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How Integrins Maintain the Pluripotent State

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Review of “Inhibition of Focal Adhesion Kinase Signaling by Integrin α6β1 Supports Human Pluripotent Stem Cell Self-Renewal” from Stem Cells by Stuart P. Atkinson

Integrins are heterodimeric transmembrane receptors for extracellular matrix (ECM) proteins which constitute the growth substrate used for the culture of human embryonic stem cells (hESCs) [1]. Through interaction with extracellular signaling pathways, they function by controlling mechanisms such as cell migration, differentiation, gene expression, and normal organ development and function.

A recent collaboration between the laboratories of Luis G. Villa-Diaz (Oakland University, MI, USA) and Paul H. Krebsbach (University of Michigan, USA) sought to identify the main integrins expressed by hESCs and how they function. Their new Stem Cells study now reports that integrin α6β1 represents the main heterodimer integrin receptor in hESCs and that the α6β1 interaction inhibits focal adhesion kinase (FAK) activity to maintain the pluripotent state [2].

Initial expression and flow cytometry analysis of hESCs cultured on Matrigel demonstrated predominant α6 and β1 integrin expression in the undifferentiated state. Parallel co-expression analysis also confirmed that integrin α6 interacted with integrin β1 in hESCs forming the α6β1 heterodimer. Interestingly, only the β1 integrin, and not the α6 subunit, proved to be important to hESC adhesion to growth substrates. However, the study noted specific downregulation of only the α6 subunit during differentiation.

Interestingly, loss of α6 integrin (so “freeing” β1 integrin) or activation of β1 integrin in hESCs led to a reduction in pluripotency-associated gene expression. Furthermore, β1 integrin also induced the expression and activity of focal adhesion kinase (FAK), which can mediate signaling from activated integrins [3]. FAK activity studies found minimal FAK activity in self-renewing hESCs, although phosphorylation and activation of FAK following hESC differentiation. Furthermore, the study also demonstrated that the N-terminal domain of FAK (NT-FAK) interacted with OCT4 and SOX2 in the nucleus of self-renewing hESCs (See Figure) and, therefore, may mediate FAK inhibition and help to maintain the pluripotent state.

This represents the first description of a pluripotency-associated signaling pathway involving integrin α6β1 and FAK signaling and will help us to understand the interplay between ECM and the pluripotent state. Furthermore, this new knowledge may promote the construction of new and better strategies to maintain and differentiate hESCs. 

References

  1. Watt FM. Role of integrins in regulating epidermal adhesion, growth and differentiation. The EMBO Journal 2002;21:3919-3926.
  2. Villa-Diaz LG, Kim JK, Laperle A, et al. Inhibition of Focal Adhesion Kinase Signaling by Integrin alpha6beta1 Supports Human Pluripotent Stem Cell Self-Renewal. Stem Cells 2016;34:1753-1764.
  3. Guan JL and Shalloway D. Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 1992;358:690-692.