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Induced pluripotent stem cells for disease modeling, cell therapy and drug discovery in genetic autonomic disorders: a review

Clinical Autonomic Research volume 29, pages 367–384 (2019)Cite this article

Abstract

The autonomic nervous system (ANS) regulates all organs in the body independent of consciousness, and is thus essential for maintaining homeostasis of the entire organism. Diseases of the ANS can arise due to environmental insults such as injury, toxins/drugs and infections or due to genetic lesions. Human studies and animal models have been instrumental to understanding connectivity and regulation of the ANS and its disorders. However, research into cellular pathologies and molecular mechanisms of ANS disorders has been hampered by the difficulties in accessing human patient-derived ANS cells in large numbers to conduct meaningful research, mainly because patient neurons cannot be easily biopsied and primary human neuronal cultures cannot be expanded.

Human-induced pluripotent stem cell (hiPSC) technology can elegantly bridge these issues, allowing unlimited access of patient-derived ANS cell types for cellular, molecular and biochemical analysis, facilitating the discovery of novel therapeutic targets, and eventually leading to drug discovery. Additionally, such cells may provide a source for cell replacement therapy to replenish lost or injured ANS tissue in patients.

Here, we first review the anatomy and embryonic development of the ANS, as this knowledge is crucial for understanding disease modeling approaches. We then review the current advances in human stem cell technology for modeling diseases of the ANS, recent strides toward cell replacement therapy and drug discovery initiatives.

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Abbreviations

PNS:

Peripheral nervous system

ANS:

Autonomic nervous system

CNS:

Central nervous system

ENS:

Enteric nervous system

iPSCs:

Induced pluripotent stem cells

hPSCs:

Human pluripotent stem cells

hiPSCs:

Human induced pluripotent stem cells

hESCs:

Human embryonic stem cells

FD:

Familial dysautonomia

HD:

Hirschsprung’s disease

NCCs:

Neural crest cells

SAP:

Sympathoadrenal progenitor

hOR-MSCs:

Human olfactory ecto-mesenchymal stem cells

HIOs:

Intestinal human organoids

GI:

Gastrointestinal tract

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Acknowledgements

We would like to thank Issa P. Bagayogo and Oliver Harschnitz for critical reading of our manuscript.

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Affiliations

  1. Center for Molecular Medicine, University of Georgia, Athens, GA, USA

    Kenyi Saito-Diaz & Nadja Zeltner

  2. Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA

    Nadja Zeltner

  3. Department of Cellular Biology, University of Georgia, Athens, GA, USA

    Nadja Zeltner

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  1. Kenyi Saito-Diaz
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Correspondence to Nadja Zeltner.

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Saito-Diaz, K., Zeltner, N. Induced pluripotent stem cells for disease modeling, cell therapy and drug discovery in genetic autonomic disorders: a review. Clin Auton Res 29, 367–384 (2019). https://doi.org/10.1007/s10286-018-00587-4

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Keywords

  • ANS disease
  • Human pluripotent stem cells
  • Induced pluripotent stem cells
  • Embryonic stem cells
  • Disease modeling
  • Disease mechanism
  • Cell therapy
  • Drug discovery
  • Familial dysautonomia
  • Hirschsprung’s disease
  • Neural crest
  • Stem cells
  • In vitro differentiation