https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/49782/1/Yamanaka_Cell_131_5.pdf

Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors

An MRI time course of 512 echo-planar images (EPI) in resting human brain obtained every 250 ms reveals fluctuations in signal intensity in each pixel that have a physiologic origin. Regions of the sensorimotor cortex that were activated secondary to hand movement were identified using functional MRI methodology (FMRI). Time courses of low frequency (< 0.1 Hz) fluctuations in resting brain were observed to have a high degree of temporal correlation (P < 10(-3)) within these regions and also with time courses in several other regions that can be associated with motor function. It is concluded that correlation of low frequency fluctuations, which may arise from fluctuations in blood oxygenation or flow, is a manifestation of functional connectivity of the brain.

Functional connectivity in the motor cortex of resting human brain using echo-planar MRI.

MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic. In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.

MicroRNA therapeutics: towards a new era for the management of cancer and other diseases

Current neural induction protocols for human embryonic stem (hES) cells rely on embryoid body formation, stromal feeder co-culture or selective survival conditions. Each strategy has considerable drawbacks, such as poorly defined culture conditions, protracted differentiation and low yield. Here we report that the synergistic action of two inhibitors of SMAD signaling, Noggin and SB431542, is sufficient to induce rapid and complete neural conversion of >80% of hES cells under adherent culture conditions. Temporal fate analysis reveals the appearance of a transient FGF5(+) epiblast-like stage followed by PAX6(+) neural cells competent to form rosettes. Initial cell density determines the ratio of central nervous system and neural crest progeny. Directed differentiation of human induced pluripotent stem (hiPS) cells into midbrain dopamine and spinal motoneurons confirms the robustness and general applicability of the induction protocol. Noggin/SB431542-based neural induction should facilitate the use of hES and hiPS cells in regenerative medicine and disease modeling and obviate the need for protocols based on stromal feeders or embryoid bodies.

/pdf/highly-efficient-neural-conversion-of-human-es-and-ips-cells-5ewq762oqw.pdf

Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling

Direct reprogramming of somatic cells provides an opportunity to generate patient- or disease-specific pluripotent stem cells. Such induced pluripotent stem (iPS) cells were generated from mouse fibroblasts by retroviral transduction of four transcription factors: Oct3/4, Sox2, Klf4 and c-Myc. Mouse iPS cells are indistinguishable from embryonic stem (ES) cells in many respects and produce germline-competent chimeras. Reactivation of the c-Myc retrovirus, however, increases tumorigenicity in the chimeras and progeny mice, hindering clinical applications. Here we describe a modified protocol for the generation of iPS cells that does not require the Myc retrovirus. With this protocol, we obtained significantly fewer non-iPS background cells, and the iPS cells generated were consistently of high quality. Mice derived from Myc(-) iPS cells did not develop tumors during the study period. The protocol also enabled efficient isolation of iPS cells without drug selection. Furthermore, we generated human iPS cells from adult dermal fibroblasts without MYC.

Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts

La presente invention concerne un procede pour ameliorer l'efficacite de l'etablissement de cellules souches pluripotentes artificielles, ledit procede consistant, dans une etape d'initialisation de noyau de cellules somatiques, a provoquer une augmentation du niveau d'activite d'au moins une proteine selectionnee dans le groupe constitue par un membre de la famille Ras, une PI3 kinase, RalGEF, Raf, un membre de la famille AKT, Rheb, TCL1 et S6K. L'invention concerne egalement un agent destine a ameliorer l'efficacite de l'etablissement de cellules souches pluripotentes artificielles, ledit agent contenant un facteur selectionne dans le groupe constitue par un membre de la famille Ras, une PI3 kinase, RalGEF, Raf, un membre de la famille AKT, Rheb, TCL1, S6K et les acides nucleiques codant pour chacun d'entre eux. En outre, l'invention concerne un procede de production de cellules souches pluripotentes artificielles, ledit procede consistant a amener des cellules somatiques a entrer en contact avec une substance d'initialisation de noyau et au moins un facteur selectionne dans le groupe constitue par un membre de la famille Ras, une PI3 kinase, RalGEF, Raf, un membre de la famille AKT, Rheb, TCL1, S6K et les acides nucleiques codant pour chacun d'entre eux.

Procédé efficace pour l'établissement de cellules souches pluripotentes artificielles

Verfahren zur effizienten herstellung induzierter pluripotenter stammzellen

La presente invention concerne un procede d'amelioration de l'efficacite de l'etablissement d'une lignee de cellules SPi, comprenant une etape consistant a transferer Lin28B ou un acide nucleique codant pour Lin28B dans une cellule somatique et, en particulier, dans une cellule somatique sur laquelle Lin28 se revele inefficace ou moins efficace que Lin28B pour ce qui est d'ameliorer l'efficacite de l'etablissement d'une lignee de cellules SPi, ainsi qu'un procede de production de cellules SPi, comprenant une etape consistant a transferer Lin28B, ou un acide nucleique codant pour Lin28B, et une substance de reprogrammation nucleaire dans une cellule somatique. L'invention concerne egalement une cellule SPi comprenant un acide nucleique codant pour Lin28B et pouvant etre obtenue par ledit procede de production d'une cellule SPi, ainsi qu'un procede de production de cellules somatiques impliquant une etape consistant a forcer la cellule SPi a se differencier en une cellule somatique.

Procédé d'établissement efficace d'une lignée de cellules souches pluripotentes induites (spi)

La presente invention concerne un procede pour produire des cellules souches pluripotentes induites de mammifere, comprenant l’introduction de facteurs de reprogrammation derives de mammifere comprenant Oct3/4 et Nanog, ou des acides nucleiques codant pour Oct3/4 et Nanog, dans des cellules somatiques derivees de mammifere et ainsi l’induction de cellules souches pluripotentes induites a partir des cellules somatiques, ou les facteurs de reprogrammation ne comprennent ni Sox2, ni un acide nucleique codant pour Sox2.

Procédé pour produire des cellules souches pluripotentes induites

Pluripotency can be induced in somatic cells by forced expression of POU domain, class 5, transcription factor 1 (OCT3/4), sex determining region Y-box 2 (SOX2), Kruppel-like factor 4 (KLF4), myelocytomatosis oncogene (c-MYC) (OSKM). However, factor-mediated direct reprogramming is generally regarded as an inefficient and stochastic event. Contrary to this notion, we herein demonstrate that most human adult dermal fibroblasts initiated the reprogramming process on receiving the OSKM transgenes. Within 7 d, ∼20% of these transduced cells became positive for the TRA-1-60 antigen, one of the most specific markers of human pluripotent stem cells. However, only a small portion (∼1%) of these nascent reprogrammed cells resulted in colonies of induced pluripotent stem cells after replating. We found that many of the TRA-1-60–positive cells turned back to be negative again during the subsequent culture. Among the factors that have previously been reported to enhance direct reprogramming, LIN28, but not Nanog homeobox (NANOG), Cyclin D1, or p53 shRNA, significantly inhibited the reversion of reprogramming. These data demonstrate that maturation, and not initiation, is the limiting step during the direct reprogramming of human fibroblasts toward pluripotency and that each proreprogramming factor has a different mode of action.

/pdf/maturation-not-initiation-is-the-major-roadblock-during-3a2vhg0x7i.pdf

Maturation, not initiation, is the major roadblock during reprogramming toward pluripotency from human fibroblasts

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