Lessons from iPSC research: Insights on peripheral nerve disease

doi:10.1016/j.neulet.2020.135358

Neuroscience Letters

Volume 738, 1 November 2020, 135358

https://doi.org/10.1016/j.neulet.2020.135358 Get rights and content

Highlights

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Use of hiPSCs allows for dissection of cellular mechanisms underlying human diseases.
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Patient-derived iPSCs instrumental to investigate peripheral diseases.
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In vitro generated Schwann cell-like cell promise regenerative potential.
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Patient-derived iPSCs enable personalized therapy.

Abstract

With the publication of their breakthrough discovery describing the induction of pluripotent stem cells (iPSCs) from mouse and human fibroblasts, Takahashi and Yamanaka have changed the scientific landscape. The possibility of deriving human pluripotent stem cells from almost any somatic cell has provided the unprecedented opportunity to study specific hereditary diseases in human cells.

In the context of diseases affecting peripheral nerves, iPSC platforms are now being increasingly utilized to investigate the underlying pathology as well as regenerative strategies. Peripheral neuropathies result in peripheral nerve damage, leading to – among other things – the degeneration of affected nerve fibers accompanied by severe sensory, motor and autonomic symptoms, often including intense pain. The generation of iPSCs from hereditary forms of peripheral neuropathies and their directed differentiation into cell types most affected by the disease can be instrumental to better understanding the pathological mechanisms underlying these disorders and to investigating cell replacement strategies for repair. In this minireview, we highlight studies that have used iPSCs to investigate the therapeutic potential of iPSC-derived Schwann cell-like cells for nerve regeneration, as well as studies using patient iPSC derivatives to investigate their contribution to disease pathology.

Section snippets

iPSCs as tool to repair peripheral nerve damage?

The common cellular phenotype across all peripheral neuropathies is progressive damage to peripheral nerves. In contrast to central nerve fibres, peripheral nerves have the ability of endogenous self-repair, and Schwann cells (SCs), glial cells of the peripheral nervous system (PNS), play a crucial role during this process. SCs are the most abundant cell type in the PNS [19]. They are derived from neural crest cells (NCs) during development and can be subdivided into myelinating,

iPSCs as tool to study hereditary forms of peripheral neuropathies

Charcot-Marie-Tooth (CMT) disease is the most frequently inherited peripheral neuropathy with 1 in 2500 people being affected. While the genetic underpinnings and the clinical presentation of CMT can be rather heterogeneous, the common clinical manifestation of the disease is progressive weakness and atrophy of the distal muscles. Mutations in more than 120 genes have been found in association with CMT or related neuropathies [14]. The most common form of CMT is CMT type 1A, which is caused by

Funding

This work is supported by the German Research Foundation SFB-1158 to KM and KSS.

Declaration of Competing Interest

The authors declare no competing interests.

Acknowledgements

We would like to thank Georgia Panagiotakos for helpful comments on the manuscript. The figure was created with BioRender.com

References (42)

K. Barrell et al.
Peripheral neuropathy
Med. Clin. North Am.
(2019)
D. Beam et al.
Outcomes of unrelated umbilical cord blood transplantation for X-linked adrenoleukodystrophy
Biol. Blood Marrow Transpl.
(2007)
M.J. Birket et al.
A human stem cell model of fabry disease implicates LIMP-2 accumulation in cardiomyocyte pathology
Stem Cell Rep.
(2019)
K.U. Boyd et al.
Nerve reconstruction in the hand and upper extremity
Clin. Plast. Surg.
(2011)
S.J. Chou et al.
Energy utilization of induced pluripotent stem cell-derived cardiomyocyte in Fabry disease
Int. J. Cardiol.
(2017)
Y. Kuramoto et al.
Generation of Fabry cardiomyopathy model for drug screening using induced pluripotent stem cell-derived cardiomyocytes from a female Fabry patient
J. Mol. Cell. Cardiol.
(2018)
H.C. Lehmann et al.
Use of engineered Schwann cells in peripheral neuropathy: hopes and hazards
Brain Res.
(2016)
B. Namer et al.
Pain relief in a neuropathy patient by lacosamide: proof of principle of clinical translation from patient-specific iPS cell-derived nociceptors
EBioMedicine
(2019)
L. Shi et al.
Modeling the pathogenesis of charcot-marie-Tooth disease type 1A using patient-specific iPSCs
Stem Cell Rep.
(2018)
K. Takahashi et al.
Induction of pluripotent stem cells from adult human fibroblasts by defined factors
Cell
(2007)

K. Takahashi et al.

Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors

Cell

(2006)

F. Yousefi et al.

Novel approaches using mesenchymal stem cells for curing peripheral nerve injuries

Life Sci.

(2019)

H. Azhary et al.

Peripheral neuropathy: differential diagnosis and management

Am. Fam. Phys.

(2010)

D.K. Borger et al.

Induced pluripotent stem cell models of lysosomal storage disorders

Dis. Model. Mech.

(2017)

Z. Cheng et al.

Establishment of induced pluripotent stem cells from aged mice using bone marrow-derived myeloid cells

J. Mol. Cell Biol.

(2011)

R. El Dib et al.

Enzyme replacement therapy for Anderson-Fabry disease

Cochrane Database Syst. Rev.

(2016)

J.A. Gomez-Sanchez et al.

After nerve injury, lineage tracing shows that myelin and remak schwann cells elongate extensively and branch to form repair schwann cells, which shorten radically on remyelination

J. Neurosci.

(2017)

L. Hofmann et al.

Characterization of small fiber pathology in a mouse model of Fabry disease

Elife

(2018)

J.M. Itier et al.

Effective clearance of GL-3 in a human iPSC-derived cardiomyocyte model of Fabry disease

J. Inherit. Metab. Dis.

(2014)

K.R. Jessen et al.

The repair Schwann cell and its function in regenerating nerves

J. Physiol.

(2016)

M. Juneja et al.

Challenges in modelling the Charcot-Marie-Tooth neuropathies for therapy development

J. Neurol. Neurosurg. Psychiatry

(2019)

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Sickle cell disease iPSC-derived sensory neurons exhibit increased excitability and sensitization to patient plasma
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Individuals living with sickle cell disease (SCD) experience severe recurrent acute and chronic pain. Challenges to gaining mechanistic insight into pathogenic SCD pain processes include differential gene expression and function of sensory neurons between humans and mice with SCD, and extremely limited availability of neuronal tissues from SCD patients. Here we used SCD patient-derived induced pluripotent stem cells (iPSCs) differentiated into sensory neurons (SCD iSNs) to begin to overcome these challenges. We characterize key gene expression and function of SCD iSNs to establish a model to investigate intrinsic and extrinsic factors that may contribute to SCD pain. Despite similarities in receptor gene expression, SCD iSNs show pronounced excitability using patch clamp electrophysiology. Further, we find that plasma taken from SCD patients during acute pain associated with a vaso-occlusive event increases the calcium responses in SCD iSNs to the nociceptive stimulus capsaicin compared to those treated with paired SCD patient plasma at steady state baseline or healthy control plasma samples. We identified high levels of the polyamine spermine in baseline and acute pain states of SCD patient plasma, which sensitizes SCD iSNs to sub-threshold concentrations of capsaicin. Together, these data identify potential intrinsic mechanisms within SCD iSNs that may extend beyond a blood-based pathology.
Cutaneous pain in disorders affecting peripheral nerves
2021, Neuroscience Letters
Citation Excerpt :
Transcriptomics analyses of keratinocytes, Schwann cells and other skin cell types can be performed on skin samples from human patients, potentially patients with a variety of peripheral neuropathies. The development of iPSC nociceptors, keratinocytes and nociceptive Schwann cells from stem cells derived from patients with cutaneous neuropathies is an exciting reality [252–255]. In vitro co-cultures of animal and/or human skin cells and sensory neurons could reveal important signaling interactions between these cell types, perhaps even how these interactions are altered upon in vitro exposure to neuropathy-inducing agents like paclitaxel.
Our ability to quickly detect and respond to harmful environmental stimuli is vital for our safety and survival. This inherent acute pain detection is a “gift” because it both protects our body from harm and allows healing of damaged tissues [1]. Damage to tissues from trauma or disease can result in distorted or amplified nociceptor signaling and sensitization of the spinal cord and brain (Central Nervous System; CNS) pathways to normal input from light touch mechanoreceptors. Together, these processes can result in nagging to unbearable chronic pain and extreme sensitivity to light skin touch (allodynia). Unlike acute protective pain, chronic pain and allodynia serve no useful purpose and can severely reduce the quality of life of an affected person. Chronic pain can arise from impairment to peripheral neurons, a phenomenon called “peripheral neuropathic pain.” Peripheral neuropathic pain can be caused by many insults that directly affect peripheral sensory neurons, including mechanical trauma, metabolic imbalance (e.g., diabetes), autoimmune diseases, chemotherapeutic agents, viral infections (e.g., shingles). These insults cause “acquired” neuropathies such as small-fiber neuropathies, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, and post herpetic neuralgia. Peripheral neuropathic pain can also be caused by genetic factors and result in hereditary neuropathies that include Charcot-Marie-Tooth disease, rare channelopathies and Fabry disease. Many acquired and hereditary neuropathies affect the skin, our largest organ and protector of nearly our entire body. Here we review how cutaneous nociception (pain perceived from the skin) is altered following diseases that affect peripheral nerves that innervate the skin. We provide an overview of how noxious stimuli are detected and encoded by molecular transducers on subtypes of cutaneous afferent endings and conveyed to the CNS. Next, we discuss several acquired and hereditary diseases and disorders that cause painful or insensate (lack of sensation) cutaneous peripheral neuropathies, the symptoms and percepts patients experience, and how cutaneous afferents and other peripheral cell types are altered in function in these disorders. We highlight exciting new research areas that implicate non-neuronal skin cells, particularly keratinocytes, in cutaneous nociception and peripheral neuropathies. Finally, we conclude with ideas for innovative new directions, areas of unmet need, and potential opportunities for novel cutaneous therapeutics that may avoid CNS side effects, as well as ideas for improved translation of mechanisms identified in preclinical models to patients.
The pathobiology of peripheral nerve disease: New clues from cell and molecular biology
2021, Neuroscience Letters
Human-Induced Pluripotent Stem Cells in Plastic and Reconstructive Surgery
2024, International Journal of Molecular Sciences
Donors for nerve transplantation in craniofacial soft tissue injuries
2022, Frontiers in Bioengineering and Biotechnology
iPSCs in Neurodegenerative Disorders: A Unique Platform for Clinical Research and Personalized Medicine
2022, Journal of Personalized Medicine

View full text

Review articleLessons from iPSC research: Insights on peripheral nerve disease

Highlights

Abstract

Section snippets

iPSCs as tool to repair peripheral nerve damage?

iPSCs as tool to study hereditary forms of peripheral neuropathies

Funding

Declaration of Competing Interest

Acknowledgements

Med. Clin. North Am.

Biol. Blood Marrow Transpl.

Stem Cell Rep.

Clin. Plast. Surg.

Int. J. Cardiol.

J. Mol. Cell. Cardiol.

Brain Res.

EBioMedicine

Stem Cell Rep.

Cell

Cell

Life Sci.

Peripheral neuropathy: differential diagnosis and management

Am. Fam. Phys.

Induced pluripotent stem cell models of lysosomal storage disorders

Dis. Model. Mech.

Establishment of induced pluripotent stem cells from aged mice using bone marrow-derived myeloid cells

J. Mol. Cell Biol.

Enzyme replacement therapy for Anderson-Fabry disease

Cochrane Database Syst. Rev.

After nerve injury, lineage tracing shows that myelin and remak schwann cells elongate extensively and branch to form repair schwann cells, which shorten radically on remyelination

J. Neurosci.

Characterization of small fiber pathology in a mouse model of Fabry disease

Elife

Effective clearance of GL-3 in a human iPSC-derived cardiomyocyte model of Fabry disease

J. Inherit. Metab. Dis.

The repair Schwann cell and its function in regenerating nerves

J. Physiol.

Challenges in modelling the Charcot-Marie-Tooth neuropathies for therapy development

J. Neurol. Neurosurg. Psychiatry

Review article
Lessons from iPSC research: Insights on peripheral nerve disease