Directing iPSC Differentiation into iTenocytes using Combined Scleraxis Overexpression and Cyclic Loading

Abstract: Regenerative therapies for tendon are falling behind other tissues due to the lack of an appropriate and potent cell therapeutic candidate. This study aimed to induce cell tenogenesis using stable Scleraxis (Scx) overexpression in combination with uniaxial mechanical stretch of mesenchymal stromal cells (MSCs) of different origins. Scleraxis (Scx) is the single direct molecular regulator of tendon differentiation known so far. Mechanoregulation is known to be a central element guiding tendon development and healing. Cells explored were bone marrow-derived (BM-)MSCs as well as MSCs differentiated from induced pluripotent stem cells (iMSCs). Upregulation of early and late tendon markers, increased collagen deposition, and morphometric and cytoskeleton-related changes in mechanically stimulated Scx-overexpressing iMSCs compared to BM-MSCs and controls. Our findings suggest that these cells can be differentiated into tenocytes and may be a better candidate for tendon cell therapy applications than BM-MSCs.