A7: Controlled Drug Delivery

NON-GENETIC AND TRANSIENT ENGINEERING OF MESENCHYMAL STEM CELL SECRETOME USING INTRACELLULAR CONTROLLED DRUG DELIVERY


Sudhir Ranganath1,2,3,4,5,6, Zhixiang Tong3,4,5, Oren Levy3,4,5, Keir Martyn3,4,5, Jeffrey Karp3,4,5, Maneesha Inamdar2,6 


1Siddaganga Institute of Technology, India;
2Jawaharlal Nehru Center for Advanced Scientific Research, India;
3Brigham & Women’s Hospital, USA
4Harvard Medical School, USA;
5Harvard–MIT Program of Health Sciences and Technology, USA;
6Institute for Stem Cell Biology and Regenerative Medicine, India 


Cell therapy using exogenous mesenchymal stem cells (MSCs) has gained limelight recently given its secretome-mediated paracrine effects, especially via potent immunomodulatory and antiinflammatory secretome. However, the complex host microenvironment is a major hindrance to controlling the MSC secretome post-transplantation. The resultant unpredictable MSC response hinders their clinical efficacy and often contributes to highly variable clinical outcomes. While genetically engineered MSCs have non-transient effects and regulatory hurdles towards clinical translation, the drug/cytokine preconditioned MSCs have highly transient effects post transplantation. To address these, we developed an intracellular controlled drug delivery approach to non-genetically and transiently modulate the pro-inflammatory secretome in human MSCs (hMSCs). Poly-L-lactideco-glycolide (PLGA) polymer was used to synthesize microparticles (~ 900 nm in size) and surface functionalized with a cationic polymer (poly-L-lysine) to enhance internalization kinetics into hMSCs. Under simulated inflammatory condition (stimulation by TNF-alpha), we demonstrate that intracellularly delivered TPCA-1 (a small molecule NF-kB inhibitor) via PLGA microparticles (TPCA-μPs) can attenuate secretion of pro-inflammatory factors from hMSCs for at least six days in vitro. On the contrary, soluble TPCA-1 preconditioning has a very transient effect on hMSC secretome. Conditioned medium (CM) derived from TPCA-μP-loaded hMSCs also showed reduced ability to attract human monocytes and prevented differentiation of human cardiac fibroblasts to myofibroblasts, compared to CM from untreated or TPCA-1-preconditioned hMSCs. In addition, Conditioned medium derived from TPCA-μP-loaded hMSCs attenuated collagen secretion from human and mouse cardiac myofibroblasts. These results demonstrate the potential utility of the microparticleengineered hMSCs in the inhibition of cardiac fibrosis. Thus, we provide a broadly applicable bioengineering solution to facilitate intracellular sustained release of agents that modulate cell 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.

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