Epigenetic memory in induced pluripotent stem cells

Abstract

Summary Somatic cell nuclear transfer and transcription factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. These two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, by different mechanisms and kinetics, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low passage induced pluripotent stem cells (iPSC) derived by factor-based reprogramming harbor residual DNA methylation signatures characteristic of their somatic tissue of origin, which favors their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an “epigenetic memory” of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSC with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSC, consistent with more effective reprogramming. Our data demonstrate that factor-based reprogramming can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modeling or treatment.

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

“…One analysis on the whole genome scale found 71 differentially methylated regions (DMR) between three iPSC lines and three ESC lines (and 2,179 between fibroblasts and iPSC) [57]. Almost half of the DMRs show incomplete epigenetic reprogramming of the differentiated cell-of-origin genome, which is in agreement with the gene expression data [24] and epigenetic memory [58]. However, not all the DMR belong to the cell-of-origin memory, indicating that iPSC also accumulate novel aberrant epigenetic states [57,59].…”

Blockade of senescence‐associated micro RNA ‐195 in aged skeletal muscle cells facilitates reprogramming to produce induced pluripotent stem cells.

“…3A) as reported in earlier findings (Li et al ., 2009; Kim et al ., 2010; Cheng et al ., 2011; Wang et al ., 2011; Rohani et al ., 2014). We reprogrammed SkMs from both young and old mice using classic Yamanaka factors, and colonies were stained with alkaline phosphatase (ALP) on day 16–18 and counted to assess reprogramming efficiency.…”

“…Previous studies have shown that older and senescent cells are more resistant to reprogramming (Li et al ., 2009; Kim et al ., 2010; Cheng et al ., 2011; Wang et al ., 2011; Rohani et al ., 2014). These observations have established the importance of current efforts underway to understand the biology of cell reprogramming in the context of chronological and replicative age.…”

“…Unlike ESCs, iPSCs are not subject to immune rejection because they are derived from a patient's own cells (Isobe et al ., 2014), and present no ethical harvesting concerns related to the obtaining human ESCs for derivation. Although murine studies reveal that cell reprogramming efficiency declines with age, the potential to generate iPSCs from a patient's own cells has emerged as a promising strategy for autologous cell‐based therapy (Li et al ., 2009; Kim et al ., 2010; Cheng et al ., 2011; Wang et al ., 2011; Rohani et al ., 2014). …”

Amniotic fluid stem cell-based models to study the effects of gene mutations and toxicants on male germ cell formation

“…50,51 In the case of iPS cells, the process of ectopic induction of pluripotency might somehow interfere with its usefulness as a biological model for germ cell formation. [52][53][54] The same is true for the facts, that the epigenetic memory of the original differentiated state is not perfectly erased during reprogramming 55,56 and that iPS cells have been reported to accumulate karyotypic abnormalities and gene mutations during propagation in culture. [57][58][59][60] AFS very likely do not harbour accumulated somatic mutations, because they are primary cells of a very early stage of human development.…”