Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Jun;56(6):1348-1364.
doi: 10.1038/s12276-024-01250-x. Epub 2024 Jun 3.

Advances and challenges in modeling inherited peripheral neuropathies using iPSCs

Affiliations
Review

Advances and challenges in modeling inherited peripheral neuropathies using iPSCs

Jonas Van Lent et al. Exp Mol Med. 2024 Jun.

Abstract

Inherited peripheral neuropathies (IPNs) are a group of diseases associated with mutations in various genes with fundamental roles in the development and function of peripheral nerves. Over the past 10 years, significant advances in identifying molecular disease mechanisms underlying axonal and myelin degeneration, acquired from cellular biology studies and transgenic fly and rodent models, have facilitated the development of promising treatment strategies. However, no clinical treatment has emerged to date. This lack of treatment highlights the urgent need for more biologically and clinically relevant models recapitulating IPNs. For both neurodevelopmental and neurodegenerative diseases, patient-specific induced pluripotent stem cells (iPSCs) are a particularly powerful platform for disease modeling and preclinical studies. In this review, we provide an update on different in vitro human cellular IPN models, including traditional two-dimensional monoculture iPSC derivatives, and recent advances in more complex human iPSC-based systems using microfluidic chips, organoids, and assembloids.

PubMed Disclaimer

Conflict of interest statement

D.L.B. has acted as a consultant in the last 2 years for AditumBio, Biointervene, Combigene, LatigoBio, GSK, Ionis, Lexicon Therapeutics, Neuvati, Olipass, Orion, Replay, SC Health Managers, Third Rock Ventures and Vida Ventures on behalf of Oxford University Innovation. L.V.D.B. is head of the Scientific Advisory Board of Augustine Therapeutics (Leuven, Belgium) and is part of the Investment Advisory Board of Droia Ventures (Meise, Belgium).

Figures

Fig. 1
Fig. 1. Schematic overview of the peripheral nerves and associated cell types involved in inherited peripheral neuropathies (IPNs).
The scheme illustrates the different subtypes of IPN: Charcot-Marie-Tooth (CMT), which affects both motor and sensory neurons; hereditary sensory and autonomic neuropathy (HSAN), which affects only sensory and/or autonomic neurons; and distal hereditary motor neuropathy (dHMN), which affects only motor neurons. The boxes on the schematic represent known cell types that contribute to/act in IPN pathogenesis. NMJ neuromuscular junction. Created with BioRender.com.
Fig. 2
Fig. 2. Graph showing all the IPN patient-specific iPSC papers published over time.
The figure shows the IPN studies published over time (black), studies with isogenic controls (red), and studies examining multiple cell types (blue). The total number of studies, including preprints, is 36, all of which are listed in Table 2.
Fig. 3
Fig. 3. Illustration of a peripheral nerve and reported phenotypes described in inherited peripheral neuropathies (IPNs) using iPSCs.
The schematic shows different phenotype terms, numbered and located within the neuron based on the reported IPN iPSC studies. These terms can then be broadly divided into the following categories: neuronal defects, mitochondrial dysfunction, Schwann cell, metabolic and protein abnormalities, inflammation, and immune response. Created with BioRender.com.
Fig. 4
Fig. 4. Current stem cell models used to study inherited peripheral neuropathies (IPNs).
The figure shows various stem cell models. The upper blue panel represents monocultures, while the lower panel illustrates more complex models, from 2D to 3D cocultures, grown in microfluidic devices or as neuromuscular assembloids or organoids containing multiple cell types. The right blue panel depicts the potential use of these models in combination with mice (known as humanized mouse models). Finally, the figure also highlights the ability of these models to contribute to the assessment of therapeutics and gene-editing approaches or the identification of potential biomarkers. Created with BioRender.com.

References

    1. Baets, J., De Jonghe, P. & Timmerman, V. Recent advances in Charcot–Marie–Tooth disease. Curr. Opin. Neurol.27, 532–540 (2014). - PubMed
    1. Pisciotta, C. & Shy, M. E. Neuropathy. Handb. Clin. Neurol 148, 653–665 (2018). - PubMed
    1. Saporta, M. A. & Shy, M. E. Inherited peripheral neuropathies. Neurol. Clin.31, 597–619 (2013). - PMC - PubMed
    1. Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med.379, 11–21 (2018). - PubMed
    1. Benson, M. D. et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N. Engl. J. Med.379, 22–31 (2018). - PubMed

MeSH terms

Supplementary concepts