Epigenetic Variation between Human Induced Pluripotent Stem Cell Lines Is an Indicator of Differentiation Capacity

Abstract

Variation in the differentiation capacity of induced pluripotent stem cells (iPSCs) to specific lineages is a significant concern for their use in clinical applications and disease modeling. To identify factors that affect differentiation capacity, we performed integration analyses between hematopoietic differentiation performance and molecular signatures such as gene expression, DNA methylation, and chromatin status, using 35 human iPSC lines and four ESC lines. Our analyses revealed that hematopoietic commitment of PSCs to hematopoietic precursors correlates with IGF2 expression level, which in turn depends on signaling-dependent chromatin accessibility at mesendodermal genes. Maturation capacity for conversion of PSC-derived hematopoietic precursors to mature blood associates with the amount and pattern of DNA methylation acquired during reprogramming. Our study therefore provides insight into the molecular features that determine the differential capacities seen among human iPSC lines and, through the predictive potential of this information, highlights a way to select optimal iPSCs for clinical applications.

Integrated analysis of hematopoietic differentiation outcomes and molecular characterization reveals unbiased differentiation capacity and minor transcriptional memory in HPC/HSC-iPSCs

“…Therefore, it is of interest to examine the correlation between lncRNAs and epigenetic memory. Notably, it has been found that the hematopoietic differentiation capability of hiPSCs can be divided into a commitment phase and a mature phase, which correlate with the expression of IGF2 and de novo methylation in reprogramming, respectively [35]. Although there were some variations in the expression of Igf2 in the iPSC lines used here, no strict correlation between the expression of Igf2 and hematopoietic differentiation capability was observed (data not shown).…”

Direct conversion from skin fibroblasts to functional dopaminergic neurons for biomedical application

“…Moreover, direct conversion of DA neurons provides an alternative for the cell-based therapy using iPSC technology. Recently, disease modeling using iPSCderived neurons has provided new insights into the cellular aspect of diseases by recapitulating patient derived cells (Nishizawa et al 2016;Mucci et al 2016;Heman-Ackah et al 2016;Jang and Ye 2016;Choi et al 2016;Mekhoubad et al 2012;Marchetto et al 2011;Soldner and Jaenisch 2012). Consequently, progerinmediated late-onset disease modeling provides the possibility of using iPSC-derived DA neurons in late-onset age-related diseases (e.g., Parkinson's diseases) (Miller et al 2013).…”

Myogenic progenitor specification from pluripotent stem cells

“…As in the case of maturation, detailed analysis of the epigenetic mechanisms behind cell differentiation will definitively help to understand why some PS cell lines are more permissive than others. Indeed, following this approach, a recent study published by the Yoshida group identified that IGF2 levels produced by human PS cells correlate with their hematopoietic potential [163]. …”