In vitro generation of hematopoietic stem cells (HSCs) from induced pluripotent stem cells (iPSCs) has the potential to provide novel therapeutic approaches for replacing bone marrow (BM) transplantation without rejection or graft versus host disease. Hitherto, however, it has proved difficult to generate truly functional HSCs transplantable to adult host mice. Here, we demonstrate a unique in vivo differentiation system yielding engraftable HSCs from mouse and human iPSCs in teratoma-bearing animals in combination with a maneuver to facilitate hematopoiesis. In mice, we found that iPSC-derived HSCs migrate from teratomas into the BM and their intravenous injection into irradiated recipients resulted in multilineage and long-term reconstitution of the hematolymphopoietic system in serial transfers. Using this in vivo generation system, we could demonstrate that X-linked severe combined immunodeficiency (X-SCID) mice can be treated by HSCs derived from gene-corrected clonal iPSCs. It should also be noted that neither leukemia nor tumors were observed in recipients after transplantation of iPSC-derived HSCs. Taken our findings together, our system presented in this report should provide a useful tool not only for the study of HSCs, but also for practical application of iPSCs in the treatment of hematologic and immunologic diseases.
SummaryTo investigate the functional relationship between the expression of genes for ethylene-responsive transcription factors (ERFs) and the expression of ethylene-responsive genes, we examined the expression of genes for ERFs and the expression of a reporter gene in transgenic tobacco that carried a gene for β-glucuronidase (GUS) under the control of the ethylene-responsive element, which includes four copies of the 11-bp consensus sequence (designated the GCC-box, TAAGAGCCGCC). In strips of leaves of transgenic tobacco, the GCC-box-mediated expression of the reporter gene was induced in response to treatment with ethylene. We also observed the ethylene-independent immediate early induction of the synthesis of mRNAs for ERFs in wounded leaves and the enhancement of this induction by cycloheximide (CHX). Since CHX suppressed the induction of mRNAs for chitinase and GUS by ethylene, protein synthesis de novo was required for induction of the ethylenedependent GCC-box-mediated transcription of genes. In contrast, the enhancement by CHX of the wound-induced expression of ERFs suggested that no synthesis of new proteins was required for the wounding signal transduction leading to rapid expression of ERFs. Methyl jasmonate did not stimulate the wounding-responsive accumulation of ERF mRNAs, but it reduced such accumulation of mRNAs for ERF1, ERF2, ERF4 and the ethylene-dependent GCC-boxmediated transcription of the reporter gene. Thus, the immediate early induction of the expression of genes for ERFs in strips of tobacco leaves appears to be a novel type of wound-responsive activation of transcription. These results suggested that the expression of ERFs was not sufficient for activation of the GCC-box-mediated transcription but the expression of ERF1, ERF2 and ERF4, and that conversion of these ERFs by ethylene to their active form might be crucial for the GCC-box-mediated activation of the transcription of defense genes.
The effects of dietary Yamabushitake mushroom (Hericium erinaceus) on lipid metabolism were examined. C57BL/6J mice were fed a high-fat diet containing hot-water extract (HW-E) and an ethanol extract (EtOH-E) of Yamabushitake mushroom. Administration of HW-E or EtOH-E with a high-fat diet for 28 d resulted in a significant decrease in body weight gain, fat weight, and serum and hepatic triacylglycerol levels. Our in vitro experiments indicated that EtOH-E acts as an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha). Quantitative analyses of hepatic mRNA levels revealed that EtOH-E administration resulted in up-regulation of mRNA for a number of PPARalpha-regulating genes in spite of the fact that the gene expression of PPARalpha did not change. These results suggest that EtOH-E improves lipid metabolism in mice fed a high-fat diet, and that these effects were mediated by modulation of lipid metabolic gene expression, at least in part via activation of PPARalpha.
Introduction
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder affecting multiple organs, including the brain, and very often associated with epileptic activity. Language acquisition and development seems to be altered in a significant proportion of patients with TSC. In the present study, we used magnetoencephalography (MEG) to investigate spatiotemporal cerebral language processing in subjects with TSC and epilepsy during a reading semantic decision task, compared to healthy control participants.
Methods
Fifteen patients with TSC and 31 healthy subjects performed a lexico-semantic decision task during MEG recording. Minimum-norm estimates (MNE) were computed allowing identification of cerebral generators of language evoked fields (EF) in each subject.
Results
Source analysis of the language EF demonstrated early bilateral medial occipital activation (125ms) followed by a fusiform gyrus activation around 135ms. At 270ms post stimuli presentation, a strong cerebral activation was recorded in the left basal temporal language area. Finally, cerebral activations were measured in Wernicke’s area followed by Broca’s area. The healthy control group showed larger and earlier language activations in Broca and Wernicke’s areas compared to TSC patients. Moreover, cerebral activation from Broca’s area was greater than activation from Wernicke’s area in both groups, but this difference between anterior and posterior regions was smaller in the TSC group. Finally, the activation latency difference between Broca and Wernicke’s areas was greater in healthy controls than in TSC patients, which shows that activations in these areas are more serial in control subjects compared to TSC patients in whom activations occur more simultaneously.
Conclusions
This is the first study to investigate cerebral language pattern in patients with TSC. Compared to healthy controls, atypical neuromagnetic language responses may reflect cerebral reorganization in these patients in response to early epileptogenic activity or presence at birth of multiple brain lesions.
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