Limits...
Progress and bottleneck in induced pluripotency.

Zhang ZN, Xu Y - Cell Regen (Lond) (2012)

Bottom Line: Significant progress has been achieved to improve the safety of iPSCs and the reprogramming efficiency.To avoid the cancer risk and spontaneous reactivation of the reprogramming factors associated with the random integration of viral vectors into the genome, several approaches have been established to deliver the reprogramming factors into the somatic cells without inducing genetic modification.Despite these progresses, recent studies have identified genetic and epigenetic abnormalities of iPSCs as well as the immunogenicity of some cells derived from iPSCs.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla California 92093-0322 USA.

ABSTRACT
With their capability to undergo unlimited self-renewal and to differentiate into all cell types in the body, induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells of individual patients with defined factors, have unlimited potential in cell therapy and in modeling complex human diseases. Significant progress has been achieved to improve the safety of iPSCs and the reprogramming efficiency. To avoid the cancer risk and spontaneous reactivation of the reprogramming factors associated with the random integration of viral vectors into the genome, several approaches have been established to deliver the reprogramming factors into the somatic cells without inducing genetic modification. In addition, a panel of small molecule compounds, many of which targeting the epigenetic machinery, have been identified to increase the reprogramming efficiency. Despite these progresses, recent studies have identified genetic and epigenetic abnormalities of iPSCs as well as the immunogenicity of some cells derived from iPSCs. In addition, due to the oncogenic potential of the reprogramming factors and the reprogramming-induced DNA damage, the critical tumor suppressor pathways such as p53 and ARF are activated to act as the checkpoints that suppress induced pluripotency. The inactivation of these tumor suppression pathways even transiently during reprogramming processes could have significant adverse impact on the genome integrity. These safety concerns must be resolved to improve the feasibility of the clinic development of iPSCs into human cell therapy.

No MeSH data available.


Related in: MedlinePlus

Tumor suppressor p53 inhibits induced pluripotency. p53 is activated by oncogenic stresses and DNA damage during reprogramming, leading to cell cycle arrest, apoptosis, or senescence, which all limit successful reprogramming. Upon activation, p53 also suppresses the expression of Nanog that is required for the transition from pre-iPSCs to iPSCs.
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Fig3: Tumor suppressor p53 inhibits induced pluripotency. p53 is activated by oncogenic stresses and DNA damage during reprogramming, leading to cell cycle arrest, apoptosis, or senescence, which all limit successful reprogramming. Upon activation, p53 also suppresses the expression of Nanog that is required for the transition from pre-iPSCs to iPSCs.

Mentions: Induced pluripotency by defined factors is a very inefficient process. A series of studies indicate that critical tumor suppressors such as p53 and ARF are major checkpoints in suppressing induced pluripotency (Figure 3) [108]. The critical tumor suppression activity of p53 is underscored by the finding that p53 is inactivated in most human cancers either by gene mutation or the disruption of pathways required for p53 activation [109]. p53 is a transcription factor that directly regulates the expression of hundred of genes. For example, p53 directly activates the expression of genes involved in cell cycle arrest (p21, 14-3-3σ), apoptosis (Puma, Noxa) and senescence (PAI-1), and suppresses the expression of genes such as MAP4 and Nanog [110]. In addition to p53-dependent transcription, p53 also plays important transcription-independent roles in physiological processes such as metabolism [111] and miRNA processing [112].Figure 3


Progress and bottleneck in induced pluripotency.

Zhang ZN, Xu Y - Cell Regen (Lond) (2012)

Tumor suppressor p53 inhibits induced pluripotency. p53 is activated by oncogenic stresses and DNA damage during reprogramming, leading to cell cycle arrest, apoptosis, or senescence, which all limit successful reprogramming. Upon activation, p53 also suppresses the expression of Nanog that is required for the transition from pre-iPSCs to iPSCs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230504&req=5

Fig3: Tumor suppressor p53 inhibits induced pluripotency. p53 is activated by oncogenic stresses and DNA damage during reprogramming, leading to cell cycle arrest, apoptosis, or senescence, which all limit successful reprogramming. Upon activation, p53 also suppresses the expression of Nanog that is required for the transition from pre-iPSCs to iPSCs.
Mentions: Induced pluripotency by defined factors is a very inefficient process. A series of studies indicate that critical tumor suppressors such as p53 and ARF are major checkpoints in suppressing induced pluripotency (Figure 3) [108]. The critical tumor suppression activity of p53 is underscored by the finding that p53 is inactivated in most human cancers either by gene mutation or the disruption of pathways required for p53 activation [109]. p53 is a transcription factor that directly regulates the expression of hundred of genes. For example, p53 directly activates the expression of genes involved in cell cycle arrest (p21, 14-3-3σ), apoptosis (Puma, Noxa) and senescence (PAI-1), and suppresses the expression of genes such as MAP4 and Nanog [110]. In addition to p53-dependent transcription, p53 also plays important transcription-independent roles in physiological processes such as metabolism [111] and miRNA processing [112].Figure 3

Bottom Line: Significant progress has been achieved to improve the safety of iPSCs and the reprogramming efficiency.To avoid the cancer risk and spontaneous reactivation of the reprogramming factors associated with the random integration of viral vectors into the genome, several approaches have been established to deliver the reprogramming factors into the somatic cells without inducing genetic modification.Despite these progresses, recent studies have identified genetic and epigenetic abnormalities of iPSCs as well as the immunogenicity of some cells derived from iPSCs.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla California 92093-0322 USA.

ABSTRACT
With their capability to undergo unlimited self-renewal and to differentiate into all cell types in the body, induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells of individual patients with defined factors, have unlimited potential in cell therapy and in modeling complex human diseases. Significant progress has been achieved to improve the safety of iPSCs and the reprogramming efficiency. To avoid the cancer risk and spontaneous reactivation of the reprogramming factors associated with the random integration of viral vectors into the genome, several approaches have been established to deliver the reprogramming factors into the somatic cells without inducing genetic modification. In addition, a panel of small molecule compounds, many of which targeting the epigenetic machinery, have been identified to increase the reprogramming efficiency. Despite these progresses, recent studies have identified genetic and epigenetic abnormalities of iPSCs as well as the immunogenicity of some cells derived from iPSCs. In addition, due to the oncogenic potential of the reprogramming factors and the reprogramming-induced DNA damage, the critical tumor suppressor pathways such as p53 and ARF are activated to act as the checkpoints that suppress induced pluripotency. The inactivation of these tumor suppression pathways even transiently during reprogramming processes could have significant adverse impact on the genome integrity. These safety concerns must be resolved to improve the feasibility of the clinic development of iPSCs into human cell therapy.

No MeSH data available.


Related in: MedlinePlus