Selection of iPSCs without mtDNA deletion for autologous cell therapy in a patient with Pearson syndrome
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Screening for genetic defects in the cells should be examinedfor clinical application. The Pearson syndrome (PS) patientharbored nuclear mutations in the POLG and SSBP1 genes,which could induce systemic large-scale mitochondrial genome(mtDNA) deletion. We investigated iPSCs with mtDNAdeletions in PS patient and whether deletion levels could bemaintained during differentiation. The iPSC clones derivedfrom skin fibroblasts (9% deletion) and blood mononuclearcells (24% deletion) were measured for mtDNA deletionlevels. Of the 13 skin-derived iPSC clones, only 3 were foundto be free of mtDNA deletions, whereas all blood-derived iPSCclones were found to be free of deletions. The iPSC cloneswith (27%) and without mtDNA deletion (0%) were selectedand performed in vitro and in vivo differentiation, such asembryonic body (EB) and teratoma formation. After differentiation,the level of deletion was retained or increased in EBs (24%) orteratoma (45%) from deletion iPSC clone, while, the absenceof deletions showed in all EBs and teratomas from deletion-freeiPSC clones. These results demonstrated that non-deletion iniPSCs was maintained during in vitro and in vivo differentiation,even in the presence of nuclear mutations, suggesting thatdeletion-free iPSC clones could be candidates for autologouscell therapy in patients.
Abstract
Screening for genetic defects in the cells should be examinedfor clinical application. The Pearson syndrome (PS) patientharbored nuclear mutations in the POLG and SSBP1 genes,which could induce systemic large-scale mitochondrial genome(mtDNA) deletion. We investigated iPSCs with mtDNAdeletions in PS patient and whether deletion levels could bemaintained during differentiation. The iPSC clones derivedfrom skin fibroblasts (9% deletion) and blood mononuclearcells (24% deletion) were measured for mtDNA deletionlevels. Of the 13 skin-derived iPSC clones, only 3 were foundto be free of mtDNA deletions, whereas all blood-derived iPSCclones were found to be free of deletions. The iPSC cloneswith (27%) and without mtDNA deletion (0%) were selectedand performed in vitro and in vivo differentiation, such asembryonic body (EB) and teratoma formation. After differentiation,the level of deletion was retained or increased in EBs (24%) orteratoma (45%) from deletion iPSC clone, while, the absenceof deletions showed in all EBs and teratomas from deletion-freeiPSC clones. These results demonstrated that non-deletion iniPSCs was maintained during in vitro and in vivo differentiation,even in the presence of nuclear mutations, suggesting thatdeletion-free iPSC clones could be candidates for autologouscell therapy in patients.
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