Since being discovered over half a century ago, mesenchymal stem cells (MSCs) have been investigated extensively to characterize their cellular and physiological influences. MSCs have been shown to possess immunosuppressive capacity through inhibiting lymphocyte activation/proliferation and pro-inflammatory cytokine secretion while simultaneously demonstrating limited allogenic reactivity, which subsequently led to the evaluation of therapeutic feasibility to treat inflammatory diseases. Novel MSC-based therapies have been efficacious on a limited scale in the treatment of autoimmune/inflammatory diseases and offer an ideal therapeutic strategy to suppress inflammation and minimize off-target effects, but will require more rigorous evaluation before moving to the clinic on a commercial scale. In these translational studies, we will investigate whether MSC-derived extracellular vesicles (EVs) can suppress the immune response and test the efficacy of serval MSC-based treatment strategies in lupus, myositis, and scleroderma.
Myositis is an autoimmune disease characterized by chronic muscle inflammation resulting in weakness and a variety of clinical manifestations. Current treatments include broad-spectrum immunosuppressive agents and, more recently, targeted immune therapy directed against inflammatory cells and mediators. While these treatments can be relatively effective, they can result in significant complications due to systemic immunological suppression. Scleroderma is an autoimmune disease that is either localized to the skin or progressively develops systemically to target other organ systems, including the blood vessels, muscles, lungs, and other internal organs. Unfortunately, most patients progress despite medical intervention, which results in a 10-year survival of only 66% and mortality rates over 30% in the first 5 years. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease associated with a myriad of genetic and epigenetic aberrations, environmental triggers, and hormonal influences. Patients with SLE have witnessed the approval of only one SLE-targeted drug within the past 50 years. With all of these autoimmune diseases, the chronic immunosuppressive therapies commonly provided to patients are associated with treatment-related morbidity and mortality.
By using the novel MSC-based therapeutic technologies, we will test if autoimmune-mediated processes and inflammatory pathology can be effectively suppressed. We have 3 potential sources of MSCs based on collaborations we have established. The first is with Sentien Biotechnologies; they have developed a bioreactor to deliver MSC secreted factors (including EVs) in an infusion-like delivery setting. We plan to use the downscaled model in mouse/rat models to generate preliminary data to be used in the submission of a grant from the National Institute of Health (NIH) small business innovation research (SBIR) grant program for clinical trial development in diseases where we have demonstrated preliminary success. In addition, we have an active academic collaboration with the bioengineer and Sentien co-founder who has an appointment in bioengineering at Rutgers. This will enable the pursuit of NIH and other funding that requires researchers from academia. Secondly, we have a collaboration with the co-founder, Vice President of Regenerative Medicine, and Head of Neuroscience Programs at Athersys Inc (Nasdaq: ATHX). Using their multipotent adult progenitor cell (MAPC) therapy, we will compare to the treatment with the EVs derived from these cells in the characterization of the immunosuppressive process. Finally, we have an on-going collaboration the department of rheumatology at Cleveland Clinic to work on an off-the-shelf MSC therapy that we are currently testing in a mouse model of rheumatic disease that we established at Ohio State.
More information on extracellular vesicles (EVs)
Previous research has indicated that the components of the MSC secretome that may be mediating this immunosuppressive function are EVs. As defined by the International Society of Extracellular Vesicles (ISEV), EVs are spherical membrane-enclosed bodies secreted by cells and can be divided into subpopulations based on size and cellular biogenesis: exosomes (50 – 150 nm) originating from multivesicular bodies; microvesicles (150 – 1000 nm) originating from the plasma membrane; and apoptotic bodies (> 1 µm) originating from the plasma membrane of dying cells. However, since the sizes of the vesicles overlap, well-defined markers still lack consensus, and the precise origination of the vesicles obtained is often unknown, ISEV has suggested to use the term EV to describe the vesicles present in experimentally purified samples. Although identified over 30 years ago and described as a mechanism by which cells eliminate unwanted proteins/molecules, incontrovertible evidence generated over the past decade has now characterized the role of EVs in cell-to-cell communication. In support of the critical role of MSC-derived EVs in regulating in vivo biological activity, size fractionation analysis of conditioned media from human MSCs revealed a 50 – 200 nm exosomal complex originating from multivesicular intracellular endosomes as the principal bioactive component reducing myocardial infarct sizes in pig and mouse models. Since extracellular particles of this size range can be consistently isolated from human sources and used successfully in the clinic following standardized differential ultracentrifugation protocols, these EVs have been the focus of recent molecular characterization and therapeutic development.
EVs facilitate cellular communication by delivering bioactive cargo containing, among other molecules, microRNAs (miRs) that can elicit functional consequences in recipient cells. Results from our previous studies have demonstrated that extracellular miRs are contained primarily within EVs and that specific miRs can act as an endogenous ligand for TLR7 and TLR8, which are upregulated in SLE patients and induced by estrogen. This novel signaling mechanism in addition to the conventional role in suppressing gene expression by targeting specific mRNA sequences make EV-encapsulated miRs potent immunoregulatory elements.
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