C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca-permeable AMPA receptor-mediated excitotoxicity.

Mutations in C9ORF72 are the most common cause of familial amyotrophic lateral sclerosis (ALS). Here, through a combination of RNA-Seq and electrophysiological studies on induced pluripotent stem cell (iPSC)-derived motor neurons (MNs), we show that increased expression of GluA1 AMPA receptor (AMPAR) subunit occurs in MNs with C9ORF72 mutations that leads to increased Ca-permeable AMPAR expression and results in enhanced selective MN vulnerability to excitotoxicity. These deficits are not found in iPSC-derived cortical neurons and are abolished by CRISPR/Cas9-mediated correction of the C9ORF72 repeat expansion in MNs.

Development of an inducible platform for intercellular protein delivery.

A challenge to protein based therapies is the ability to produce biologically active proteins and their ensured delivery. Various approaches have been utilised including fusion of protein transduction domains with a protein or biomolecule of interest. A compounding issue is lack of specificity, efficiency and indeed whether the protein fusions are actually translocated into the cell and not merely an artefact of the fixation process.

Chondrocytes Derived From Mesenchymal Stromal Cells and Induced Pluripotent Cells of Patients With Familial Osteochondritis Dissecans Exhibit an Endoplasmic Reticulum Stress Response and Defective Matrix Assembly.

Unlabelled: : Familial osteochondritis dissecans (FOCD) is an inherited skeletal defect characterized by the development of large cartilage lesions in multiple joints, short stature, and early onset of severe osteoarthritis. It is associated with a heterozygous mutation in the ACAN gene, resulting in a Val-Met replacement in the C-type lectin domain of aggrecan. To understand the cellular pathogenesis of this condition, we studied the chondrogenic differentiation of patient bone marrow mesenchymal stromal cells (BM-MSCs).

Somatic cell nuclear transfer: origins, the present position and future opportunities.

Nuclear transfer that involves the transfer of the nucleus from a donor cell into an oocyte or early embryo from which the chromosomes have been removed was considered first as a means of assessing changes during development in the ability of the nucleus to control development. In mammals, development of embryos produced by nuclear transfer depends upon coordination of the cell cycles of donor and recipient cells. Our analysis of nuclear potential was completed in 1996 when a nucleus from an adult ewe mammary gland cell controlled development to term of Dolly the sheep.

From germ cell preservation to regenerative medicine: an exciting research career in biotechnology.

Collection, manipulation, assessment, and storage of mammalian gametes, embryos, and stem cells are providing important opportunities in agriculture, research, and medicine. Semen and embryo freezing in livestock are used in breeding schemes, especially in cattle and for international trade, with no risk of spreading disease. In human medicine, they are used in treatment of infertility.

Toward the development of a global induced pluripotent stem cell library.

The ability to preselect the donor genotype of iPSC lines provides important opportunities for immune matching in cell therapy. Here we propose that an international assessment should be made of how immune incompatibility can best be managed and how a network of GMP HLA homozygous haplobanks could be operated.

Comment on "Drug screening for ALS using patient-specific induced pluripotent stem cells".

Egawa et al. recently showed the value of patient-specific induced pluripotent stem cells (iPSCs) for modeling amyotrophic lateral sclerosis in vitro. Their study and our work highlight the need for complementary assays to detect small, but potentially important, phenotypic differences between control iPSC lines and those carrying disease mutations.

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy.

Glial proliferation and activation are associated with disease progression in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia. In this study, we describe a unique platform to address the question of cell autonomy in transactive response DNA-binding protein (TDP-43) proteinopathies. We generated functional astroglia from human induced pluripotent stem cells carrying an ALS-causing TDP-43 mutation and show that mutant astrocytes exhibit increased levels of TDP-43, subcellular mislocalization of TDP-43, and decreased cell survival.

SUMOylation of HNF4α regulates protein stability and hepatocyte function.

The coordination of signalling pathways within the cell is vital for normal human development and post-natal tissue homeostasis. Gene expression and function is therefore tightly controlled at a number of levels. We investigated the role that post-translational modifications play during human hepatocyte differentiation.

Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability.

Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 (TARDBP) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation and their differentiation into neurons and functional motor neurons.

Rat eggs cannot wait: Spontaneous exit from meiotic metaphase-II arrest.

Mammalian eggs await fertilisation while arrested at the second metaphase stage of meiotic division. A network of signalling pathways enables the establishment and maintenance of this metaphase-II arrest. In the absence of fertilisation, mammalian eggs can spontaneously exit metaphase II when parthenogenetically stimulated, or sometimes without any obvious stimulation.

Lineage-specific distribution of high levels of genomic 5-hydroxymethylcytosine in mammalian development.

Methylation of cytosine is a DNA modification associated with gene repression. Recently, a novel cytosine modification, 5-hydroxymethylcytosine (5-hmC) has been discovered. Here we examine 5-hmC distribution during mammalian development and in cellular systems, and show that the developmental dynamics of 5-hmC are different from those of 5-methylcytosine (5-mC); in particular 5-hmC is enriched in embryonic contexts compared to adult tissues.

The evolving biology of cell reprogramming.

Modern stem cell biology has achieved a transformation that was thought by many to be every bit as unattainable as the ancient alchemists' dream of transforming base metals into gold. Exciting opportunities arise from the process known as 'cellular reprogramming' in which cells can be reliably changed from one tissue type to another. This is enabling novel approaches to more deeply investigate the fundamental basis of cell identity.

Histone H4K20me3 and HP1α are late heterochromatin markers in development, but present in undifferentiated embryonic stem cells.

We report here that the formation of heterochromatin in cell nuclei during mouse development is characterised by dynamic changes in the epigenetic modifications of histones. Our observations reveal that heterochromatin in mouse preimplantation embryos is in an immature state that lacks the constitutive heterochromatin markers histone H4 trimethyl Lys20 (H4K20me3) and chromobox homolog 5 (HP1α, also known as CBX5). Remarkably, these somatic heterochromatin hallmarks are not detectable--except in mural trophoblast--until mid-gestation, increasing in level during foetal development.

Nuclear transfer to eggs and oocytes.

We review experiments in which somatic cell nuclei are transplanted singly to enucleated eggs (metaphase II) in amphibia and mammals and as multiple nuclei to the germinal vesicle of amphibian oocytes (prophase I). These experiments have shown the totipotency of some somatic cell nuclei, as well as switches in cell type and changes in gene expression. Abnormalities of nuclear transplant embryo development increase greatly as nuclei are taken from progressively more differentiated donor cells.

Biomedical and social contributions to sustainability.

Over the past two or three centuries, biomedical advances have provided methods to prevent and treat infectious diseases. These changes have greatly reduced human suffering and enhanced sustainability by allowing people to live longer and healthier lives. The challenge for the coming centuries will be to ensure that these longer, healthier lives are also more productive lives.