In the developing CNS, subtypes of neurons and glial cells are generated according to a schedule that is defined by cell-intrinsic mechanisms that function at the progenitor-cell level. However, no critical molecular switch for the temporal specification of CNS progenitor cells has been identified. We found that chicken ovalbumin upstream promoter-transcription factor I and II (Coup-tfI and Coup-tfII, also known as Nr2f1 and Nr2f2) are required for the temporal specification of neural stem/progenitor cells (NSPCs), including their acquisition of gliogenic competence, as demonstrated by their responsiveness to gliogenic cytokines. COUP-TFI and II are transiently co-expressed in the ventricular zone of the early embryonic CNS. The double knockdown of Coup-tfI/II in embryonic stem cell (ESC)-derived NSPCs and the developing mouse forebrain caused sustained neurogenesis and the prolonged generation of early-born neurons. These findings reveal a part of the timer mechanisms for generating diverse types of neurons and glial cells during CNS development.

Neural stem/progenitor cell (NSPC) multipotency is highly regulated so that specific neural networks form during development. NSPCs cannot respond to gliogenic signals without acquiring gliogenic competence and decreasing their neurogenic competence as development proceeds. Coup-tfI and Coup-tfII are triggers of these temporal NSPC competence changes. However, the downstream effectors of Coup-tfs that mediate the neurogenic-togliogenic competence transition remain unknown. Here, we identified the microRNA-17/106 (miR-17/106)-p38 axis as a critical regulator of this transition. Overexpression of miR-17 inhibited the acquisition of gliogenic competence and forced stage-progressed NSPCs to regain neurogenic competence without altering the methylation status of a glial gene promoter. We also identified Mapk14 (also known as p38) as a target of miR-17/106 and found that Mapk14 inhibition restored neurogenic competence after the neurogenic phase. These results demonstrate that the miR-17/106-p38 axis is a key regulator of the neurogenic-to-gliogenic NSPC competence transition and that manipulation of this axis permits bidirectional control of NSPC multipotency.reatments of central nervous system (CNS) injury and diseases have become more promising with advances in modern medicine. Recent progress in stem cell biology has drawn attention to stem cells as innovative resources for transplantation therapies and individualized drug screenings (1, 2). Multipotent neural stem/progenitor cells (NSPCs) that give rise to all types of neural cells can now be readily obtained from induced pluripotent stem cells. However, specific and efficient induction of homogeneous target cell populations from NSPCs remains difficult because of the complex mechanisms that regulate NSPC development and differentiation. Therefore, further elucidation of how specific cell types can be generated from NSPCs is required to facilitate therapeutic applications.We recently used a newly developed embryonic stem cell (ESC)-derived neurosphere culture system to investigate the molecular mechanisms that govern NSPC differentiation (3). Although NSPCs are multipotent, and are thus able to differentiate into neurons and glial cells, neurogenesis largely precedes gliogenesis during CNS development in vertebrates. The neurogenesis-to-gliogenesis switch requires temporal identity transitions of NSPCs (4). Importantly, our neurosphere culture system recapitulates neural development in vivo. Using this system, we found that Coup-tfI and Coup-tfII (also known as Nr2f1 and Nr2f2, respectively) are critical molecular switches in the temporal identity transition of NSPCs (3). Remarkably, Coup-tfs do not repress neurogenesis or promote gliogenesis but, instead, change the competence of NSPCs. Although Coup-tfs permit alterations by changing the responsiveness of NSPCs to extrinsic gliogenic signals, the critical regulators and/or drivers of this process remain largely unknown. The aim of this study was to determine the molecular machinery underlying the neurogenicto-g...

IntroductionHepatic stellate cells reside within the perisinusoidal space of Disse beneath the endothelial barrier and undergo a gradual transition from a quiescent, vitamin A-storing phenotype to an activated myofibroblast-like phenotype after liver injury. [1][2][3][4][5] These activated stellate cells synthesize large amounts of extracellular matrix proteins, such as collagens I, III, IV, V, and VI, fibronectin, laminin, and proteoglycans, during liver fibrogenesis. [6][7][8] Hepatic stellate cells have long cytoplasmic processes that run parallel to the sinusoidal endothelial wall, make contact with numerous hepatocytes, and function as liver-specific pericytes. 4,9,10 As hepatic stellate cells contract and relax in response to various vasoactive mediators, they may play a role in the regulation of sinusoidal tone and blood flow in normal liver. 10,11 Accordingly, hepatic stellate cells are associated with liver fibrosis and portal hypertension. However, the exact nature and origin of hepatic stellate cells have not been fully elucidated, despite the pathophysiologic implications.Hepatic stellate cells express mesenchymal markers, such as vimentin, desmin, and ␣-smooth muscle actin (␣-SMA), or neural/ neuroectodermal markers, such as glial fibrillary acidic protein (GFAP), neural cell adhesion molecule, and synaptophysin. 2,5,[12][13][14][15][16] Based on these characteristic phenotypes, the embryonic origin of hepatic stellate cells is thought to be the septum transversum mesenchyme or neural crest. 2,17,18 Cassiman et al 19 reported that hepatic stellate cells do not descend from the neural crest in transgenic mice expressing yellow fluorescent protein in all neural crest cells and their derivatives, and they may derive from the septum transversum mesenchyme, endoderm, or the mesothelial liver capsule. On the other hand, the origin of hepatic stellate cells in the adult liver has remained obscure.Recently, some investigators have demonstrated that crude bone marrow (BM) cells can populate the hepatic stellate cells of lethally irradiated mice. 20,21 Because adult BM contains both hematopoietic stem cells and mesenchymal stem cells, it is unclear which type of stem cell truly contributes to hepatic stellate cells. Previous reports revealed that glomerular mesangial cells in kidney and perivascular pericyte-like cells in brain are derived from hematopoietic stem cells in mice that received single hematopoietic stem-cell transplants. 22,23 Interestingly, both cell types are considered to belong to the myofibroblast family. More recently, it has also been reported that fibroblasts and myofibroblasts in many organs and tissues originate from hematopoietic stem cells. 24 From the observation that myofibroblasts are of hematopoietic stem-cell origin and the notion that the quiescent hepatic stellate cells switch to activated myofibroblast-like cells in association with inflammation, we hypothesized that hepatic stellate cells may also be derived from hematopoietic stem cells.To test our hypothesis, we generated c...

The results from this study provide further evidence for the role of circulating fibrocytes in fibrotic lung diseases.