Preventive and Therapeutic Effects of Bone Marrow Stem Cell-Derived Exosomes on Spine Dural Fibrosis - PROJECT SUMMARY/ABSTRACT Failed back surgery syndrome (FBSS) refers to a cluster of symptoms in spinal cord and nerve roots after spinal surgery, especially laminectomy and discectomy, and up to 40% of patients have experienced chronic nerve radicular pain and lower extremity weakness. The main cause of FBSS is the compression of dura and nerve roots due to spinal dural fibrosis, including epidural fibrosis and peridural adhesion. Multiple factors leading to dural fibrosis are the inflammatory response post-surgical trauma and excessive matrix deposition by highly activated myofibroblasts. Spinal dural fibrosis, if not properly treated by conservative management, can generally worsen, which may require surgical treatments. However, success of these surgical interventions is only 30-35%, and up to 20% of patients have more serious condition. Thus, there is a critical and urgent need to prevent and treat spinal dural fibrosis. Exosomes have attracted attention due to their great potential as an inhibitor of dural fibrosis. Damaged tissues are repaired by the paracrine signaling of exosomes rather than direct proliferation and differentiation and this paracrine effect implies that exosome therapy has a clinical advantage over stem cell transplantation in terms of immune response and tumorigenesis. Mesenchymal stromal/stem cells (MSCs) are promising sources of exosomes, and MSC-derived exosomes showed an evident reduction of fibrosis in liver and lung. The long-term goal is to develop a minimally invasive anti-fibrosis therapy for spine dural fibrosis. To achieve that goal, we propose to evaluate the effects of exosomes on reduction of alpha smooth muscle actin (α-SMA), type I collagen, and contractile activities in human myofibroblasts and the in vivo preventive effects in a rat laminectomy model. Our central hypotheses are that: exosomes have the potential to alleviate myofibroblast activities, and hydrogel will allow sustained release of exosomes and restrict fibroblast migration as a physical barrier between the dura mater and posterior tissue. The hypotheses have been devised on the basis of our preliminary data, which revealed that MSC-derived exosomes showed both preventive and therapeutic potential in exogenously induced bovine myofibroblasts by transforming growth factor beta 1 (TGF-β1). The reduction of α-SMA expression as a myofibroblast marker was notable in pre- and post-TGF-β1 treatment with exosomes. At the completion of the proposed R21 project, our expected outcomes are to define the therapeutic potential of exosomes for prevention of peridural fibrosis and to identify microRNAs (miRNA) that may regulate anti-fibrotic effects. These results will have a very important positive impact by providing preliminary data for our future R01 grant application, which will be to evaluate in vivo therapeutic effects of MSC-derived exosomes treated after induction of dural fibrosis and to synthesize target miRNAs to avoid stem cell culture as a means of exosome production. Synthetic miRNAs will be loaded in engineered exosomes for in vivo delivery, thereby replacing MSC culture as a potential means of exosome production.
