Cell Reprogramming Preserving Epigenetic Age: Advantages and Limitations
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REVIEW
Cell Reprogramming Preserving Epigenetic Age: Advantages and Limitations E. M. Samoylova1,a* and V. P. Baklaushev1 1
Federal Research Clinical Center, FMBA of Russia, 115682 Moscow, Russia a email: [email protected] Received July 28, 2020 Revised July 28, 2020 Accepted August 5, 2020
Abstract—Our understanding of cell aging advanced significantly since the discovery of this phenomenon by Hayflick and Moorhead in 1961. In addition to the wellknown shortening of telomeric regions of chromosomes, cell aging is closely asso ciated with changes of the DNA methylation profile. Establishing, maintaining, or reversing epigenetic age of a cell is cen tral to the technology of cell reprogramming. Two distinct approaches – iPSC and transdifferentiationbased cell repro gramming – affect differently epigenetic age of the cells. The iPSCbased reprogramming protocols are generally believed to result in the reversion of DNA methylation profiles towards less differentiated states, while the original methylation pro files are preserved in the direct transdifferentiation protocols. Clearly, in order to develop adequate model of CNS patholo gies, one has to have thorough understanding of the biological roles of DNA methylation in the development, maintenance of functional activity, tissue and cell diversity, restructuring of neural networks during learning, as well as in agingassociat ed neuronal decline. Direct cell reprogramming is an excellent alternative and a valuable supplement to the iPSCbased technologies both as a source of mature cells for modeling of neurodegenerative diseases, and as a novel powerful strategy for in vivo cell replacement therapy. Further advancement of the regenerative and personalized medicine will strongly depend on optimization of the production of patientspecific autologous cells involving alternative approaches of direct and indirect cell reprogramming that take into account epigenetic age of the starting cell material. DOI: 10.1134/S0006297920090047 Keywords: regenerative medicine, epigenetic clock, direct cell reprogramming, induced pluripotent stem cells, embryonic stem cells, telomeres, methylome
INTRODUCTION Compared to other higher primates, humans are exceptionally longlived, with an upper estimate of natu ral lifespan of 115 years [1]. Human longevity has a sig Abbreviations: 5mC, 5methylcytosine; Ascl1, Achaetescute homolog 1; BAM, Brn2/Ascl1/Myt1L; Brn2, POU domain, class 3, transcription factor 2; CH, dinucleotide, where H = adenine (A), cytosine (C), or thymine (T); CpG, 5′ cytosine phosphateguanine3′ dinucleotide; ESCs, embryonic stem cells; FUS, Fused in Sarcoma; H3K27me3, histone H3 tri methylated at lysine 27; H3K4me3, histone H3 trimethylated at lysine 4 residue; hmC, hydroxymethylcytosine; hmCG, hydroxymethylcytosineguanine dinucleotide; iPSCs, induced pluripotent stem cells; Myt1L, Myelin transcription factor 1 like protein; mCH, methylated dinucleotide, where H = ade nine (A), cytosine (C), or thymine (T); NeuroD1, neuronal differentiation; Ng
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