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.
Highlights
Such observations indicate that: (1) some genomic modifications recurrently seen must confer adaptive advantage to both cell types; (2) the reprogramming process is not responsible for a certain portion of the instability seen in human iPSCs (hiPSCs); (3) some modifications could be linked to the specific pluripotent cellular type; (4) other genomic alterations might not be observed due to their detrimental effect on pluripotency or survival of the cells [i.e., many aneuploidies, for instance, result in diminished fitness of cells or whole organisms (Sheltzer and Amon, 2011)]
Low-level random aneuploidy has been described as a natural phenomenon in the human brain, ; because chromosomal losses and gains have been observed at higher frequencies in some brain pathologies, an aneuploidy frequency limit and/or chromosomal-specific aneuploidy type separating healthy from diseased brains seems to exist
In order for induced pluripotent stem cells (iPSCs) to be safely used as a cell repository for damaged or deteriorating tissue, as well as being able to modeling aspects of any given disease, they must retain the original tissue characteristics
Summary
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. 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. It is necessary to appreciate, to which extent, aneuploid pluripotent stem cells are suitable for regenerative medicine and neurological modeling and the limits that separate constitutive from disease-related aneuploidy. Recent findings regarding chromosomal instability in PSCs and within the brain will be discussed
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