Balancing serendipity and reproducibility: Pluripotent stem cells as experimental systems for intellectual and developmental disorders

Abstract

Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) and their differentiation into neural lineages is a revolutionary experimental system for studying neurological disorders, including intellectual and developmental disabilities (IDDs). However, issues related to variability and reproducibility have hindered translating preclinical findings into drug discovery. Here, we identify areas for improvement by conducting a comprehensive review of 58 research articles that utilized iPSC-derived neural cells to investigate genetically defined IDDs. Based upon these findings, we propose recommendations for best practices that can be adopted by research scientists as well as journal editors.

Graphical abstract

Figure 1

Publication quality over time Review and scoring of 58 primary articles published between 2010 and 2018 (x axis) utilizing iPSCs to investigate genetically defined IDDs. (A) Each publication was scored on a scale of 0–23 (y axis) and arranged in chronological order (x axis). (B) iPSC derivation and quality controls were scored on a scale of 0–8 (y axis) and arranged in chronological order (x axis). For graphs for the other two categories, see Figure S1. Numbers of iPSC lines and patients modeled is indicated by the size and color of the circles, respectively. A smooth regression line (blue) and confidence band (gray shade) are shown using geom_smooth function through ggplot2 in R.

Figure 2

Score distribution analysis of publication quality (A) Overall score distribution (x axis) of 58 primary articles published from 2010 to 2014 (n = 28, red) or 2015 to 2018 (n = 30, turquoise). Dashed lines in corresponding colors indicate mean scores of 16.07 and 14.83, respectively (p = 0.08087). (B) Score distributions (x axis) and comparison between the two groups of articles for each main category evaluated: iPSC derivation and QC (top, p = 0.00958), experimental design, background information (center, p = 0.53114), and neuronal differentiation and quality control (bottom, p = 0.80436). p values determined by two-sample t testing.

Figure 3

Technical variables that differ by laboratory and protocol during generation of neurons from iPSCs (A and B) Variables that differ during specification and differentiation of iPSCs into (A) glutamatergic cortical excitatory neurons and (B) GABAergic cortical inhibitory neurons are shown. These include signaling cues/additives, basal media, culture conditions, and whether differentiation is conducted in monolayer (ML), or adherent or non-adherent embryoid body (aEB/EB) culture. (C) Variables that differ during generation of cortical excitatory neurons from iPSCs by NGN2 overexpression. This figure summarizes data from studies assessed in Tables S4, S5, and S6. Abbreviations and definitions of terms are in Table S8. Scale bars, 50 μm in (A and B) and 130 μm in (C).