Enhanced Telomere Rejuvenation in Pluripotent Cells Reprogrammed via Nuclear Transfer Relative to Induced Pluripotent Stem Cells

• Terc−/− ntESCs have greater differentiation potential than Terc−/− iPSCs
• Telomere lengthening and capping are more active in Terc−/− ntESCs
• Stronger rescue of mitochondria dysfunction occurs in Terc−/− ntESCs
• Mitochondrial maturation defects limit Terc−/− iPSC differentiation potential

SummaryAlthough somatic cell nuclear transfer (SCNT) and induction of pluripotency (to form iPSCs) are both recognized reprogramming methods, there has been relatively little comparative analysis of the resulting pluripotent cells. Here, we examine the capacity of these two reprogramming approaches to rejuvenate telomeres using late-generation telomerase-deficient (Terc−/−) mice that exhibit telomere dysfunction and premature aging. We found that embryonic stem cells established from Terc−/− SCNT embryos (Terc−/− ntESCs) have greater differentiation potential and self-renewal capacity than Terc−/− iPSCs. Remarkably, SCNT results in extensive telomere lengthening in cloned embryos and improved telomere capping function in the established Terc−/− ntESCs. In addition, mitochondrial function is severely impaired in Terc−/− iPSCs and their differentiated derivatives but significantly improved in Terc−/− ntESCs. Thus, our results suggest that SCNT-mediated reprogramming mitigates telomere dysfunction and mitochondrial defects to a greater extent than iPSC-based reprogramming. Understanding the basis of this differential could help optimize reprogramming strategies.

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