Controlled Inhibition of the Mesenchymal Stromal Cell Pro-inflammatory Secretome via Microparticle Engineering

Abstract

Summary: Mesenchymal stromal cells (MSCs) are promising therapeutic candidates given their potent immunomodulatory and anti-inflammatory secretome. However, controlling the MSC secretome post-transplantation is considered a major challenge that hinders their clinical efficacy. To address this, we used a microparticle-based engineering approach to non-genetically modulate pro-inflammatory pathways in human MSCs (hMSCs) under simulated inflammatory conditions. Here we show that microparticles loaded with TPCA-1, a small-molecule NF-κB inhibitor, when delivered to hMSCs can attenuate secretion of pro-inflammatory factors for at least 6 days in vitro. Conditioned medium (CM) derived from TPCA-1-loaded hMSCs also showed reduced ability to attract human monocytes and prevented differentiation of human cardiac fibroblasts to myofibroblasts, compared with CM from untreated or TPCA-1-preconditioned hMSCs. Thus, we provide a broadly applicable bioengineering solution to facilitate intracellular sustained release of agents that modulate signaling. We propose that this approach could be harnessed to improve control over MSC secretome post-transplantation, especially to prevent adverse remodeling post-myocardial infarction. : Inamdar, Karp, and colleagues have integrated small-molecule-mediated and microparticle engineering approaches to modulate the MSC secretome. Through this, the pro-inflammatory components were inhibited, yet generally the beneficial anti-inflammatory and pro-angiogenic components were maintained. In vitro functional relevance was demonstrated by inhibiting key processes of cardiac fibrosis. It is anticipated that this non-genetic, transient cell engineering approach has broad therapeutic relevance.