Sophia Hoar | December 24th, 2024
As with most research subjects, neurological disorders can be studied using a myriad of models. Among the most common models implemented in a wet lab setting are animal models, post-mortem brain tissue, and, most recently, induced pluripotent stem cells. Neurological disorders can further be elucidated in dry lab contexts through techniques such as computational models, magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), and many more. Each research method features its individual strengths and limitations, necessitating a combinatorial approach to most deeply understand the physiology of neurological disorders. One of the most recently developed cutting-edge technologies pioneering new frontiers in neuroscience is induced pluripotent stem cells (iPSCs).
What are stem cells?
Stem cells are cells that have not yet been “differentiated” in the body. In other words, the genes that assign all cells a particular role in the body and distinguish them structurally from other cells have not yet been expressed. Thus, the origins of an epithelial cell (skin cell) are the same as that of a hepatocyte (liver cell) and a pneumocyte (lung cell). Different environmental signals interact with the cell to influence which genes are expressed in a stem cell, leading to its differentiation into a specific cell type, such as a neuron (nerve cell).
Connecting stem cells to induced pluripotent stem cells
Within a scientific context, the ability to access stem cells and modulate their differentiation presents immense potential in research, particularly in the study of disorders in humans for which tissue samples cannot be acquired from living human subjects. This is the case with neurological disorders. However, adult stem cells are of limited supply in the body and are difficult to isolate and purify. Further, the use of embryonic stem cells challenges ethical conduct principles in research.
Herein lies the utility of iPSC technology. This technology takes a regenerable sample of cells from a human subject that poses no detriment to the participant such as skin cells, blood, or urine, and applies specific transcription factors (molecules that modulate gene expression) to the sample to reprogram these cells such that they become undifferentiated, blank-slate stem cells. Next, these cells are cultured under conditions controlled by the researcher to induce differentiation into the desired cells of study. In the case of neurological disorder studies, these cells might be differentiated into neurons, astrocytes, glia, or other cell types that make up the brain.
Strengths of the iPSC model
iPSCs are a powerful model in that when the somatic (body) cells of study participants are reprogrammed, the topography of their genome is maintained. In other words, mutations — flaws in the genetic code that can be innocuous or cause diseases — remain present in the genetic material of the iPSC. Such preservation is imperative in patient-derived iPSCs, which are iPSCs obtained from a patient who has a condition that is being studied. For neurological disorders, this could include a multitude of conditions from schizophrenia to autism to multiple sclerosis. By comparing patient-derived iPSCs to iPSCs from a healthy control group, scientists can get a functional look at how cells behave in a perturbed state relative to how they perform their roles in healthy individuals, providing insight not only into the physiology of a disease but also how that pathology progresses over time. Thus, the primary strength of iPSCs lies in their ability to model neurological disorders functionally, using human cells without requiring post-mortem tissue, and in a way that is highly reflective of the genome of the participant.
Limitations of the iPSC model
Nonetheless, many limitations offset the strengths of iPSCs. For instance, it can be challenging to study the progression of late-onset conditions such as Parkinson’s Disease since the maturation of models must be rapidly accelerated by the medium in which they are grown to effectively study disease manifestations. Further, while the accuracy of the genome retained from reprogramed patient-derived and control-derived iPSCs presents a reliable model, it can be challenging to ascertain which genetic components of these models are contributing to the disease and which are merely components of an individual’s unique genetic profile. The reprogramming of these cells may also be incomplete, meaning participants’ specific epigenetic signatures might be retained by the iPSC’s genome.
Perhaps the greatest limitation of iPSCs is their inability to fully mimic the exact conditions of the human brain. In other words, they cannot capture complete biological integrity. As an in vitro model (something that is studied “in glass” such as through cell culture, rather than in an organism, as with animal models), the capacity of iPSCs to reflect exactly what is occurring in a real human brain is constrained by scientists’ ability to emulate the environment in which a human brain exists. Although the medium in which iPSCs are cultured is generally reflective of this environment, there are limitations to the accuracy of their structural arrangement in space. Notable progress has been made in transitioning from 2D iPSC cultures to 3D organoids through the use of biomaterials as scaffolding on which the iPSCs can self-organize in a manner that parallels true anatomical structural arrangements in the brain. However, there remains much work to be done before these models achieve a degree of biological integrity that can comprehensively model neurological disorders.
Researchers, including those in the Lippmann Lab at the Vanderbilt Institute of Nanoscale Science and Engineering, are exploring avenues to attain more accurately-rendered iPSC models. In the Lippmann Lab, this work takes the form of several distinct projects. One such project investigates how various biomaterials, such as hydrogels, can be incorporated into the cell cultures of iPSCs to improve the biological integrity of the model. With the assistance of scaffolds such as biomaterials, the self-organizing behavior of iPSCs may be able to better approximate the structure of an actual human brain.
As a relatively nascent technique discovered in 2006, many of the limitations to current iPSC models have immense potential to be improved. While replicating the human brain’s full complexity without the use of brain tissue samples presents a challenging task, iPSCs are paving the way for more accurate and functional models of neurological diseases. Continued advancements in this field could revolutionize our understanding of the pathophysiology of neurological disorders, launching new avenues to treatment.
References
Li, L., Chao, J., & Shi, Y. (2017). Modeling neurological diseases using iPSC-derived neural
cells. Cell and Tissue Research, 380(3), 143-151.
https://doi.org/10.1007/s00441-017-2713-x.
Wang, H. (2018). Modeling Neurological Diseases With Human Brain Organoids. Frontiers in
Synaptic Neuroscience, 10(1), https://doi.org/10.3389/fnsyn.2018.00015.
Xie, N. & Tang, B. (2016). The Application of Human iPSCs in Neurological Diseases: From
Bench to Bedside. Stem Cells International, 2016(1),
https://doi.org/10.1155/2016/6484713
Zhang, D. Y., Song, H., & Ming, G. (2020). Modeling neurological disorders using brain
organoids. Seminars in Cell & Developmental Biology, 111(1), 4-14.