Concise Review: Genomic Instability in Human Stem Cells: Current Status and Future Challenges

Abstract

Genomic instability is recognized as one of the most important hurdles in the expanding field of stem cell-based therapies. In the recent years, an accumulating body of evidence has shown that human stem cells undergo a diverse program of biological changes upon ex vivo cultivation that include numerical and structural chromosomal abnormalities, point mutations, variation of telomere length, and epigenetic instability. As the field moves forward, the growing awareness of the risk factors associated with human genome plasticity strongly advocates for the use of extensive genetic screening as part of a quality control platform to attest to the safety of stem cell-based products. Here we present a timely and comprehensive review that addresses the current status and emerging trends of the field, ultimately underscoring the need to implement new regulatory standards able to streamline the route to therapeutic applications. STEM CELLS

Integrity of Induced Pluripotent Stem Cell (iPSC) Derived Megakaryocytes as Assessed by Genetic and Transcriptomic Analysis

“…Genomic instability in human pluripotent stem cells (hPSCs) has been recognized since the early 2000s [16, 17]. The first reports included large-scale genomic differences with karyotypic abnormalities including trisomies [16, 18] and more recently, sub-chromosomal abnormalities such as gene duplications/deletions and point mutations [19–21].…”

Chromosomal Abnormalities in Embryonic and Somatic Stem Cells

“…Duplication of 1q11q32, whole or partial gain of chromosomes 12 and 17, duplication of the 20q11.21 region or aneuploidy of chromosome X have been reported by many independent laboratories ( table 1 ) [Brimble et al, 2004;Draper et al, 2004;Inzunza et al, 2004;Mitalipova et al, 2005;Imreh et al, 2006;Baker et al, 2007;Lefort et al, 2008Lefort et al, , 2009Spits et al, 2008;International Stem Cell Initiative, 2011]. The recurrence of these specific types of mutations, linked to the presence of additional copies of some specific genes, may confer carrier cells with a selective and/or proliferative advantage, higher culture adaptation and resistance to apoptosis [Clark et al, 2004;Rosler et al, 2004;Caldas and Brenton, 2005;Maitra et al, 2005;Baker et al, 2007;Lefort et al, 2008;Navarro et al, 2008;Spits et al, 2008;Blum and Benvenisty, 2009;Werbowetski-Ogilvie et al, 2009;International Stem Cell Initiative, 2011;Oliveira et al, 2014].…”

“…During the last decade, several papers evidenced the difficulty of SCs to maintain a correct chromosome complement during prolonged expansion [for reviews see Rebuzzini et al, 2011;Oliveira et al, 2014]. After a brief description of the main techniques used for the karyotype analysis, this review will give a detailed overview of the chromosome abnormalities described in both pluripotent SCs (ESCs and iPSCs) and SSCs, and the possible causes of their origin during prolonged culture.…”

Nuclear Reprogramming by Defined Factors: Quantity Versus Quality

“…Genomic stability and epigenomic assembly are two of the most influential parameters that determine cell quality [33,79,80]. While complete nuclear resetting and an intact genome are essential in yielding functional and safe cells, an aberrant epigenomic landscape or genetic mutations might lead to unstable and dysfunctional cells that hold a high tumorigenic potential.…”