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Using Induced Pluripotent Stem Cells to Model Human Disease
Human induced pluripotent stem cells (iPSCs) have many potential applications in health and medicine. Although the promise of employing iPSCs for cell therapy is far from being realized, iPSCs are being used today in drug discovery and development.
Using iPSCs to assess drug toxicity enables toxicity evaluations to be performed early in the drug development process (compared to the later time frames typically employed for in vivo animal studies). More about using stem cells for drug development can be found in a previous blog titled “How Stem Cells Can Play a Major Role in Developing New Therapeutics.”
In addition to drug development, human iPSCs can be used to create in vitro disease models. Models employing patient-derived cells allow researchers to examine the disease and mechanisms of action, and in many cases, provide a closer match to the actual pathological state than animal models. Earlier this month, STEMCELL Technologies hosted a webinar titled “Modeling Human Neurological Disease with Induced Pluripotent Stem Cells,” where they provided an excellent overview of the use of iPSCs to create a model for neurological disease.
In the first portion of the webinar, Dr. Vivian Lee, Senior Scientist, STEMCELL Technologies talked about the current technologies for developing iPSC disease models, focusing on their use in neuroscience research. Some of the advantages/challenges of the various methods were discussed.
Topics covered include:
- Starting somatic cell types
- Reprogramming systems (e.g. virus, DNA, RNA)
- Maintenance and characterization of iPSCs
- Differentiation methods
Variability in techniques and quality of starting cells can affect the success of neural differentiation from human embryonic stem (ES) and iPS cells. STEMCELL Technologies offers tools to support each step of the process, from TeSR™-E7™ reprogramming medium to mTeSR™1 maintenance medium and STEMdiff™ differentiation reagents. The STEMdiff™ Neural Induction System provides a complete workflow and robust protocols for the derivation of neural progenitor cells using both embryoid body (EB) and monolayer culture methods.
Dr. Lee also touched on why iPSCs are such a valuable tool for disease modeling. Main points are: 1) many cells can be generated from iPSCs for experiments whereas neurological tissue from humans can be difficult to obtain, and 2) animal models, while important, may not sufficiently correlate the human disease being studied. iPSCs have been generated from patients with many different neurological diseases such as spinal muscular atrophy, Huntington’s disease, Machado-Joseph disease, and familial dysautonomia. Another advantage to using iPSCs is that they can also be used to study multifactorial diseases, which can be difficult in animal models. Lastly, Dr. Lee discussed the general principles of patterning neural progenitor cells into different types of neurons and glia cells in the central nervous systems.
In the second part of the webinar, Dr. Marina Bershteyn from UC San Francisco presented her work that uses iPSCs to study Miller-Dieker Syndrome, the most severe form of type 1 lissencephaly. This is caused by the deletion of the distal portion of chromosome 17, which affects proteins that regulate neuron migration, resulting in a failure of brain folding and a completely smooth brain. She produced iPSCs from patient-derived fibroblasts and showed that those iPSCs could self-renew, and were pluripotent by their ability to differentiate into three germ layers. Using the STEMdiff™ Neural Induction System, she generated 2- and 3-D cultures with neural rosettes and examined the phenotype and behavior of these cells, including time-lapse live imaging of the migrating neural progenitor cells. The example provided by Dr. Bershteyn highlights how iPSCs can be used to model a human disease and provide insights in ways that animal models or other in vitro methods could not. The information and topics covered in the webinar can provide a framework for using iPSCs to study the development of the human nervous system and etiologies of neurological disorders.