Genetic and epigenetic variations in iPSCs: potential causes and implications for application

Abstract

The ability to reprogram somatic cells to induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine. However, recent studies on the genetic and epigenetic variations in iPSCs have raised concerns that these variations may compromise the utility of iPSCs. In this Perspective, we review the current understanding of genetic and epigenetic variations in iPSCs, trace their causes, discuss the implications of these variations for iPSC applications, and propose approaches to cope with these variations.

Figure 1. Sources of genetic variations in iPSC lines

Genetic variations of iPSC lines may have different sources. (A) Individual starting somatic cells (diamond) within a culture (rounded rectangle) bear subtle genetic variations (colored crosses), which can be captured and manifested in the iPSC (circle) lines for the clonal nature of the transcription factor (TF)-mediated iPSC derivation process. (I) Given that reprogramming occurs stochastically among the starting cell population, the genetic variations captured in iPSC lines may have random patterns. (II) If reprogramming preferentially takes place in cells bearing genetic variations conferring selective advantage (green crosses), the iPSC-manifested variations may show functional enrichment. (B) The reprogramming process per se may introduce variations. The cells that undergo reprogramming may have enhanced genomic instability (striped circles), resulting in de novo mutations in iPSCs. Early-passage iPSCs may display mosaicism of de novo mutations, which are subjected to selection along passaging. Mutations conferring advantage in self-renewal or proliferation (green crosses) eventually prevails the culture; those deleterious for cell survival (red crosses) are selected against in culture; while other neutral mutations (crosses with other colors) undergo genetic drift. (C) Mutations that arise during prolonged culturing are subjected to similar selection described in B.

Figure 2. Genetic and epigenetic variations, their causes, functional consequences and impacts on application

iPSCs derived from transcription factor (TF)-mediated reprogramming may bear different types of genetic (blue boxes) or epigenetic variations (purple boxes) that can be introduced from varied sources (grey boxes) during the derivation and manipulationsof iPSCs. These variations may lead to different functional consequences (red boxes) that need to be considered when iPSCs or their derivatives are used for applications (green boxes). Solid lines, reported or definite connections; dotted lines, potential connections.