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Review
. 2022 Jan 6;29(1):11-35.
doi: 10.1016/j.stem.2021.12.008.

Human stem cell models of neurodegeneration: From basic science of amyotrophic lateral sclerosis to clinical translation

Elisa Giacomelli  1 , Björn F Vahsen  2 , Elizabeth L Calder  1 , Yinyan Xu  3 , Jakub Scaber  2 , Elizabeth Gray  2 , Ruxandra Dafinca  2 , Kevin Talbot  4 , Lorenz Studer  5
Affiliations
Review

Human stem cell models of neurodegeneration: From basic science of amyotrophic lateral sclerosis to clinical translation

Elisa Giacomelli et al. Cell Stem Cell. .

Abstract

Neurodegenerative diseases are characterized by progressive cell loss leading to disruption of the structure and function of the central nervous system. Amyotrophic lateral sclerosis (ALS) was among the first of these disorders modeled in patient-specific iPSCs, and recent findings have translated into some of the earliest iPSC-inspired clinical trials. Focusing on ALS as an example, we evaluate the status of modeling neurodegenerative diseases using iPSCs, including methods for deriving and using disease-relevant neuronal and glial lineages. We further highlight the remaining challenges in exploiting the full potential of iPSC technology for understanding and potentially treating neurodegenerative diseases such as ALS.

Keywords: ALS; FTD; astrocytes; clinical translation; disease modeling; microglia; motor neurons: cortical neurons; neurodegenerative diseases; pluripotent stem cells.

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Conflict of interest statement

Declaration of interests L.S. is a scientific co-founder and paid consultant of BlueRock Therapeutics and he is listed as an inventor of several patents owned by MSKCC related to hiPSC-differentiation technologies.

Figures

Figure 1.
Figure 1.. Physiological interactions between neurons, microglia and astrocytes in the brain and spinal cord:
Neuronal and glial cells interact through various contact-dependent and -independent mechanisms under homeostatic conditions.
Figure 2.
Figure 2.. Challenges and possible solutions in modeling ALS using hiPSC technology.
Several challenges, such as weak technical reproducibility and lack of modelling inter-cellular crosstalk, remain to be resolved to improve disease modelling with hiPSC models. Amongst others, possible solutions include cell purification strategies and the development of more complex, multicellular and three-dimensional culture systems.
Figure 3.
Figure 3.. Overcoming biological variability through isogenic controls and cell purification strategies.
hiPSCs are typically generated by reprogramming skin biopsy-derived fibroblasts into pluripotency. Reprogramming-induced variability between different hiPSC clones can be reduced by generating isogenic control lines, where the mutant allele is corrected through gene-editing. Variability acquired during differentiation can be reduced by cell purification and ribosome affinity purification strategies.
See this image and copyright information in PMC

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