Stem Cells

Studying Age-related Neurological Disease with Pluripotent Stem Cells – Part 1

Posted on 17 May 2021

From 1990-2016, global deaths from neurological disease have risen by 39%, showing that neurological disease contributes to a growing proportion of global disease, predominantly impacting both extremes of the human age spectrum; the very young and the very old [1].

Neurological diseases impact the central and peripheral nervous system, often resulting in impairment of mental capacity, motor function, language, learning capabilities or other neurological functions.

Proportional contribution of various neurological disorders to the overall burden of neurological disorders. Source: The global burden of neurological disorders: translating evidence into policy

Recent breakthroughs and technological advancements in genomic sequencing has enabled the genetic screening of patients suffering from neurological disease, leading to an increasingly large library of genetic causes of these disorders being revealed [2].

However, mapping the entire pathogenetic pathway from an identified genetic cause of a disease, through the downstream molecular mechanisms, to the expressed phenotype is an altogether much more challenging task, and is one that is yet to be fully completed for the majority of neurological conditions.

Disease models are crucial in understanding underlying cause of the disease.

Studies on transgenic animal models, especially mice, have provided valuable insight into a variety of environmental and genetic conditions that impact neuronal functions and brain development. The major benefit of using animal models is that they enable the observation of disease pathology in a living organism.

Animal studies, however, have their limitations. Species differences mean that animal models almost always fail to accurately mimic the complex nature of human neurological phenotypes. This is due to physiological dissimilarities between mice and human central nervous systems. It has been estimated that in terms of neuron population and volume the human cerebral cortex is far larger than that of mice, signifying a structure of far greater complexity [3].

Difference in brain size and morphology between mouse (A,D), macaque monkey (B,E) and human (C,F). Source: Renewed focus on the developing human neocortex

One of the major challenges of studying neurological disease is the inaccessibility of disease tissue, which is why disease models using patient-derived cells have been so rare. To circumvent this problem, transformed cell lines provide another disease model that has been utilised. However, these do not precisely represent human tissue homeostasis or metabolism [5].

In 1998, Thomson et al. derived embryonic stem cell (ESC) lines from human blastocysts. ESCs provided a source of pluripotent cells which have the potential to differentiate into any cell type in the body, providing a new in vitro human model to study disease [6]. However, a massive hurdle for this technology was the ethical issues which surrounded isolating stem cells from embryos. Many countries chose to prohibit this practice.

Stem Cell. Source: docwirenews

The introduction of induced pluripotent stem cell (iPSCs) technology in 2006 by Dr. Shinji Yamanaka was a revolutionary moment. It demonstrated the ability to artificially induce pluripotent stem cells, which meant that stem cells no longer needed to be sourced from an embryo [7]. The principle was initially proven in mice, however, shortly after, Dr. Yamanaka, along with two separate independent labs, showed that this was also applicable to human somatic cells.

Induced pluripotent stem cells. Source: metaworks

In this series of articles, which will be published over the next few days, use of iPSC technology in disease modelling in age-related neurological conditions.


References

[1] Feigin, V. L. et al. (2019) ‘Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016’, The Lancet Neurology. Lancet Publishing Group, 18(5), pp. 459–480. doi: 10.1016/S1474-4422(18)30499-X.

[2]Barral, S. and Kurian, M. A. (2016) ‘Utility of induced pluripotent stem cells for the study and treatment of genetic diseases: Focus on childhood neurological disorders’, Frontiers in Molecular Neuroscience, 9(SEP2016), pp. 1–11. doi: 10.3389/fnmol.2016.00078.

[3] Baldassari, S. et al. (2020) ‘Brain Organoids as Model Systems for Genetic Neurodevelopmental Disorders’, Frontiers in Cell and Developmental Biology, 8(October), pp. 1–9. doi: 10.3389/fcell.2020.590119.

[4] Hibaoui, Y. and Feki, A. (2012) ‘Human pluripotent stem cells: Applications and challenges in neurological diseases’, Frontiers in Physiology. Frontiers, p. 267. doi: 10.3389/fphys.2012.00267.

[5] Thomson, J. A. et al. (1998) ‘Embryonic Stem Cell Lines Derived from Human Blastocysts’, Science, 282, pp. 1145–1147. Available at: http://science.sciencemag.org/.

[6] Takahashi, K. et al. (2007) ‘Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors’, Cell, 131(5), pp. 861–872. doi: 10.1016/j.cell.2007.11.019.


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