α6-Integrin alternative splicing: distinct cytoplasmic variants in stem cell fate specification and niche interaction

alpha 6-Integrin subunit (also known as CD49f) is a stemness signature that has been found on the plasma membrane of more than 30 stem cell populations. A growing body of studies have focused on the critical role of alpha 6-containing integrins (alpha 6 beta 1 and alpha 6 beta 4) in the regulation of stem cell properties, lineage-specific differentiation, and niche interaction. a6-Integrin subunit can be alternatively spliced at the post-transcriptional level, giving rise to divergent isoforms which differ in the cytoplasmic and/or extracellular domains. The cytoplasmic domain of integrins is an important functional part of integrin-mediated signals. Structural changes in the cytoplasmic domain of alpha 6 provide an efficient means for the regulation of stem cell responses to biochemical stimuli and/or biophysical cues in the stem cell niche, thus impacting stem cell fate determination. In this review, we summarize the current knowledge on the structural variants of the alpha 6-integrin subunit and spatiotemporal expression of alpha 6 cytoplasmic variants in embryonic and adult stem/progenitor cells. We highlight the roles of alpha 6 cytoplasmic variants in stem cell fate decision and niche interaction, and discuss the potential mechanisms involved. Understanding of the distinct functions of alpha 6 splicing variants in stem cell biology may inform the rational design of novel stem cell-based therapies for a range of human diseases.