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Epigenetic Priming - The Key to Effective Stem Cell Therapies for the Injured Heart?

Review of “Epigenetic Priming of Human Pluripotent Stem Cell‐Derived Cardiac Progenitor Cells Accelerates Cardiomyocyte Maturation” from STEM CELLS by Stuart P. Atkinson 

The relative immaturity of human pluripotent stem cell (hPSC)‐derived cardiomyocytes has limited their applications in disease modeling, drug development, and in therapeutic approaches, a failing that has prompted the development of multiple strategies that promote functional maturation. However, these often time‐consuming, cumbersome, and perhaps even clinically irrelevant methods contribute only minimally to the overall maturation status of resultant hPSC‐derived cardiomyocytes. 

Interestingly, recent studies have highlighted the importance of cell‐intrinsic processes in cardiomyocyte maturation and epigenetic factors in particular [1, 2] and so, researchers led by Timothy J. Kamp (University of Wisconsin‐Madison, USA) explored epigenetic priming of hPSC‐derived cardiac progenitor cells (CPCs) as a means to improve subsequent cardiomyocyte differentiation and provide cells with the required maturation status. 

Biermann et al. now report in a new STEM CELLS article how epigenetic priming with polyinosinic‐polycytidylic acid (pIC) [3-5], a simple clinically‐approved chemically-defined biopolymer that acts as a double‐stranded RNA and innate immunity activator, accelerates hPSC-CPC differentiation and promotes cardiomyocyte maturation in vitro and also in vivo after heterotopic transplantation [6]. 

Does epigenetic priming represent the key to effective stem cell therapies for the injured heart?

The authors differentiated CPCs from hPSCs employing monolayer differentiation and temporal Wnt signaling modulation, with pIC treatment commencing during early CPC formation. While treatment with pIC failed to alter the expression of common CPC surface markers and cardiac transcription factors or the final purity of cardiomyocytes, the epigenetic priming of CPCs did foster enhanced maturity of resultant cardiomyocytes, as evidenced by increased cell size, greater contractility, faster electrical upstrokes, increased oxidative metabolism, and a more mature sarcomeric structure and composition. Encouragingly, these in vitro improvements also extended in vivo, as the authors discovered that primed hPSC-CPCs formed more substantial and mature cardiomyocyte grafts compared to unprimed hPSC-CPCs when heterotopically transplanted into immunodeficient mouse models.

So how does pIC priming achieve this feat of maturation? Using RNA-sequencing analysis, the authors discovered that pIC modulated early Notch signaling and cardiomyogenic transcriptional programs in hPSC-CPCs. At the epigenetic levels, pIC caused an increased in the deposition of acetylation of H3K9, an epigenetic modification that promotes gene transcription, at core promoters of cardiac myofilament genes and the Notch ligand, JAG1, thereby prompting their earlier transcription and, hence, the earlier onset of electromechanical contractions of differentiated hPSC‐derived cardiomyocytes.

The authors believe that pIC priming represents a safe, effective, and practical means to generate functionally mature hPSC-CMs in vitro or in vivo when compared to other strategies, such as genetic modification. To this end, subsequent studies will aim to explore how primed hPSC-CPCs repair the injured heart and the effects of pIC priming on other progenitor cells in the hope of influencing their therapeutic potential.

For more on epigenetic priming, hPSC-derived cardiomyocytes, and cell therapy for the injured heart, stay tuned to the Stem Cells Portal!

References

  1. Piccini I, Araúzo-Bravo M, Seebohm G, et al., Functional high-resolution time-course expression analysis of human embryonic stem cells undergoing cardiac induction. Genomics Data 2016;10:71-74.
  2. Tompkins JD, Jung M, Chen C-y, et al., Mapping Human Pluripotent-to-Cardiomyocyte Differentiation: Methylomes, Transcriptomes, and Exon DNA Methylation "Memories". EBioMedicine 2016;4:74-85.
  3. Lee J, Sayed N, Hunter A, et al., Activation of Innate Immunity Is Required for Efficient Nuclear Reprogramming. Cell 2012;151:547-558.
  4. Hodgkinson CP, Pratt RE, Kirste I, et al., Cardiomyocyte Maturation Requires TLR3 Activated Nuclear Factor Kappa B. STEM CELLS 2018;36:1198-1209.
  5. Sayed N, Wong Wing T, Ospino F, et al., Transdifferentiation of Human Fibroblasts to Endothelial Cells. Circulation 2015;131:300-309.
  6. Biermann M, Cai W, Lang D, et al., Epigenetic Priming of Human Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Accelerates Cardiomyocyte Maturation. STEM CELLS 2019;37:910-923.