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

The Immunogenicity of iPSC derivatives. The abnormal overexpression of immunogenic proteins such as Hormad1 and Zg16 in iPSC-derived cells leads to the antigen-specific T cell activation. APC, antigen presenting cells; MHC, major histocompatibility complex; TCR, T cell receptor.
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Fig2: The Immunogenicity of iPSC derivatives. The abnormal overexpression of immunogenic proteins such as Hormad1 and Zg16 in iPSC-derived cells leads to the antigen-specific T cell activation. APC, antigen presenting cells; MHC, major histocompatibility complex; TCR, T cell receptor.

Mentions: While it has been generally assumed that autologous cells derived from patient-specific iPSCs should be immune tolerated by the patient, it is possible that the genetic and epigenetic abnormalities of iPSCs could contribute to minor antigens in some hESC-derived cells. Several reports have shown that transplantation of iPSC-derived cells could ameliorate disease phenotypes in mouse models without apparently immune rejection [106, 107]. However, these studies were carried out in either immune privileged site or in lethally irradiated mice. Taking advantage of the capability of iPSCs to form teratomas that contain all lineages of cells in the body, recent studies have demonstrated that, unlike ESC-derived cells that are not immunogenic in syngeneic hosts, some cells derived from iPSCs are immunogenic in the syngeneic recipients due to the abnormal expression of minor antigens in some cells in the teratomas during the differentiation of iPSCs (Figure‚ÄČ2) [42]. While remaining to be confirmed, the abnormal overexpression of the minor antigens might be due to the abnormal epigenetics of iPSCs. In addition, the contribution of the coding sequence mutations to the immunogenicity of iPSC-derived cells remains to be examined.Figure 2


Progress and bottleneck in induced pluripotency.

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

The Immunogenicity of iPSC derivatives. The abnormal overexpression of immunogenic proteins such as Hormad1 and Zg16 in iPSC-derived cells leads to the antigen-specific T cell activation. APC, antigen presenting cells; MHC, major histocompatibility complex; TCR, T cell receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: The Immunogenicity of iPSC derivatives. The abnormal overexpression of immunogenic proteins such as Hormad1 and Zg16 in iPSC-derived cells leads to the antigen-specific T cell activation. APC, antigen presenting cells; MHC, major histocompatibility complex; TCR, T cell receptor.
Mentions: While it has been generally assumed that autologous cells derived from patient-specific iPSCs should be immune tolerated by the patient, it is possible that the genetic and epigenetic abnormalities of iPSCs could contribute to minor antigens in some hESC-derived cells. Several reports have shown that transplantation of iPSC-derived cells could ameliorate disease phenotypes in mouse models without apparently immune rejection [106, 107]. However, these studies were carried out in either immune privileged site or in lethally irradiated mice. Taking advantage of the capability of iPSCs to form teratomas that contain all lineages of cells in the body, recent studies have demonstrated that, unlike ESC-derived cells that are not immunogenic in syngeneic hosts, some cells derived from iPSCs are immunogenic in the syngeneic recipients due to the abnormal expression of minor antigens in some cells in the teratomas during the differentiation of iPSCs (Figure‚ÄČ2) [42]. While remaining to be confirmed, the abnormal overexpression of the minor antigens might be due to the abnormal epigenetics of iPSCs. In addition, the contribution of the coding sequence mutations to the immunogenicity of iPSC-derived cells remains to be examined.Figure 2

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