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A key challenge for clinical application of induced pluripotent stem cells (iPSC) to accurately model and treat human pathologies depends on developing a method to generate genetically stable cells to reduce long‐term risks of cell transplant therapy. Here, we hypothesized that  CYCLIN D1  repairs DNA by highly efficient homologous recombination (HR) during reprogramming to iPSC that reduces genetic instability and threat of neoplastic growth. We adopted a synthetic mRNA transfection method using clinically compatible conditions with  CYCLIN D1  plus base factors ( OCT3/4 ,  SOX2 ,  KLF4 ,  LIN28)  and compared with methods that use  C‐MYC . We demonstrate that  CYCLIN D1  made iPSC have (a) lower multitelomeric signal, (b) reduced double‐strand DNA breaks, (c) correct nuclear localization of RAD51 protein expression, and (d) reduced single‐nucleotide polymorphism (SNP) changes per chromosome, compared with the classical reprogramming method using  C‐MYC .  CYCLIN D1  iPSC have reduced teratoma Ki67 cell growth kinetics and derived neural stem cells successfully engraft in a hostile spinal cord injury (SCI) microenvironment with efficient survival, differentiation. We demonstrate that  CYCLIN D1  promotes double‐stranded DNA damage repair predominantly through HR during cell reprogramming to efficiently produce iPSC.  CYCLIN D1  reduces general cell stress associated with significantly lower  SIRT1  gene expression and can rescue  Sirt1  null mouse cell reprogramming. In conclusion, we show synthetic mRNA transfection of  CYCLIN D1  repairs DNA during reprogramming resulting in significantly improved genetically stable footprint in human iPSC, enabling a new cell reprogramming method for more accurate and reliable generation of human iPSC for disease modeling and future clinical applications.

stem cells

A synthetic mRNA cell reprogramming method using  CYCLIN D1  promotes DNA repair, generating improved genetically stable human induced pluripotent stem cells