iPSCs and Drug Research
Overview
Induced pluripotent stem cells (iPSCs) can be used as a stem cell source to facilitate disease modelling and drug discovery. In disease modelling, researchers study the mechanism of how pathologies develop and influence the function of cells, tissue and organs in a certain disease. Knowing how disease develops in human body is essential to drug research because it helps scientists identify what specific cells the disease affect and how it causes damage to tissue function. Then scientists can work to develop drugs that target a certain cell or mechanism. On the other hand, iPSCs can also be used as a stem cell source to culture disease-affected tissue for drug screening and testing.
Let’s walk through the following case study on how iPSCs can be used in studying neurodegenerative diseases
Case Study:
iPSCs in Neurodegenerative Disease Research
Neurons
First, let’s review the anatomy and physiology of neurons.
Neurons are the most basic unit of the nervous system. The body consists of an interconnected network of neurons. Neurons sends sensory information to the brain for processing and relays responses from the brain to different body parts by conducting and transmitting information between each other. Neurons mainly reside in the brain and spinal cord and extend to different body parts.
Figure 1 shows the different parts of a neuron.
Cell body: Located at the end of a neuron and contains the
nucleus
Dendrites: Branches out from the cell body and receives
electrical signal
Axon: A bunch of nerve fibers that transmit electrical signal
from the cell body to the synapse.
Synapse: The space between the axon terminal of one neuron
and the dendrites of the next neuron
Neurotransmitter: The signaling molecule in the synapse that transmits
electrical signal from one neuron to another
Myelin sheath: A layer of insulation and protection around the axon
to increase electric signal transmission
Glial cells: Cells that provide support to neurons and do not
participate in signal transmission
Oligondendrocyte: A type of glial cell that forms the myelin sheath
Figure 1: Anatomy of a neuron
Neurodegenerative diseases
Neurodegenerative diseases refer to pathologies in the nervous system that result in the degeneration and loss of neurons and glial cells, which lead to the loss of structure, function and cell death. Such diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis, amyotrophic lateral sclerosis (ALS), etc.. So far, there is no cure to neurodegenerative diseases. Although extensive research on these diseases are being conducted, the underlying cause and mechanisms are yet to be discovered. Disease modelling and drug development of neurodegenerative diseases are mainly impeded by the lack of human neural cell sources that can be used in research.
Why are iPSCs Useful for Neurodegenerative Disease Research?
By adulthood, neurons barely self-repair, undergo mitosis or regenerate. Therefore, it is nearly impossible to obtain human neurons in great amount for research purposes. In addition, neurons are difficult to culture and preserve in vitro. Therefore, current disease modelling is mostly done in animal models, which do not necessarily represent human body conditions. In order to study the mechanisms behind neurodegenerative diseases, human neural cells are needed to facilitate disease modeling and drug screening.
Due to the ability of iPSCs to differentiate into a wide range of cell types, they are able to provide disease-specific cells to facilitate the research on a certain disease. For example, iPSCs can be programmed to differentiate into neurons and oligodendrocytes, which are present in all neurodegenerative diseases. iPSCs are also patient-specific and can be used to develop customized drug for each patient.
Figure 2 illustrates the two ways iPSCs can be used in disease modeling and drug screening. Firstly, somatic cells can be harvested from a healthy individual and programmed into iPSCs. These “healthy” iPSCs can then differentiate into neural cells for drug screening and toxicity tests. Secondly, somatic cells can be harvested from patients carrying a specific neurodegenerative disease. When iPSCs are produced from these cells, they will carry the disease-specific genes and differentiate into disease-affected neurons. These “sick” neurons can then be used for disease modeling or drug testing. Patient-specific iPSCs can also be used to study whether they can be modified to produce “healthy” cells.
Example of How iPSCs Are Used Alzheimer’s Disease Modeling
Background
Alzheimer’s disease (AD) is the most common form of chronic neurodegenerative diseases and the 6th leading cause of death in the U.S. In Alzheimer’s disease, neurons degenerate and lose their functions, which lead to a decrease in brain volume and impair neurological activities. Patients usually experience a decline in memory, cognition and sense of space as the symptoms worsen with age.
Figure 2: The use of healthy iPSCs and disease-affected iPSCs in drug research
Pathologies involved in AD include intracellular neurofibrillary tangles (NFT) and plaque formation. The video shown above illustrates the pathologies in detail. NFT refers to the detachment of a kind of protein called tau from the microtubules in the neural fibers of an axon. Tau aggregate and deposit on the outside of the neural fibers. On the other hand, genetic mutation also leads to the overproduction of amyloid precursor protein (APP) and its peptide amyloid- β (Aβ), which aggregate and form plaque among the neural fibers. NFT and plaque significantly impair electrical signal transmission and cause neurons to deteriorate. Although these pathologies are identified through research, the mechanisms behind the onset and development of the pathologies are still unknown.
iPSCs in AD
As iPSCs technology matures, they become more widely used in AD modeling because they are able to provide sufficient disease-specific cell types for research. iPSCs from healthy individuals are able to provide healthy neurons and glial cells, while those from AD patients are able to generate disease-affected neural cells. Disease-affected neural cells, especially those carrying mutations in APP and in genes that cause NFT and plaque, are essential to AD modeling. These disease-affected cells are able to reproduce the development of NFT and plaque and demonstrate the mechanisms behind the development pathologies. Researchers will be able to use this information to investigate potential treatments of AD and conduct drug screening on disease-affected iPSCs.
Conclusion
iPSCs are essential to drug research, especially in disease modelling and drug screening because they are able to provide access to many different disease-specific cell types. In neurodegenerative diseases, iPSCs are able to provide sufficient neural cells from human sources that are previously impossible to obtain, which make them a promising source for disease modelling and drug screening.
Besides Alzheimer’s disease, iPSCs are also used in research on Parkinson’s disease, ALS, multiple sclerosis, Down Syndrome and many other neurological diseases.
If you would like more information on this topic, please check the reference for links to the papers and videos used on this page.
Reference:
Neurons - National Library of Medicine - PubMed Health. (n.d.). Retrieved December 04, 2017, from https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024269/
Figure 1 credit to this paper
Wenbin Wan, Lan Cao, Bill Kalionis, Shijin Xia, and Xiantao Tai, “Applications of Induced Pluripotent Stem Cells in Studying the Neurodegenerative Diseases,” Stem Cells International, vol. 2015, Article ID 382530, 11 pages, 2015. doi:10.1155/2015/382530
<https://www.hindawi.com/journals/sci/2015/382530/>
Figure 2 credit to this paper
“What is Alzheimer’s Disease?”
https://www.youtube.com/watch?time_continue=63&v=7_kO6c2NfmE
Sarah E. Sullivan, Tracy L. Young-Pearse, Induced pluripotent stem cells as a discovery tool for Alzheimer׳s disease, In Brain Research, Volume 1656, 2017, Pages 98-106, ISSN 0006-8993, https://doi.org/10.1016/j.brainres.2015.10.005.
<http://www.sciencedirect.com/science/article/pii/S0006899315007428>
Figure 3 credit to http://www.quantumday.com/2012/05/spin-labeled-fluorene-compounds.html
Figure 3: Pathologies in AD patient's brain
What is Alzheimer's disease?
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