Among the key properties that distinguish adult mammalian stem cells from their more differentiated progeny is the ability of stem cells to remain in a quiescent state for prolonged periods of time1,2. However, the molecular pathways for the maintenance of stem cell quiescence remain elusive. Using adult muscle stem cells (“satellite cells” (SCs)) as a model system, we show that the microRNA (miRNA) pathway is essential for the maintenance of the quiescent state. SCs lacking a functional miRNA pathway spontaneously exit quiescence and enter the cell cycle. We identified quiescence-specific miRNAs in the SC lineage by microarray analysis. Among these, microRNA-489 (miR-489) is highly expressed in quiescent SCs and quickly down-regulated during SC activation. Further analysis revealed that miR-489 functions as a regulator of SC quiescence by post-transcriptionally suppressing the oncogene DEK, a protein that localizes to the more differentiated daughter cell during asymmetric division of SCs and promotes the transient proliferative expansion of myogenic progenitors. Our results provide the first evidence of the miRNA pathway in general, and a specific miRNA, miR-489, in actively maintaining the quiescent state of an adult stem cell population.

The spinal cord is a fascinating structure responsible for coordinating movement in vertebrates. Spinal motor neurons control muscle activity by transmitting signals from the spinal cord to diverse peripheral targets. We profiled 43,890 single-nucleus transcriptomes from the adult mouse spinal cord using fluorescence-activated nuclei sorting to enrich for motor neuron nuclei. We identified 16 sympathetic motor neuron clusters, which are distinguishable by spatial localization and expression of neuromodulatory signaling genes. We found surprising skeletal motor neuron heterogeneity in the adult spinal cord, including transcriptional differences that correlate with electrophysiologically and spatially distinct motor pools. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neuron (γ*). Collectively, these data provide a single-cell transcriptional atlas ( http://spinalcordatlas.org ) for investigating the organizing molecular logic of adult motor neuron diversity, as well as the cellular and molecular basis of motor neuron function in health and disease.

Pancreatic beta cell apoptosis is important in the pathogenesis and potential treatment of Type 1 diabetes. We investigated whether Humanin, a recently described survival factor for neurons, could improve the survival of beta cells and delay or treat diabetes in the NOD model. Humanin reduced apoptosis induced by serum starvation in NIT-1 cells and decreased apoptosis induced by cytokine treatment. Humanin induced Stat3 and ERK phosphorylation over a 24 hour time course. Specific inhibition of Stat3 resulted in nullifying the protective effect of Humanin. Humanin normalized glucose tolerance in diabetic NOD mice treated for 6-weeks and their pancreata revealed decreased lymphocyte infiltration and severity. In addition, Humanin delayed/prevented the onset of diabetes in NOD mice treated for 20 weeks. In summary, Humanin treatment decreases cytokine-induced apoptosis in beta cells in vitro and improved glucose tolerance and onset of diabetes in NOD mice in vivo. This indicates that Humanin may be useful for islet protection and survival in a spectrum of diabetes-related therapeutics.

Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs—including the α-2a adrenergic receptor, ADRA2A—increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes.

All four interventions to reduce the harm from tobacco use appear to be highly cost effective and should be considered as priorities in the context of Vietnam. The government may initially consider graphic warning labels and tax increase, followed by other interventions.