Human Pluripotent Stem Cell-Derived Atrial and Ventricular Cardiomyocytes Develop from Distinct Mesoderm Populations

Topics overview: Functions of Regulatory T cells (Tregs), Why diseases and cancer are inherent parts of the aging process, Host Genetics and Gut Microbiome, Functions of Mesoderm Populations, Glial Contributions to Schizophrenia

1. Metabolic Regulation of Tregs in Cancer: Opportunities for Immunotherapy

The promising outcomes observed in cancer immunotherapy are evidence that the immune system provides a powerful arsenal for the restriction of tumor outgrowth; however, the immunosuppressive tumor microenvironment (TME) is known to impair antitumor immunity and impede the efficacy of cancer immunotherapies. Regulatory T cells (Tregs), which prevent overt immune responses and autoimmunity, accumulate aberrantly in some types of tumor to suppress antitumor immunity and support the establishment of an immunosuppressive microenvironment. Ablation of Tregs has been shown to not only unleash antitumor immunity and interrupt formation of an immunosuppressive TME, but also lead to severe autoimmune disorders. Therefore, it is essential to develop approaches to specifically target intratumoral Tregs. Herein, Haiping Wang at Faculty of Biology and Medicine, University of Lausanne in Vaud, Switzerland and his colleagues summarize the immunomodulatory functions of Tregs in the TME and discuss how metabolic regulation of Tregs can facilitate intratumoral Treg accumulation.

Tregs are a subtype of CD4 T cells important for the prevention of autoimmunity. Their immunosuppressive activity can also promote tumor progression. Targeting Tregs is an attractive approach to unleash host antitumor immunity. Since Tregs are also important in other tissues, specific targeting of intratumoral Tregs is required. Metabolic stress in the TME can prevent the antitumor activity of intratumoral tumor-specific T cells. The competition for nutrients between T cells and cancer cells and production of immunosuppressive metabolites by cancer cells might contribute to declined effector functions of intratumoral tumor-specific T cells.

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2. NAD+ Deficits in Age-Related Diseases and Cancer

The phenomenon of aging has gained widespread attention in recent times. Although significant advances have been made to better understand aging and its related pathologies including cancer, there is not yet a clear mechanism explaining why diseases and cancer are inherent parts of the aging process. Finding a unifying equation that could bridge aging and its related diseases would allow therapeutic development and solve an immense human health problem to live longer and better. In this review, Amanda Garrido at Spanish National Cancer Research Centre in Madrid, Spain and his colleagues discuss NAD+ reduction as the central mechanism that may connect aging to its related pathologies and cancer. NAD+ boosters would ensure and ameliorate health quality during aging.

The increase in life expectancy during the last decades was accompanied by a rise in the incidence of diseases related to aging, including cancer. Diseases and cancer are inherent parts of the aging process and aging can be considered as a disease among other diseases while we age. NAD+ levels are described to decrease during aging, likely through changes in metabolic reactions leading to NAD+ synthesis. Models for age-related diseases and cancer show reductions in NAD+ pools. Boosting NAD+ through precursors such as NAM, NMN or NR may increase longevity and prevent age-related diseases and cancer in animal models. Beneficial effects of dietary restriction on lifespan and cancer may converge to increases in NAD+ levels.

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3. Host Genetics and Gut Microbiome: Challenges and Perspectives

The mammalian gut is colonized by trillions of microorganisms collectively called the microbiome. It is increasingly clear that this microbiome has a critical role of in many aspects of health including metabolism and immunity. While environmental factors such as diet and medications have been shown to influence the microbiome composition, the role of host genetics has only recently emerged in human studies and animal models. In this review, Alexander Kurilshikov at University of Groningen in Groningen, The Netherlands and his colleagues summarize the current state of microbiome research with an emphasis on the effect of host genetics on the gut microbiome composition. They focus particularly on genetic determinants of the host immune system that help shape the gut microbiome and discuss avenues for future research.

A proportion of gut bacteria are heritable. The impact of host genetics on the gut microbiome in humans is being revealed through genome-wide association studies. The effect size of host genetics on the microbiome appears to be modest. Several associations are found between the microbiome and genes associated with diet, innate immunity, vitamin D receptors, and metabolism. A consistent genetic signal comes from pattern recognition receptor molecules, particularly C-type lectins.

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4. Human Pluripotent Stem Cell-Derived Atrial and Ventricular Cardiomyocytes Develop from Distinct Mesoderm Populations

The ability to direct the differentiation of human pluripotent stem cells (hPSCs) to the different cardiomyocyte subtypes is a prerequisite for modeling specific forms of cardiovascular disease in vitro and for developing novel therapies to treat them. Here Jee Hoon Lee at McEwen Centre for Regenerative Medicine and Princess Margaret Cancer Center in Toronto, Canada and his colleagues have investigated the development of the human atrial and ventricular lineages from hPSCs, and they show that retinoic acid signaling at the mesoderm stage of development is required for atrial specification. Analyses of early developmental stages revealed that ventricular and atrial cardiomyocytes derive from different mesoderm populations that can be distinguished based on CD235a and RALDH2 expression, respectively. Molecular and electrophysiological characterization of the derivative cardiomyocytes revealed that optimal specification of ventricular and atrial cells is dependent on induction of the appropriate mesoderm. Together these findings provide new insights into the development of the human atrial and ventricular lineages that enable the generation of highly enriched, functional cardiomyocyte populations for therapeutic applications.

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5. Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia

In this study, Martha S. Windrem at Department of Neurology and Center for Translational Neuromedicine, University of Rochester Medical Center in New York, USA and her colleagues investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Their approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls. The SCZ glial chimeras also showed delayed astrocytic differentiation and abnormal astrocytic morphologies. When established in myelin wild-type hosts, SCZ glial mice showed reduced prepulse inhibition and abnormal behavior, including excessive anxiety, antisocial traits, and disturbed sleep. RNA-seq of cultured SCZ human glial progenitor cells (hGPCs) revealed disrupted glial differentiation-associated and synaptic gene expression, indicating that glial pathology was cell autonomous. Their data therefore suggest a causal role for impaired glial maturation in the development of schizophrenia and provide a humanized model for its in vivo assessment.

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