Triggering the activation of Activin A type II receptor in human adipose stem cells towards tenogenic commitment using mechanomagnetic stimulation

Stem cell therapies hold potential to stimulate tendon regeneration and homeostasis, which is maintained in response to the native mechanical environment. Activins are members of the mechano-responsive TGF-β superfamily that participates in the regulation of several downstream biological processes. Mechanosensitive membrane receptors such as activin can be activated in different types of stem cells via magnetic nanoparticles (MNPs) through remote magnetic actuation resulting in cell differentiation. In this work, we target the Activin receptor type IIA (ActRIIA) in human adipose stem cells (hASCs), using anti-ActRIIA functionalized MNPs, externally activated through a oscillating magnetic bioreactor. Upon activation, the phosphorylation of Smad2/3 is induced allowing translocation of the complex to the nucleus, regulating tenogenic transcriptional responses. Our study demonstrates the potential remote activation of MNPs tagged hASCs to trigger the Activin receptor leading to tenogenic differentiation. These results may provide insights toward tendon regeneration therapies. Schematic illustration of the process of hASCs-MNPs-ActRIIA labeling and stimulation with magnetic field to target the Activin A receptor, initiating the intracellular signaling through activation of TGF-β/Smad2/3 towards tenogenesis. The activation of the ligand-receptor complex via magneto-mechanical stimulation was confirmed by the assessment of Smad2/3 phosphorylation in hASCs. Moreover, the remote activation of MNPs tagged hASCs resulted in improved collagenous enriched matrix and tenogenic commitment of hASCs, demonstrating potential for the modulation of signaling pathways involved in tendon regeneration. [Display omitted]