The Role Of PICH Plays In Somatic Cell Reprogramming To Induced Pluripotent Stem Cells

Embryonic stem cells(ESCs)and induced pluripotent stem cells(iPSCs)encounter more replication stress during rapid proliferation and self-renewal must preserve genetic integrity to prevent the accumulation of mutations throughout the genome of the individual and to prevent the transmission of those mutations to subsequent differential cells and organs.Induced pluripotent stem cells are similar to ESCs in terms of morphology,gene expression,epigenetic status and in vitro differentiation capability,raising new hope for personalized clinical therapy.However,evidence shows that genomic instability arises in generated induced pluripotent stem cells when four factors expression during the somatic cells reprogramming,which would affect their clinical applications.So increasing the efficiency of reprogramming and maintaining stability of iPSCs are important for iPSCs used in clinical therapy.Maintenance of genomic integrity is critical for accurate inhabitation of genetic information.It relies on successful replication of the chromosome DNA followed by uniform segregation during mitosis.Plk1-interacting checkpoint ??helicase??(PICH)is a member of SNF2-family,a DNA translocate that appears to play a role specifically in mitosis.PICH is a marker of “ultra-fine DNA bridges”(UFBs)that connect the two segregating sister chromosome in the anaphase of mitosis.The UFBs resolving deficiency result in sister chromosome cannot segregate during anaphase,which may result genomic instability.PICH plays an important role in protecting genomic stability by promoting sister chromatid disjunction.However,its roles in somatic cell reprogramming remain poorly understood.In this study,we found that PICH expression was significantly elevated in m ESCs and iPSCs compared with MEFs,Whereas PICH deficiency enhanced genomic instability and inhibited reprogramming of MEFs to iPSCs.We also discovered that PICH can interact with Rif1,and loss of Rif1 can inhibit reprogramming efficiency significantly.Both PICH and Rif1 play important role in DNA damage response.We observed that increased DNA replication stress during reprogramming can inhibit iPSCs generation,and reducing Pich-/--MEFs replication stress during reprogramming can recover the efficiency of iPSC.Therefore,our data suggest that PICH is important for MEFs reprogramming,and it may interact with Rif1 to reduce the reprogramming induced replication stress generated,thereby ensuring successful reprogramming.