Implications of aneuploidy for stem cell biology and brain therapeutics

Abstract

Understanding the cellular basis of neurological disorders have advanced at a slow pace, especially due to the extreme invasiveness of brain biopsying and limitations of cell lines and animal models that have been used. Since the derivation of pluripotent stem cells (PSCs), a novel source of cells for regenerative medicine and disease modeling has become available, holding great potential for the neurology field. However, safety for therapy and accurateness for modeling have been a matter of intense debate, considering that genomic instability, including the gain and loss of chromosomes (aneuploidy), has been repeatedly observed in those cells. Despite the fact that recent reports have described some degree of aneuploidy as being normal during neuronal differentiation and present in healthy human brains, this phenomenon is particularly controversial since it has traditionally been associated with cancer and disabling syndromes. It is therefore necessary to appreciate, to which extent, aneuploid pluripotent stem cells are suitable for regenerative medicine and neurological modeling and also the limits that separate constitutive from disease-related aneuploidy. In this review, recent findings regarding chromosomal instability in PSCs and within the brain will be discussed.

Development of a cell line from the American eel brain expressing endothelial cell properties

“…This is suggested by recent research on the mammalian brain. In the human brain, neural progenitor cells are frequently found to be aneuploid (Rehen et al 2005;Devalle et al 2012), and during the long-term cultivation of mouse neural precursor cells, aneuploidy and an increased differentiation potential developed (Nguyen et al 2013).…”

The genomically mosaic brain: Aneuploidy and more in neural diversity and disease

“…Mosaic aneuploidies create – by definition – genomic diversity amongst populations of brain cells, which would be expected to have functional consequences based on changes in gene expression produced by aneuploidy [17, 58, 60-63]. Maintenance of seemingly neutral or beneficial aneuploidies [79] and euploid cells may therefore be the end-result of selective pressures that are a consequence of mosaic, somatic genomic alterations during CNS development [65]. The concept of beneficial aneuploidies is particularly intriguing, in that the loss or gain of the chromosome may provide some ability to the cell that makes it more “fit” than other cells from the same organism (for example, increased stress resistance or an enhanced functional capacity within a neural network).…”

DNA Aneuploidy in Porcine Bone Marrow–Derived Mesenchymal Stem Cells Undergoing Osteogenic and AdipogenicIn VitroDifferentiation

“…This finding can be correlated with the increased ability of the cells to undergo mitotic proliferation, which, in turn, may lead to their acquisition of a precancerous immortality state triggered by DNA aneuploidy-mediated mutagenic alterations in gene expression (Casado et al, 2012;Røsland et al, 2009;Tang et al, 2012). These profound mutagenic genome transformations can be induced by either a decreased/ hypoploid level of nuclear DNA (nDNA) molecules (i.e., a monosomic and/or nullisomic number of nonsister chromatids less than 4C -2 and/or 4C -4, respectively) or their elevated/hyperploid level (i.e., a trisomic and/or uniparentally disomic or tetrasomic number of nonsister chromatids less than 4C + 2 and/or 4C or 4C + 4) (Devalle et al, 2012;Josse et al, 2010;Li et al, 2005;Qin et al, 2009). …”

“…Aneuploid chromosome complements are most frequently caused by a weakened or completely inactive mitotic checkpoint and the resulting nondisjunction of sister chromatids during the anaphase segregation of nonhomologous daughter chromosomes. Multiple aneuploid chromosomal losses and/or the presence of supernumerary individual chromosomes can also be caused by anaphasic lagging in the unequal separation of sister chromatids during the movement of nonhomologous chromosomes from the center of the mitotic spindle toward the spindle poles (Devalle et al, 2012;Foudah et al, 2009;Qin et al, 2009;Zhang et al, 2007).…”