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 (a-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-ß1). The reduction of
a-SMA expression as a myofibroblast marker was notable in pre- and post-TGF-ß1 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.
