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

The “reversion of cell fate from differentiated states back into totipotent or pluripotent states” has been an interest of many scientists for a long time. With the help of knowledge accumulated by those scientists, we succeeded in converting somatic cells to a pluripotent cell lineage by the forced expression of defined factors. These established induced pluripotent stem (iPS) cells have similar features to embryonic stem (ES) cells, including pluripotency and immortality. The iPS cell technology provides unprecedented opportunities for regenerative medicine and drug discovery.

Induction of pluripotency by defined factors

Classic cadherins mediate calcium-dependent cell-cell adhesion in a variety of animals, but there are marked differences in their domain structures between chordate and nonchordate animals. The extracellular domain of chordate-type classic cadherins (type I and type II classic cadherins) consists of five tandem repeats of conserved sequences called EC domains, whereas that of nonchordate-type classic cadherins (designated as type III classic cadherin) contains a variable number of EC domains, followed by a characteristic domain complex made of laminin-A globular domains and EGF-like repeats. In the present study, we identified a novel vertebrate type III cadherin showing high sequence similarity to Drosophila N-cadherin, and named this molecule chicken Hz-cadherin (cHz-cadherin), because of the distinct expression in horizontal cells of the neural retina. cHz-cadherin functioned as an adhesion molecule when introduced into cultured cells. Database search revealed one cHz-cadherin homologue in zebrafish and two in puffer fish, but none in other vertebrate species examined. These observations indicate that type III classic cadherins have been conserved in vertebrate species, being expressed by limited cells types, but lost in particular phylogenic groups of the vertebrates.

Identification of a nonchordate-type classic cadherin in vertebrates: chicken Hz-cadherin is expressed in horizontal cells of the neural retina and contains a nonchordate-specific domain complex.

ABSTRACT Oligodendrocytes, the myelinating cells of the central nervous system, possess great potential for disease modeling and cell transplantation-based therapies for leukodystrophies. However, caveats to oligodendrocyte differentiation protocols ( Ehrlich et al., 2017; Wang et al., 2013; Douvaras and Fossati, 2015) from human embryonic stem and induced pluripotent stem cells (iPSCs), which include slow and inefficient differentiation, and tumorigenic potential of contaminating undifferentiated pluripotent cells, are major bottlenecks towards their translational utility. Here, we report the rapid generation of human oligodendrocytes by direct lineage conversion of human dermal fibroblasts (HDFs). We show that the combination of the four transcription factors OLIG2, SOX10, ASCL1 and NKX2.2 is sufficient to convert HDFs to induced oligodendrocyte precursor cells (iOPCs). iOPCs resemble human primary and iPSC-derived OPCs based on morphology and transcriptomic analysis. Importantly, iOPCs can differentiate into mature myelinating oligodendrocytes in vitro and in vivo. Finally, iOPCs derived from patients with Pelizaeus Merzbacher disease, a hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, showed increased cell death compared with iOPCs from healthy donors. Thus, human iOPCs generated by direct lineage conversion represent an attractive new source for human cell-based disease models and potentially myelinating cell grafts.

/pdf/generation-of-functional-human-oligodendrocytes-from-dermal-22sw05in.pdf

Generation of functional human oligodendrocytes from dermal fibroblasts by direct lineage conversion

Cette invention concerne une methode permettant d'ameliorer la mise en place efficace de l'induction de cellules souches pluripotentes, ladite methode consistant a mettre en contact une proteine impliquee dans la formation d'une ligne primitive (PrS), de preference Foxh1, ou un acide nucleique codant ladite proteine avec une cellule somatique lors d'une etape de reprogrammation nucleaire. L'invention concerne egalement une methode de production de cellules souches pluripotentes induites consistant a mettre en contact la proteine impliquee dans la formation de la ligne primitive (PrS) ou un acide nucleique codant ladite proteine, et la ou les substances de reprogrammation nucleaire avec une cellule somatique.

Méthode de mise en place efficace de l'induction de cellules souches pluripotentes

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Induction of pluripotency by defined factors

Identification of a nonchordate-type classic cadherin in vertebrates: chicken Hz-cadherin is expressed in horizontal cells of the neural retina and contains a nonchordate-specific domain complex.

Generation of functional human oligodendrocytes from dermal fibroblasts by direct lineage conversion

Induction of pluripotency by defined factors

Méthode de mise en place efficace de l'induction de cellules souches pluripotentes