Unlike mouse ESCs and iPSCs that represent the ‘naïve’ state and are homogeneous, human ESCs and iPSCs represent the ‘primed’ state and are heterogeneous in both cell population and differentiation potential181,182. Moreover, the reprogramming process can result in not only fully reprogrammed iPSCs but also partially reprogrammed cells, which may have different differentiation potential183,184. Therefore, human iPSCs need to be carefully selected and thoroughly characterized for their pluripotency before clinical applications185. Further basic research on reprogramming mechanisms may help researchers to develop methods that allow generation of a standardized human iPSC state, which would lead to reduced technical variability and enable the identification of true biological phenotypes. Besides clonal variation in iPSC differentiation efficiency, another obstacle for disease modeling is line-to-line variation in the maturation of differentiated cells. The acquisition of mature cells requires improved culture conditions and the use of fate conversion with gene regulation119. A recent technology, the microRNA switch124, is expected to increase the maturation quality of iPSC-differentiated cells and reduce clonal variation.
