Mechanically regulated differentiation of adipose-derived mesenchymal stem cells by PDA-functionalized injectable microgels towards intervertebral disc repair

Abstract Mechanotransduction refers to the cellular mechanism by which mechanical cues from the extracellular matrix (ECM) are sensed and transduced into biochemical signals, playing a critical role in regulating stem cell differentiation. In degenerative intervertebral disc (IVD) disease, the mechanical microenvironment undergoes pathological alterations, most notably a marked increase in ECM stiffness. This aberrant mechanical milieu disrupts cellular fate decisions and poses a critical barrier to successful endogenous regeneration. To address this limitation, poly(acrylamide-co-acrylic acid) (P(AAm-co-AA)) microgels with tunable elastic moduli were synthesized via inverse emulsion polymerization. These microgels were subsequently functionalized with polydopamine (PDA) to enhance cellular adhesion, thereby facilitating cytoskeletal remodeling and activation of mechanotransductive signaling pathways. Notably, a compliant matrix with an elastic modulus of approximately 2 kPa was found to enhance nucleus pulposus (NP)-like differentiation of adipose-derived mesenchymal stem cells in differentiation-inducing medium, as evidenced by significantly upregulated expression of NP marker genes (COL2, ACAN, SOX9). This effect was correlated with the translocation of yes-associated protein 1 (YAP). In vivo studies demonstrated that implantation of these microgels into degenerated discs led to restoration of disc height and increased ECM deposition within the NP region, as demonstrated by imaging and immunohistochemical results. Collectively, this work highlights the potential of microgel-based delivery platforms with tunable mechanical properties as a promising strategy to facilitate stem cell differentiation and promote IVD regeneration.