The Srivastava Lab's research interest revolves around developing cell- and extracellular vesicles-based therapies for neuroinflammatory and traumatic disorders.
Platelet-Derived Extracellular Vesicles for Hemorrhage Control and Prevention of Hemorrhagic Shock
Severe hemorrhage is one of the most common causes of death in the combat military population. A shift in practice from primarily fluid-based resuscitation to administration of balanced blood products have improved early outcomes following traumatic injury. In particular, recent research has shown that early transfusion of platelets promotes hemostasis and improve survival in severely injured patients. However, the short shelf life, storage sensitivity, reported storage lesion, and in some cases, occurrence of transfusion-related acute lung injury is some of the major limitations to the use of platelets in austere environments. Platelet-derived extracellular vesicles (PEVs) are nanoparticles secreted from platelets that express surface receptors and contain multiple types of RNA, proteins, lipids and DNA. PEVs share many functional features with platelets, such as high hemostatic capacity, but are more advantageous to platelet transfusions given their stability following freeze-thaw cycles and potential for lyophilization. These qualities eliminate logistical barriers of shelf-life limitations, storage, and transportation that preclude use of platelets in austere environments. Previous data from our group demonstrate that patients with trauma-induced coagulopathy exhibit a reduction in circulating PEVs, suggesting PEVs are critical for supporting hemostasis and preventing the development of TIC. In response to these findings, our subsequently published work showed that PEVs could support the robust generation of thrombin, control bleeding, and prevent the development of hemorrhagic shock in a rodent liver laceration model. Further, our preliminary data demonstrate that PEVs can prevent thrombin-induced endothelial barrier disruption by protecting junctional protein arrangement. Given that loss of endothelial barrier integrity and subsequent hyper-permeability is a key mechanism in the pathogenesis of trauma and HS-induced multiple organ dysfunction (MOD), these data suggest that PEVs could not only improve short-term outcomes by controlling hemorrhage, but may also improve long-term outcomes by preventing the development of MOD. The goal of this project is to evaluate the effects of PEVs in acute hemorrhage control following severe injury, prevention of MOD, and to characterize the effects of PEVs in modulating endothelial function.
Therapeutic Potential of Mesenchymal Stromal Cell-derived Extracellular Vesicles in Ischemic Stroke
Ischemic stroke is a leading cause of morbidity and mortality worldwide and, despite reperfusion either via thrombolysis or thrombectomy, stroke patients often suffer from lifelong disabilities. These persistent neurological deficits may be improved by treating the ischemia/reperfusion (I/R) injury that occurs following ischemic stroke. There are currently no approved therapies to treat I/R injury, and thus it is imperative to find new therapies to decrease the burden of ischemic stroke and related diseases. Mesenchymal stem cells (MSCs) are studied most extensively for their therapeutic roles, which appear to be derived from their paracrine activity. Recent studies by our group and others suggest a critical therapeutic role for extracellular vesicles (EVs) secreted by MSCs (MSC-EVs). In this international collaborative project, we seek to understand the therapeutic potential of MSCs and MSC-EVs in ischemic stroke. We also aim to identify the molecular mechanisms responsible for the beneficial effects of the treatments and circulating biomarkers predictive of functional outcome.