iPSC modeling of rare pediatric disorders

https://doi.org/10.1016/j.jneumeth.2019.108533Get rights and content

Highlights

  • Human induced pluripotent stem cells (iPSCs) are an established model system.

  • Rare neurological diseases exert a profound burden on the pediatric population.

  • Neurodevelopmental effects due to rare genetic changes can utilize iPSC models.

  • iPSCs allow functional analyses and spatial disease modeling in human neurons.

Abstract

Discerning the underlying pathological mechanisms and the identification of therapeutic strategies to treat individuals affected with rare neurological diseases has proven challenging due to a host of factors. For instance, rare diseases affecting the nervous system are inherently lacking in appropriate patient sample availability compared to more common diseases, while animal models often do not accurately recapitulate specific disease phenotypes. These challenges impede research that may otherwise illuminate aspects of disease initiation and progression, leading to the ultimate identification of potential therapeutics. The establishment of induced pluripotent stem cells (iPSCs) as a human cellular model with defined genetics has provided the unique opportunity to study rare diseases within a controlled environment. iPSC models enable researchers to define mutational effects on specific cell types and signaling pathways within increasingly complex systems. Among rare diseases, pediatric diseases affecting neurodevelopment and neurological function highlight the critical need for iPSC-based disease modeling due to the inherent difficulty associated with collecting human neural tissue and the complexity of the mammalian nervous system. Rare neurodevelopmental disorders are therefore ideal candidates for utilization of iPSC-based in vitro studies. In this review, we address both the state of the iPSC field in the context of their utility and limitations for neurodevelopmental studies, as well as speculating about the future applications and unmet uses for iPSCs in rare diseases.

Section snippets

Pluripotent cellular models for rare diseases – derivation and discrepancies

Before the development of iPSCs as a model system, pluripotent cell models were limited to embryonic stem cells (ESCs). ESCs are typically derived during early embryonic development and maintain indefinite pluripotent proliferation in cell culture settings (Thomson et al., 1998). ESCs were first derived from mouse blastocysts in 1981 (Evans and Kaufman, 1981; Jones and Thomson, 2000) and then later from human blastocysts in 1998 from the inner cell mass (ICM) of early-stage embryos (Thomson et

Conclusions

iPSCs offer a genetically unique, developmentally plastic, and niche model system for studying rare neurological diseases where patient neural tissue has limited availability or rodent models offer less than ideal utility. This model has been used for disease-causing mechanism discovery, differentiation assays, and drug developmental studies. The theoretically infinite proliferative capabilities of iPSCs, as well as their ability to generate cells from all three germ layers, makes them ideal

Acknowledgements

This research was supported by the National Institutes of Health (grant numbers P20GM103620 and P20GM103548).

References (144)

  • K.A. Dufendach et al.

    Clinical outcomes and modes of death in timothy syndrome: a multicenter international study of a rare disorder

    JACC Clin. Electrophysiol.

    (2018)
  • Z. Guo et al.

    In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model

    Cell Stem Cell

    (2014)
  • C.W. Habela et al.

    Modeling synaptogenesis in schizophrenia and autism using human iPSC derived neurons

    Mol. Cell. Neurosci.

    (2016)
  • T. Halevy et al.

    Molecular mechanisms regulating the defects in fragile X syndrome neurons derived from human pluripotent stem cells

    Stem Cell Rep.

    (2015)
  • W. Hu et al.

    Direct conversion of normal and alzheimer’s disease human fibroblasts into neuronal cells by small molecules

    Cell Stem Cell

    (2015)
  • M. Ilieva et al.

    Psychiatry in a dish: stem cells and brain organoids modeling autism Spectrum disorders

    Biol. Psychiatry

    (2018)
  • H.W. Kim et al.

    Differential effects on sodium current impairments by distinct SCN1A mutations in GABAergic neurons derived from Dravet syndrome patients

    Brain Dev.

    (2018)
  • N. Kishi et al.

    MeCP2 functions largely cell-autonomously, but also non-cell-autonomously, in neuronal maturation and dendritic arborization of cortical pyramidal neurons

    Exp. Neurol.

    (2010)
  • P. Klemmer et al.

    Proteomics, ultrastructure, and physiology of hippocampal synapses in a fragile X syndrome mouse model reveal presynaptic phenotype

    J. Biol. Chem.

    (2011)
  • H. Kurosawa

    Methods for inducing embryoid body formation: in vitro differentiation system of embryonic stem cells

    J. Biosci. Bioeng.

    (2007)
  • M. Lam et al.

    Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality

    Exp. Cell Res.

    (2019)
  • C.T. Lee et al.

    3D brain Organoids derived from pluripotent stem cells: promising experimental models for brain development and neurodegenerative disorders

    J. Biomed. Sci.

    (2017)
  • X. Li et al.

    Fast generation of functional subtype astrocytes from human pluripotent stem cells

    Stem Cell Rep.

    (2018)
  • X. Li et al.

    Small-molecule-Driven direct reprogramming of mouse fibroblasts into functional neurons

    Cell Stem Cell

    (2015)
  • Y. Li et al.

    Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons

    Cell Stem Cell

    (2013)
  • Y.H. Loh et al.

    Reprogramming of T cells from human peripheral blood

    Cell Stem Cell

    (2010)
  • A. Lundin et al.

    Human iPS-Derived astroglia from a stable neural precursor state show improved functionality compared with conventional astrocytic models

    Stem Cell Rep.

    (2018)
  • N. Maherali et al.

    Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution

    Cell Stem Cell

    (2007)
  • M.C. Marchetto et al.

    A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells

    Cell

    (2010)
  • J. Mariani et al.

    FOXG1-dependent dysregulation of GABA/Glutamate neuron differentiation in autism spectrum disorders

    Cell

    (2015)
  • A.S. Monzel et al.

    Derivation of human midbrain-specific organoids from neuroepithelial stem cells

    Stem Cell Rep.

    (2017)
  • K. Muguruma et al.

    Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells

    Cell Rep.

    (2015)
  • K. Nagai et al.

    A transcriptional repressor MeCP2 causing Rett syndrome is expressed in embryonic non-neuronal cells and controls their growth

    Brain Res. Dev. Brain Res.

    (2005)
  • E.M. Abud et al.

    iPSC-derived human microglia-like cells to study neurological diseases

    Neuron

    (2017)
  • R.E. Amir et al.

    Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2

    Nat. Genet.

    (1999)
  • G. Ananiev et al.

    Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model

    PLoS One

    (2011)
  • T. Andoh-Noda et al.

    Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage

    Mol. Brain

    (2015)
  • K. Ardhanareeswaran et al.

    The use of stem cells to study autism spectrum disorder

    Yale J. Biol. Med.

    (2015)
  • J.A. Bagley et al.

    Fused cerebral organoids model interactions between brain regions

    Nat. Methods

    (2017)
  • J. Baio et al.

    Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2014

    Surveill. Summ.

    (2018)
  • M. Baker

    1,500 scientists lift the lid on reproducibility

    Nature

    (2016)
  • S.E. Bianconi et al.

    Pathogenesis, epidemiology, diagnosis and clinical aspects of smith-lemli-Opitz syndrome

    Expert Opin. Orphan Drugs

    (2015)
  • F. Birey et al.

    Assembly of functionally integrated human forebrain spheroids

    Nature

    (2017)
  • A. Bongso et al.

    Isolation and culture of inner cell mass cells from human blastocysts

    Hum. Reprod.

    (1994)
  • R.A. Bradley et al.

    Regionally specified human pluripotent stem cell-derived astrocytes exhibit different molecular signatures and functional properties

    Development

    (2019)
  • M. Caiazzo et al.

    Direct generation of functional dopaminergic neurons from mouse and human fibroblasts

    Nature

    (2011)
  • B. Cakir et al.

    Engineering of human brain organoids with a functional vascular-like system

    Nat. Methods

    (2019)
  • I. Canals et al.

    Rapid and efficient induction of functional astrocytes from human pluripotent stem cells

    Nat. Methods

    (2018)
  • Z. Cao et al.

    Clustered burst firing in FMR1 premutation hippocampal neurons: amelioration with allopregnanolone

    Hum. Mol. Genet.

    (2012)
  • T. Chailangkarn et al.

    Modeling Williams syndrome with induced pluripotent stem cells

    Neurogenesis Austin

    (2017)
  • Cited by (11)

    • Neurobiological insights into twice-exceptionality: Circuits, cells, and molecules

      2022, Neurobiology of Learning and Memory
      Citation Excerpt :

      One promising approach to study molecular mechanisms in human cells is the use of induced pluripotent stem cells (iPSCs). iPSCs provide an encouraging avenue for the study of rare or genetically complex conditions (Freel, Sheets, & Francis, 2020; Drakulic et al., 2020). iPSCs can be harmlessly derived from the skin or blood of an individual with 2e.

    • Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities

      2021, Cell Reports Medicine
      Citation Excerpt :

      Altogether, the findings presented in this study indicate that HUWE1 plays a vital role in regulation of p53 signaling during human neurodevelopment and suggest an important contribution of the HUWE1-p53 pathway in stem cell differentiation, an imbalance of which has the capacity to cause the onset of neurodevelopmental XLIDs. A frequent limitation in rare disease studies such as this one is a low number of participants and limited availability of samples from donors.39 This is a particular challenge in hiPSCs-based research, in which multiple patient samples are ideally reprogrammed and compared in parallel.39,40

    View all citing articles on Scopus
    View full text