and techniques can be used for different purposes and, as long as all quality controls are rigorously employed, the question is how to maximise the generation of robust, reproducible data on steroid hormones and their crucial roles in human fetal development and subsequent functions.

Insulin is expressed by enteroendocrine cells during human fetal development

Generation of beta cells via transdifferentiation of other cell types is a promising avenue for the treatment of diabetes. Here, we reconstruct a single cell atlas of enteroendocrine cells in the human fetal and neonatal small intestine. We identify a subset of fetal enteroendocrine K/L cells that express high levels of insulin and other beta cell genes. Our findings highlight a potential extra-pancreatic source of beta cells and exposes its molecular blueprint.

Anesthesia for Neonatal Myelomeningocele

Myelomeningocele, also known as spina bifida aperta (often shortened to the nonspecific name “spina bifida”) is a congenital disorder of the spine. In infants with a myelomeningocele, the neural tube has not closed, and the vertebral arches have not fused during development, leading to spinal cord and meningeal herniation through the skin. Because of the high potential for injury and infection of the exposed spinal cord, which could lead to lifetime disability, these lesions are typically repaired within 24 to 48 hours after birth. A myelomeningocele occurs before day 28 of human fetal development and is an abnormality in which the posterior neural tube closes incompletely. The outcome is a vertebral column deformity, through which the meningeal-lined sac herniates. After the bony defect is created, the hypothesized mechanism of meningeal herniation is that the pulsations of cerebrospinal fluid act progressively to balloon out the spinal cord. If the sac is filled with spinal nerves or the spinal cord, it is known as a myelomeningocele; if the sac is empty, it is called a meningocele.

Human fetal microglia acquire homeostatic immune-sensing properties early in development

Microglia, immune cells of the central nervous system (CNS), are important for tissue development and maintenance and are implicated in CNS disease, but we lack understanding of human fetal microglia development. Single-cell gene expression and bulk chromatin profiles of microglia at 9 to 18 gestational weeks (GWs) of human fetal development were generated. Microglia were heterogeneous at all studied GWs. Microglia start to mature during this developmental period and increasingly resemble adult microglia with CNS-surveilling properties. Chromatin accessibility increases during development with associated transcriptional networks reflective of adult microglia. Thus, during early fetal development, microglia progress toward a more mature, immune-sensing competent phenotype, and this might render the developing human CNS vulnerable to environmental perturbations during early pregnancy.

Chloride channels regulate differentiation and barrier functions of the mammalian airway

The conducting airway forms a protective mucosal barrier and is the primary target of airway disorders. The molecular events required for the formation and function of the airway mucosal barrier, as well as the mechanisms by which barrier dysfunction leads to early onset airway diseases, remain unclear. In this study, we systematically characterized the developmental landscape of the mouse airway using single-cell RNA sequencing and identified remarkably conserved cellular programs operating during human fetal development. We demonstrated that in mouse, genetic inactivation of chloride channel Ano1/Tmem16a compromises airway barrier function, results in early signs of inflammation, and alters the airway cellular landscape by depleting epithelial progenitors. Mouse Ano1-/-mutants exhibited mucus obstruction and abnormal mucociliary clearance that resemble the airway defects associated with cystic fibrosis. The data reveal critical and non-redundant roles for Ano1 in organogenesis, and show that chloride channels are essential for mammalian airway formation and function.