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Linking Connexin Expression to the Pluripotent State of Stem Cells

Review of “Dynamic regulation of connexins in stem cell pluripotency” from STEM CELLS by Stuart P. Atkinson

Communication between cells via gap junctions composed of connexin proteins occurs in both cells of the early embryo and pluripotent stem cells (PSCs); however, the exact role of gap junctional intercellular communication (GJIC) in pluripotent stem cells remain a controversial topic. Various studies undertaken with mouse embryonic stem cells (mESCs) have failed to find a common ground regarding the contribution of connexins to the pluripotency and survival of stem cells [1, 2], while other studies suggest that GJIC aids the establishment, survival, and maintenance of pluripotency in human (h)PSCs [3-5]. In the hope of more fully understanding the role of connexins and GJIC in pluripotency, researchers led by Jessica L. Esseltine (Memorial University of Newfoundland, Canada) recently assessed the expression levels of connexins in human and mouse PSCs; the results published in STEM CELLS suggest that the level of connexin expression depends on the stem cell state [6].

Comparative analyses of human and mouse PSCs established a distinct connexin expression pattern for pluripotent states; developmentally-primitive naïve PSCs expressed significantly lower levels of connexins when compared to differentiation-primed PSCs (mRNA and protein), which expressed high levels of connexins such as Cx43. The authors propose that the distinct transcription profiles observed may derive from differential regulation by pluripotency-associated transcription factors expressed in each cell state. 

In agreement with the previous findings, the pharmacological inhibition of GJIC failed to influence cell survival, self‐renewal, and pluripotency in naïve human PSCs, but significantly impacted primed PSCs; however, the loss of Cx43 expression via CRISPR‐Cas9 gene ablation failed to exert any significant influence on naïve and primed mouse and human PSCs. Furthermore, comparisons between cell types also highlighted the expression of several additional connexin transcripts in mouse PSCs not found in human PSCs (including Cx26, Cx30, and Cx30.3), highlighting the existence of species‐specific differences. 

Overall, the authors highlight the differential expression of connexin genes along the in vitro “pluripotency continuum” and a level of species-specificity and propose the differential expression of pluripotency-associated transcription factors within pluripotent states as the driving force behind differential connexin expression profiles.

For more on the link between the expression of connexins and the pluripotent status of mouse and human PSCs, stay tuned to the Stem Cells Portal!

References

  1. Todorova MG, Soria B, and Quesada I, Gap junctional intercellular communication is required to maintain embryonic stem cells in a non-differentiated and proliferative state. Journal of Cellular Physiology 2008;214:354-362.
  2. Wörsdörfer P, Maxeiner S, Markopoulos C, et al., Connexin Expression and Functional Analysis of Gap Junctional Communication in Mouse Embryonic Stem Cells. STEM CELLS 2008;26:431-439.
  3. Sharovskaya YY, Philonenko ES, Kiselev SL, et al., De Novo Reestablishment of Gap Junctional Intercellular Communications During Reprogramming to Pluripotency and Differentiation. Stem Cells and Development 2012;21:2623-2629.
  4. Ke Q, Li L, Yao X, et al., Enhanced generation of human induced pluripotent stem cells by ectopic expression of Connexin 45. Scientific Reports 2017;7:458.
  5. Wong RCB, Dottori M, Koh KLL, et al., Gap junctions modulate apoptosis and colony growth of human embryonic stem cells maintained in a serum-free system. Biochemical and Biophysical Research Communications 2006;344:181-188.
  6. Esseltine JL, Brooks CR, Edwards NA, et al., Dynamic regulation of connexins in stem cell pluripotency. STEM CELLS 2020;38:52-66.