Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells

Abstract

Induced pluripotent stem cells (iPSCs) have been derived from various somatic cell populations through ectopic expression of defined factors. It remains unclear whether iPSCs generated from different cell types are molecularly and functionally similar. Here we show that iPSCs obtained from mouse fibroblasts, hematopoietic and myogenic cells exhibit distinct transcriptional and epigenetic patterns. Moreover, we demonstrate that cellular origin influences the in vitro differentiation potentials of iPSCs into embryoid bodies and different hematopoietic cell types. Notably, continuous passaging of iPSCs largely attenuates these differences. Our results suggest that early-passage iPSCs retain a transient epigenetic memory of their somatic cells of origin, which manifests as differential gene expression and altered differentiation capacity. These observations may influence ongoing attempts to use iPSCs for disease modeling and could also be exploited in potential therapeutic applications to enhance differentiation into desired cell lineages.

Concise Review: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells: Close Enough or Yet Too Far Apart?

“…The majority of epigenetic aberrations in iPSC are only present in early passage numbers, and therefore can be considered transient epigenetic memory [58,67]. However, it has also been noted that some transcripts and chromatin marks are persistent in the later passage number iPSC and even in their differentiated progeny [59].…”

“…Possibly, it occurs through a more passive and cell division dependent resetting of the epigenetic cell state. This is corroborated by several facts-higher passage number iPSC (p16 in mice) lose the differences in gene expression and can no longer be clustered together by their cells of origin [24,67]. The preferential differentiation capabilities of iPSC to its tissue of origin are dispersed either by longer passaging [67], chemical treatment influencing epigenetic machinery (5-azacytidine, Trichostatin A), or sequential differentiation-reprogramming cycles into the desired direction [58].…”

“…Recently, two articles analyzed the epigenetic memory of mouse iPSC in more detail [58,67]. iPSC derived from the same cell of origin can be clustered together on the basis of their gene expression and DNA methylation.…”

“…iPSC derived from the same cell of origin can be clustered together on the basis of their gene expression and DNA methylation. More interestingly, there is a functional significance of the donor cell gene expression, where iPSC differentiation back into the cell of origin brings an advantage over iPSC differentiation into an unrelated lineage [58,67]. The epigenetic basis of this memory is linked either to DNA methylation [58] or to histone modifications [67].…”

Unsupervised lineage‐based characterization of primate precursors reveals high proliferative and morphological diversity in the OSVZ

“…Compared with conventional parametric or hierarchical clustering models (Polo et al, 2010), the HMT approach takes the tree‐based nature of the data into account when identifying clusters, revealing the order relationships in lineages. These order relationships are then used to better define progeny.…”