Mike May earned an M.S. in biological engineering from the University of Connecticut and a Ph.D. in neurobiology and behavior from Cornell University. He worked as an associate editor at American Scientist, and he is the author of hundreds of articles for clients that include Nature, Science, Scientific American and many others.
In 2006, Shinya Yamanaka and his team at Kyoto University in Japan reported that they could reprogram mouse fibroblasts into induced pluripotent stem cells (iPSCs). In brief, that means that they took a differentiated cell and made an undifferentiated one, and the latter could be turned into various kinds of cells, like muscle, nerve and so on. Today, scientists around the world use iPSCs to study a variety of neurodegenerative diseases, including Alzheimer’s Disease, Parkinson’s Disease and others.
Given the breadth of this field—with over 1500 publications on the area of iPSCs and neurodegeneration generated in 2016—there is a wealth of information and one research scientist with experience working with iPSCs to study neurodegeneration suggested several recent articles [1–5]. Here we discuss a few of the more recent innovations in working with neutral iPSCs.
Pluripotent cells can be used in various studies of neurodegeneration. According to Alice Pébay, associate professor and head of the neuroregeneration research unit at the University of Melbourne in Australia, the key benefit of using iPSCs to study neurodegenerative disorders is “access to human samples—human patient cells that will carry the genetic information of interest.” She adds that this is “especially important for diseases which do not yet have good animal models.”
Despite the gigantic opportunities in neurodegenerative medicine from iPSCs, scientists face some challenges. For one thing, “iPSC-derived cells are closer to fetal cells than adult cells, and this needs to be taken into consideration for modelling diseases” says Pébay. But she points out that the cells could be aged. For example, Lorenz Studer—director of the center for stem cell biology at the Memorial Sloan Kettering Cancer Center—and his colleagues aged some human iPSCs with the protein progerin. [6]
In addition, Pébay points out that the sample size can be very important to get adequate statistical results.
By handling these challenges, however, scientists can explore new areas of neurodegeneration with iPSCs in ways that cannot be done easily without them.
Commercial kits
Various companies now offer kits that can be used to study neurodegenerative diseases with iPSCs. For example, Sam Lloyd-Burton, senior product marketing manager at STEMCELL Technologies, says, “Customers use our specialized differentiation kits to generate the types of neurons that are affected by neurodegenerative diseases from human pluripotent stem cells.”
These customers start with iPSCs generated from patients with the neurodegenerative disease, and then use the kit to make the kind of cells needed. “Many studies are aimed at investigating the presymptomatic stages of disease, whereas others apply stresses to uncover age-related phenotypes,” Lloyd-Burton explains.
For example, Lloyd-Burton points out that a scientist can start with human PSCs or neural progenitor cells, and then use STEMCELL Technologies’ STEMdiff “to generate forebrain-type neurons, midbrain-type dopaminergic neurons and astrocytes.” She adds, “For example, the STEMdiff Dopaminergic Neuron Differentiation and Maturation Kits can be used to generate midbrain-type dopaminergic neurons for modeling Parkinson’s.”
Even more options lie ahead. “In the near future,” says Lloyd-Burton, “we will also be offering cryopreserved neural progenitor cells and pre-differentiated neuronal and glial precursors, from various backgrounds, for people who would like the convenience of a ready-to-use vial of cells.”
Ready-to-go cells
Some companies provide neural progenitor cells (NPCs) that can make various neuronal cells, like neurons and glial cells. For example, Lonza produces its NHNP-Normal Human Neural Progenitors and medium. These can be used to study the development of neuronal systems and their functions, as well as diseases and the development of new drugs.
According to Brett Spangler, product manager at Lonza, “Cryopreserved Human Neural Progenitors, NHNPs, are guaranteed to contain more than 1.2 million viable cells per ampoule and test positive for Neuronal Class II Beta Tubulin and Glial Fibrillary Acid Protein, GFAP, following differentiation.” He adds, “All cells test negative for mycoplasma, bacteria, yeast and fungi.” A customer also gets a certificate of analysis for each product.
To simplify using these cells, customers can also purchase medium from Lonza. Spangler recommends the “NPMM Neural Progenitor Maintenance BulletKit Medium for recovery from cryopreservation and maintenance as neurospheres” and “ NPDM Neural Progenitor Differentiation BulletKit Medium + 25 ng/ml brain-derived neurotrophic factor, BDNF, for non-directed differentiation of neurospheres into neurons, astrocytes and oligodendrocytes.”
For scientists interested in using these cells or media, Lonza can provide technical support and guidance. For instance, Spangler says, “Lonza can offer a protocol for maintaining and differentiating these cells and can provide suggestions for customers looking to direct differentiation either more towards astrocytes or more towards neuronal cells—otherwise, you get a mixed population.” He adds, “Our scientific support group is also a great asset available to customers to troubleshoot whenever necessary.”
Preventing blindness
Age-related macular degeneration (AMD) is a major cause of blindness among Americans who are 65 years old or older, according to the U.S. Centers for Disease Control and Prevention.
This neurodegenerative disease damages the macula, which is the part of the retina that provides sharp vision. Pébay’s team uses human iPSCs to study AMD. As she says, “We generated iPSCs from patients carrying specific genetic risks and who present with AMD.”
Pébay and her colleagues use those iPSCs to make a differentiated type of cell called retinal pigment epithelium. These cells “together with photoreceptors, degenerate in AMD,” Pébay explains. “We are assessing whether the cells obtained from patients with AMD show specific phenotypes, that can be linked to specific cellular pathways.”
This work could reveal targets that could lead to the development of therapies for AMD. Likewise, using iPSCs to study neurodegeneration in its various forms helps scientists understand the processes behind the diseases and damage, which can reveal potential avenues to therapies.
References
[1] Flaherty, EK, Brennand, KJ. Using hiPSCs to model neuropsychiatric copy number variations (CNVs) has potential to reveal underlying disease mechanisms. Brain Research, 2015. [PMID: 26581337]
[2] Ross, CA, Akimov, SS. Human-induced pluripotent stem cells: potential for neurodegenerative diseases. Human Molecular Genetics, 23:17-26, 2014. [PMID: 24824217]
[3] Srikanth, P, Young-Pearse, TL. Stem cells on the brain: modeling neurodevelopmental and neurodegenerative diseases using human induced pluripotent stem cells. Journal of Neurogenetics, 28: 5-29,2014. [PMID: 24628482]
[4] Sun, Y, Dolmetsch, RE. How induced pluripotent stem cells are informing drug discovery in psychiatry. Swiss Medical Weekly, 2016. [PMID: 26752334]
[5] Young-Pearse, TL, Morrow, EM. Modeling developmental neuropsychiatric disorders with iPSC technology: challenges and opportunities. Current Opinion in Neurobiology, 2016. [PMID: 26517284]
[6] Miller, JD, et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell, 2013. [PMID: 24315443]
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