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

Abstract

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.

Remote triggering of TGF-β/Smad2/3 signaling in human adipose stem cells laden on magnetic scaffolds synergistically promotes tenogenic commitment

“…Our group has recently reported on magnetic responsive fibrous scaffolds for tendon TE, suggesting activation of YAP/TAZ signaling in response to magnetic stimulus [11] . These strategies may have an important role in tenogenic differentiation of stem cells [11][12][13][14] and/or in the modulation of the inflammatory response [15 , 16] , envisioning improved repair outcomes. Signaling cascades act as transducers of mechanical forces into downstream mechanosensory molecules.…”

Aspirin promotes tenogenic differentiation of tendon stem cells and facilitates tendinopathy healing through regulating the GDF7/Smad1/5 signaling pathway

“…J. Liu et al () also reported that BMP12 induced tenogenic differentiation of TSCs through Smad1/5/8 signaling. Activins are members of the mechano‐responsive TGF‐β superfamily that participates in the regulation of several downstream biological processes, Goncalves et al () also showed that triggering the activation of Activin A type II receptor in human adipose stem cells toward tenogenic commitment using mechanomagnetic stimulation. Interestingly, Schweitzer et al () showed that BMP signaling (BMP2/BMP4/BMP7) restricted SCX expression of tendon progenitor in the early limb bud stage.…”

Nanoparticles as Versatile Tools for Mechanotransduction in Tissues and Organoids

“…This approach is transferrable to other lineages, requiring mainly the modification of the magnetic NP functionalization to target different receptors of interest. For instance, when targeting the activin receptor type IIA on human adipose stem cells, a varying magnetic field helped activate the receptor and promoted tenogenic differentiation, providing a promising result for tendon repair applications (Gonçalves et al, 2018). Interestingly, magnetic NPs can also impose such high forces that cell death can result -in some case this may be valuable, for example to mechanically disrupt and destroy cancer cells (Shen et al, 2017) such as malignant glioma cells in-tumor-bearing mice, which could be destroyed by the application of a rotating magnetic field to internalized disk shaped permalloy magnetic NPs (Cheng et al, 2016).…”