Experimental modelling of human disorders enables the definition of the cellular and molecular mechanisms underlying diseases and the development of therapies for treating them. The availability of human pluripotent stem cells (PSCs), which are capable of self-renewal and have the potential to differentiate into virtually any cell type, can now help to overcome the limitations of animal models for certain disorders. The ability to model human diseases using cultured PSCs has revolutionized the ways in which we study monogenic, complex and epigenetic disorders, as well as early- and late-onset diseases. Several strategies are used to generate such disease models using either embryonic stem cells (ES cells) or patient-specific induced PSCs (iPSCs), creating new possibilities for the establishment of models and their use in drug screening.

Pluripotent stem cells in disease modelling and drug discovery

A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans Here we describe a novel recombinant adeno-associated virus that restricts gene expression to GABAergic interneurons within the telencephalon We demonstrate that the viral expression is specific and robust, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in both mice and non-genetically tractable species, thus opening the possibility to study GABAergic function in virtually any vertebrate species

/pdf/a-viral-strategy-for-targeting-and-manipulating-interneurons-4gluuqv9az.pdf

A viral strategy for targeting and manipulating interneurons across vertebrate species

Microglia, the immune cells of the brain, are crucial to proper development and maintenance of the CNS, and their involvement in numerous neurological disorders is increasingly being recognized. To improve our understanding of human microglial biology, we devised a chemically defined protocol to generate human microglia from pluripotent stem cells. Myeloid progenitors expressing CD14/CX3CR1 were generated within 30 days of differentiation from both embryonic and induced pluripotent stem cells (iPSCs). Further differentiation of the progenitors resulted in ramified microglia with highly motile processes, expressing typical microglial markers. Analyses of gene expression and cytokine release showed close similarities between iPSC-derived (iPSC-MG) and human primary microglia as well as clear distinctions from macrophages. iPSC-MG were able to phagocytose and responded to ADP by producing intracellular Ca2+ transients, whereas macrophages lacked such response. The differentiation protocol was highly reproducible across several pluripotent stem cell lines.

Directed Differentiation of Human Pluripotent Stem Cells to Microglia.

Induced pluripotent stem cell (iPSC) technologies have provided in vitro models of inaccessible human cell types, yielding new insights into disease mechanisms especially for neurological disorders. However, without due consideration, the thousands of new human iPSC lines generated in the past decade will inevitably affect the reproducibility of iPSC-based experiments. Differences between donor individuals, genetic stability and experimental variability contribute to iPSC model variation by impacting differentiation potency, cellular heterogeneity, morphology, and transcript and protein abundance. Such effects will confound reproducible disease modelling in the absence of appropriate strategies. In this Review, we explore the causes and effects of iPSC heterogeneity, and propose approaches to detect and account for experimental variation between studies, or even exploit it for deeper biological insight.

/pdf/addressing-variability-in-ipsc-derived-models-of-human-26eks3mgks.pdf

Addressing variability in iPSC-derived models of human disease: guidelines to promote reproducibility.

Use of clinical-grade human induced pluripotent stem cell (iPSC) lines as a starting material for the generation of cellular therapeutics requires demonstration of comparability of lines derived from different individuals and in different facilities This requires agreement on the critical quality attributes of such lines and the assays that should be used Working from established recommendations and guidance from the International Stem Cell Banking Initiative for human embryonic stem cell banking, and concentrating on those issues more relevant to iPSCs, a series of consensus workshops has made initial recommendations on the minimum dataset required to consider an iPSC line of clinical grade, which are outlined in this report Continued evolution of this field will likely lead to revision of these guidelines on a regular basis

Quality control guidelines for clinical-grade human induced pluripotent stem cell lines.

A modular, robotic system for reprogramming to induced pluripotent stem cells in high-throughput and automated fashion.

Automated, high-throughput derivation, characterization and differentiation of induced pluripotent stem cells.

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Automated, high-throughput derivation, characterization and differentiation of induced pluripotent stem cells.