ABSTRACT
The influence of individual-level factors such as pretraumatic risk and protective factors and the availability of unit-level and enterprise-level factors on psychological health outcomes have been previously considered individually, but have not been considered in tandem across the U.S. Military psychological health system. We use the existing literature on military psychological health to build a conceptual system dynamics model of the U.S. Military psychological health system "service-cycle" from accession and deployment to future psychological health screening and treatment. The model highlights a few key observations, challenges, and opportunities for improvement for the system that relate to several topics including the importance of modeling operational demand combined with the population's psychological health as opposed to only physical health; the role of resilience and post-traumatic growth on the mitigation of stress; the positive and negative effects of pretraumatic risk factors, unit support, and unit leadership on the service-cycle; and the opportunity to improve the system more rapidly by including more feedback mechanisms regarding the usefulness of pre- and post-traumatic innovations to medical leaders, funding authorities, and policy makers.
Subject(s)
Delivery of Health Care/methods , Health Policy , Mental Health Services/organization & administration , Military Personnel/psychology , Models, Psychological , Stress Disorders, Post-Traumatic/diagnosis , Stress, Psychological/diagnosis , Adaptation, Psychological , Decision Making , Delivery of Health Care/standards , Humans , Leadership , Mental Health , Risk Factors , Stress Disorders, Post-Traumatic/therapy , Stress, Psychological/psychology , United StatesABSTRACT
MicroRNAs influence hematopoietic differentiation, but little is known about their effects on the stem cell state. Here, we report that the microRNA processing enzyme Dicer is essential for stem cell persistence in vivo and a specific microRNA, miR-125a, controls the size of the stem cell population by regulating hematopoietic stem/progenitor cell (HSPC) apoptosis. Conditional deletion of Dicer revealed an absolute dependence for the multipotent HSPC population in a cell-autonomous manner, with increased HSPC apoptosis in mutant animals. An evolutionarily conserved microRNA cluster containing miR-99b, let-7e, and miR-125a was preferentially expressed in long-term hematopoietic stem cells. MicroRNA miR-125a alone was capable of increasing the number of hematopoietic stem cells in vivo by more than 8-fold. This result was accomplished through a differentiation stage-specific reduction of apoptosis in immature hematopoietic progenitors, possibly through targeting multiple proapoptotic genes. Bak1 was directly down-regulated by miR-125a and expression of a 3'UTR-less Bak1 blocked miR-125a-induced hematopoietic expansion in vivo. These data demonstrate cell-state-specific regulation by microRNA and identify a unique microRNA functioning to regulate the stem cell pool size.
Subject(s)
DEAD-box RNA Helicases/physiology , Endoribonucleases/physiology , Hematopoietic Stem Cells/cytology , MicroRNAs/physiology , Animals , Apoptosis/genetics , Cell Count , Cell Differentiation , Down-Regulation , Homeostasis , Mice , Molecular Sequence Data , Ribonuclease III , bcl-2 Homologous Antagonist-Killer Protein/geneticsABSTRACT
Lineage specification is a critical issue in developmental and regenerative biology. We hypothesized that microRNAs (miRNAs) are important participants in those processes and used the poorly understood regulation of megakaryocyte-erythrocyte progenitors (MEPs) in hematopoiesis as a model system. We report here that miR-150 modulates lineage fate in MEPs. Using a novel methodology capable of profiling miRNA expression in small numbers of primary cells, we identify miR-150 as preferentially expressed in the megakaryocytic lineage. Through gain- and loss-of-function experiments, we demonstrate that miR-150 drives MEP differentiation toward megakaryocytes at the expense of erythroid cells in vitro and in vivo. Moreover, we identify the transcription factor MYB as a critical target of miR-150 in this regulation. These experiments show that miR-150 regulates MEP fate, and thus establish a role for miRNAs in lineage specification of mammalian multipotent cells.
