Many diseases remain incurable and cause untold human suffering and incalculable public health costs. Examples that immediately come to mind include osteoarthritis, auto-immune diseases such as multiple sclerosis and Crohn’s disease, spinal cord paralysis, diabetes types I and II, chronic obstructive pulmonary disease, emphysema, cirrhosis of the liver, congestive heart failure, degenerative brain conditions, and cancer. There is an urgent need for new therapeutic approaches that slow the progression, reduce the impact, or reverse the course of these conditions. Stem cells exhibit mechanisms that protect cells and tissues from injury, and enhance repair and regeneration potentially contributing to a novel paradigm of disease treatment. However, there is a critical gap in knowledge concerning the mechanisms by which stem cells exert these effects after transplantation. Our mission is to discover new clinical applications and technologies that exploit the properties of stem cells for maximum therapeutic benefit, and to test those new approaches in realistic animal models (veterinary patients).
How stem cells work
While many details of the molecular mechanisms by which stem cells exert therapeutic benefits in animal models and humans are unknown, the major actions are thought to include (1) engraftment and provision of healthy cells to damaged tissues, (2) release of chemical signals (free or membrane bound) that activate or protect resident cells without engraftment, (3) transfer of mitochondria to damaged cells, and/or (4) re-tuning of innate immune cells (e.g. macrophages). Mounting evidence supports an important role for paracrine signaling from stem cells. Paracrine signals are communicated by stem cells through soluble mediators (e.g. growth factors) or extracellular vesicles ranging 40-1000 nm, the latter of which contain biologically active cargo including proteins, mRNA, and miRNA, as well as DNA. The cargo within extracellular vesicles (EV) is protected from proteases and RNases/DNases thus EV can transmit functional biological signals unabatedly over long distances. The relative contribution of soluble vs. extracellular vesicle-associated mediators to paracrine signaling is debated, and is a major question our laboratory is investigating through in vitro and in vivo animal models. Understanding these mechanisms is crucial to developing the next generation of stem cell-based therapies.
Our long term goals
Our long-term goal is to develop effective cell-based therapies for diseases in which inflammation and auto-immunity are pivotal to the pathogenesis. Two major obstacles to the advancement of stem cells in this regard include (1) a clear understanding of the mechanisms by which stem cells produce benefits, e.g. paracrine mechanisms and (2) evaluation of stem cells in realistic animal models before proceeding to human trials. Patients seen by veterinarians and physicians both experience similar problems, with respect to disease pathology, clinical symptoms, time-course, and patient management. Therefore, spontaneous disease models in veterinary patients (dogs, cats, horses, sheep, goats) are particularly useful to test safety and biological activity of stem cells prior to their consideration for human trials. As a regenerative medicine laboratory affiliated with the Cummings School of Veterinary Medicine at Tufts, we are immersed in a rich scholarly and service-oriented environment which fosters novel evidenced-based approaches to medicine in our patients. Our Affiliated Faculty and trainees are focused on developing novel cell-based therapeutics to address disease processes in our veterinary patients, and relating these findings to human health.