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Sproul A.A.,New York Stem Cell Foundation Research Institute | Sproul A.A.,Columbia University
Molecular Aspects of Medicine | Year: 2015

Human pluripotent stem cells (PSCs) have the capacity to revolutionize medicine by allowing the generation of functional cell types such as neurons for cell replacement therapy. However, the more immediate impact of PSCs on treatment of Alzheimer's disease (AD) will be through improved human AD model systems for mechanistic studies and therapeutic screening. This review will first briefly discuss different types of PSCs and genome-editing techniques that can be used to modify PSCs for disease modeling or for personalized medicine. This will be followed by a more in depth analysis of current AD iPSC models and a discussion of the need for more complex multicellular models, including cell types such as microglia. It will finish with a discussion on current clinical trials using PSC-derived cells and the long-term potential of such strategies for treating AD. © 2015 Elsevier Ltd. All rights reserved. Source

Sagi I.,Hebrew University of Jerusalem | Chia G.,Columbia University | Golan-Lev T.,Hebrew University of Jerusalem | Peretz M.,Hebrew University of Jerusalem | And 7 more authors.
Nature | Year: 2016

Diploidy is a fundamental genetic feature in mammals, in which haploid cells normally arise only as post-meiotic germ cells that serve to ensure a diploid genome upon fertilization. Gamete manipulation has yielded haploid embryonic stem (ES) cells from several mammalian species, but haploid human ES cells have yet to be reported. Here we generated and analysed a collection of human parthenogenetic ES cell lines originating from haploid oocytes, leading to the successful isolation and maintenance of human ES cell lines with a normal haploid karyotype. Haploid human ES cells exhibited typical pluripotent stem cell characteristics, such as self-renewal capacity and a pluripotency-specific molecular signature. Moreover, we demonstrated the utility of these cells as a platform for loss-of-function genetic screening. Although haploid human ES cells resembled their diploid counterparts, they also displayed distinct properties including differential regulation of X chromosome inactivation and of genes involved in oxidative phosphorylation, alongside reduction in absolute gene expression levels and cell size. Surprisingly, we found that a haploid human genome is compatible not only with the undifferentiated pluripotent state, but also with differentiated somatic fates representing all three embryonic germ layers both in vitro and in vivo, despite a persistent dosage imbalance between the autosomes and X chromosome. We expect that haploid human ES cells will provide novel means for studying human functional genomics and development. Source

Yeh C.,Cornell University | Li A.,Cornell University | Li A.,New York Stem Cell Foundation Research Institute | Chuang J.-Z.,Cornell University | And 4 more authors.
Developmental Cell | Year: 2013

Primary cilia undergo cell-cycle-dependent assembly and disassembly. Emerging data suggest that ciliary resorption is a checkpoint for S phase reentry and that the activation of phospho(T94)Tctex-1 couples these two events. However, the environmental cues and molecular mechanisms that trigger these processes remain unknown. Here, we show that insulin-like growth-1 (IGF-1) accelerates G1-S progression by causing cilia to resorb. The mitogenic signals of IGF-1 are predominantly transduced through IGF-1 receptor (IGF-1R) on the cilia of fibroblasts and epithelial cells. At the base of the cilium, phosphorylated IGF-1R activates an AGS3-regulated Gβγ signaling pathway that subsequently recruits phospho(T94)Tctex-1 to the transition zone. Perturbing any component of this pathway in cortical progenitors induces premature neuronal differentiation at the expense of proliferation. These data suggest that during corticogenesis, a cilium-transduced, noncanonical IGF-1R-Gβγ-phospho(T94)Tctex-1 signaling pathway promotes the proliferation of neural progenitors through modulation of ciliary resorption and G1 length. © 2013 Elsevier Inc. Source

Zhang Y.S.,Columbia University | Sevilla A.,Mount Sinai School of Medicine | Sevilla A.,New York Stem Cell Foundation Research Institute | Wan L.Q.,Columbia University | And 3 more authors.
Stem Cells | Year: 2013

Developmental gradients of morphogens and the formation of boundaries guide the choices between self-renewal and differentiation in stem cells. Still, surprisingly little is known about gene expression signatures of differentiating stem cells at the boundaries between regions. We thus combined inducible gene expression with a microfluidic technology to pattern gene expression in murine embryonic stem cells. Regional depletion of the Nanog transcriptional regulator was achieved through the exposure of cells to microfluidic gradients of morphogens. In this way, we established pluripotency-differentiation boundaries between Nanog expressing cells (pluripotency zone) and Nanog suppressed cells (early differentiation zone) within the same cell population, with a gradient of Nanog expression across the individual cell colonies, to serve as a mimic of the developmental process. Using this system, we identified strong interactions between Nanog and its target genes by constructing a network with Nanog as the root and the measured levels of gene expression in each region. Gene expression patterns at the pluripotency-differentiation boundaries recreated in vitro were similar to those in the developing blastocyst. This approach to the study of cellular commitment at the boundaries between gene expression domains, a phenomenon critical for understanding of early development, has potential to benefit fundamental research of stem cells and their application in regenerative medicine. Stem Cells 2013;31:1806-1815 © AlphaMed Press. Source

News Article
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An embryonic stem cell with just half a genome was generated by scientists, according to findings published in the journal Nature. The haploid stem cells are the first human cells capable of cell division with just one copy of the genome, allowing easier genetic manipulation and analysis, according to the American and Israeli researchers. “One of the greatest advantages of using haploid human cells is that it is much easier to edit their genes,” said Ido Sagi, the also of the Hebrew University of Jerusalem, who corresponded briefly with Laboratory Equipment by email. The technique involved triggering unfertilized human egg cells, highlighting the genome with a fluorescent dye and then isolating the haploid stem cells, according to the scientists, some of whom are from Columbia University Medical Center and the New York Stem Cell Foundation Research Institute. The stem cells are pluripotent, with the ability to become a litany of other kinds of cells, including those of major organs. “This study has given us a new type of human stem cell which will have an important impact on human genetic and medical research,” said Nissim Benvenisty, director of the Azrieli Center for Stem Cells and Genetic Research at the Hebrew University of Jerusalem. “These cells will provide researchers with a novel tool for improving our understanding of human development.” Sagi told Laboratory Equipment that the easiest application of the technique would be for genetic screening. The haploid cells were easier to scan for a particular mutation which allowed resistance to certain cellular toxicity – and the analysis could translate to all sorts of genetic variants, he said. “Unlike many previous genetic studies in humans, which focused on editing specific genes, with haploid cells we are not limited to predetermined, targeted genetic changes,” said Sagi. “This means that we can generate millions of different mutations, forming a library of mutants that can help us understand what genes in the genome are involved in specific biological processes that interest us.” Because the 23-chromosome stem cells are easier to work with than the natural diploid cells humans developed through evolution, it could provide a new look into the fundamentals of life, they add. “We expect that haploid human embryonic stem cells will provide novel means for studying human functional genomics and development,” the authors conclude. Previous breakthroughs have produced haploid stem cells from fish and mice - which have proven valuable in genetic analysis, according to the scientific literature.

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