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Large Novel Cohort Highlights the Factors Influencing Human Reprogramming

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Review of “Epigenetic Enzymes, Age, and Ancestry Regulate the Efficiency of Human iPSC Reprogramming” from STEM CELLS by Stuart P. Atkinson 

Recent studies hoping to discover factors that influence the generation of human induced pluripotent stem cells (hiPSCs) have reported no correlation between donor cell age and reprogramming efficiency [1-3]. However, researchers from the laboratory of Trevor K. Archer (National Institute of Environmental Health Sciences, North Carolina, USA) believed that small sample sizes, the different parental somatic cells employed, and the diverse genetic backgrounds involved may mask some important conclusions. 

Now, the team’s new STEM CELLS study reports on the effect of donor demographics on hiPSC reprogramming efficiency via the creation of a large novel cohort of human dermal fibroblasts and hiPSCs from healthy human donors [4]. Mackey et al. now establish that donor age, ancestry, and the expression of chromatin remodeling complex components all significantly affect reprogramming efficiency.

The authors created a sex and ancestry balanced cohort of 240 hiPSC lines derived from low passage human dermal fibroblasts from 80 healthy donors (20 African American women and 21 men & 19 European American women and 20 men) of 21 to 64 years of age split into groups of above or below 33 years of age. The reprogramming process employed the expression of OCT4, SOX2, c-Myc, KLF4, NANOG, and LIN28 via non-integrating episomal vectors to generate hiPSCs validated as pluripotent via assessments of morphology, growth rate, gene expression, and alkaline phosphatase staining. Additionally, randomly selected hiPSCs were successfully tested for their ability to form teratomas. Of note, the authors highlighted the intrinsic capacity of cells from all donors to be reprogrammed to generate hiPSC colonies, arguing against a stochastic process and for a process controlled by distinct genetic and molecular mechanisms.

Interestingly, the study then discovered that donor demographics influenced SWI/SNF subunit variability and that the expression of the BRG1, BAF155, and BAF60a chromatin remodeling-associated factors strongly correlating with hiPSC reprogramming efficiency. Additionally, the authors established higher efficiency hiPSC reprogramming for samples derived from either younger donors (<33 years of age) and African American donors, while there existed no correlation with donor sex.

The authors hope that their large and diverse cohort can complement already existing cohorts [5, 6] to become a vital resource for researchers seeking to validate observational results from human population studies and to perform detailed mechanistic studies in an adequately controlled manner. 

For more on how age, ancestry, and the expression of chromatin remodeling factor expression influence human induced pluripotent stem cell reprogramming, stay tuned to the Stem Cells Portal.

References

  1. Li H, Collado M, Villasante A, et al., The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 2009;460:1136-9.
  2. Mahmoudi S and Brunet A, Aging and reprogramming: a two-way street. Curr Opin Cell Biol 2012;24:744-56.
  3. Phanthong P, Raveh-Amit H, Li T, et al., Is aging a barrier to reprogramming? Lessons from induced pluripotent stem cells. Biogerontology 2013;14:591-602.
  4. Mackey LC, Annab LA, Yang J, et al., Epigenetic Enzymes, Age, and Ancestry Regulate the Efficiency of Human iPSC Reprogramming. STEM CELLS 2018;36:1697-1708.
  5. Panopoulos AD, D'Antonio M, Benaglio P, et al., iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types. Stem Cell Reports 2017;8:1086-1100.
  6. Lee G, Papapetrou EP, Kim H, et al., Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 2009;461:402-6.