Epigenetic stability of human pluripotent stem cells

Epigenetic regulation in pluripotent stem cells: does it matter? Human pluripotent stem cells (hPSC) potentially stand as promising therapeutic tools for degenerative diseases. Through their capacity to differentiate to any cell type, they offer the possibility of a renewable source of replacement cells to treat various diseases including Parkinson’s and Alzheimer’s diseases. These cells can be obtained by two different means (Figure 9.1). Since 1998 (Thomson et al., 1998), it has been possible to derive human embryonic stem cells (hESCs) from the inner cell mass cells of blastocysts with the potential to self-renew indefinitely but also to give rise to the three embryonic germ layers (endoderm, ectoderm, and mesoderm) when differentiating. Since 2007 (Takahashi et al., 2007; Yu et al., 2007), induced pluripotent stem cells have also been derived from adult differentiated cells by reprogramming; they harbor self-renewing properties and are able to differentiate into cells of all three germ layers. In order to use hPSC for therapeutic purposes, extensive culture protocols are needed to maintain the population of undifferentiated cells. During these long-lasting culture periods, stem cells are susceptible to various changes, genetic as well as epigenetic, which could jeopardize their medical use. Genetic alterations have been carefully monitored in hESCs (Maitra et al., 2005; Baker et al., 2007) and occur frequently in these cell types: the most recurrent karyotypic changes are a gain of chromosomes 12 and 17 and to a lesser extent of the X chromosome (Baker et al., 2007). Whereas genetic abnormalities are now reasonably counter-selected for in routine hESCs expansion, less is known about epigenetic stability in pluripotent stem cell culture and how it could affect downstream applications. Recent studies have deployed tremendous efforts to unravel the epigenomes of human embryonic stem cells (Meissner, 2010) in terms of histone modifications profiles (Guenther et al., 2007; Pan et al., 2007; Zhao et al., 2007; Xie et al., 2009; Hawkins et al., 2010) as well as DNA methylation distribution (Lister et al., 2009; Laurent et al., 2010). This type of analysis was also conducted for induced pluripotent stem cells mostly in order to compare them with hESCs (Hawkins et al., 2010; Meissner, 2010). However, all these studies do not address the potential stability or instability of these newly well-defined epigenomes and its implication concerning therapeutic issues.