On average, one American has stroke every 40 seconds, and one dies every 4 minutes. Of the different types of stroke, acute ischemic stroke is the most common, and successful treatment of this medical condition remains very challenging. The """"""""clot busting"""""""" drug tissue plasminogen activator (tPA) is the only drug approved for clinical use for acute ischemic stroke. However the drug must be initiated within 4.5 h of stroke onset or risk detrimental side effects including intracerebral hemorrhagic transformation (HT). Therefore, an important clinical problem is to develop methods that will extend the limited therapeutic time window of tPA or reduce complications associated with delayed treatment of tPA. The granulocyte-colony stimulating factor (G-CSF) has been shown to exert neuroprotective effects in animal models of ischemia. It is not yet known if the drug could attenuate detrimental side effects of delayed tPA treatment in ischemic stroke. Furthermore, we have shown in a rat model of traumatic brain injury (TBI) that G-CSF monotherapy reduced neuroinflammation in the gray and white matter areas and also ameliorated TBI-induced impairment in endogenous neurogenesis. These findings taken together with reported neuroprotective effects of G-CSF in animal models of ischemia led us to hypothesize that the treatment of G-CSF will also reduce HT associated with delayed treatment of tPA (Aim 1). Treatment with G-CSF mobilizes cells from the bone marrow to the peripheral blood including CD34+ bone marrow stem cells which contain endothelial progenitor cells (EPCs). Several studies suggested that beneficial effects of G-CSF in stroke (e.g. angiogenesis, vasculogenesis, etc.) are mediated by EPCs. Moreover, in a previous study, we have also shown that transplantation of human cerebral endothelial cells attenuated stroke-induced motor and neurological deficits in rats via enhancement of vasculogenesis. In light of these findings, we hypothesized that G-CSF mobilizes EPCs in the setting of tPA-induced HT in stroke, and EPCs attenuate HT via enhancement of vasculogenesis or angiogenesis, processes that preserve the cerebrovasculature (Aim 2). Delayed tPA-induced HT has been attributed to effects of tPA on the neurovascular unit and also via disruption of the blood brain barrier (BBB). We hypothesized that another mechanism underlying neuroprotective effects of G-CSF is via preservation of the integrity of the BBB through vasculogenic and angiogenic effects of recruited EPCs. The long-term goal of this study is to demonstrate that G-CSF in tandem with tPA will reduce delayed tPA-associated complications and also extend the thrombolytic efficacy of tPA. The overall impact is that at the completion of this study, the findings from this work will lay the foundation for the clinical evaluation of G-CSF in attenuating HT associated with delayed treatment of tPA.
Successful treatment of acute ischemic stroke remains a major challenge in clinical medicine. Only 3% to 5% of patients receive tissue plasminogen (tPA) therapy for acute ischemic stroke and delayed treatment of tPA (i.e. beyond 4.5 h of stroke onset) has been associated with serious complications including hemorrhagic transformation (HT) and neurotoxicity. The goal of this study is to provide groundbreaking evidence that will advance the potential clinical application of G-CSF in reducing HT associated with delayed treatment of tPA. Our long-term goal is to demonstrate that G-CSF in combination with tPA will reduce the detrimental side effects of delayed tPA treatment and also extend the thrombolytic efficacy of tPA.
|Liska, Grant M; Lippert, Trenton; Russo, Eleonora et al. (2018) A Dual Role for Hyperbaric Oxygen in Stroke Neuroprotection: Preconditioning of the Brain and Stem Cells. Cond Med 1:151-166|
|Dewan, Shyam; Schimmel, Samantha; Borlongan, Cesar V (2018) Treating childhood traumatic brain injury with autologous stem cell therapy. Expert Opin Biol Ther 18:515-524|
|Marcet, Paul; Santos, Nicole; Borlongan, Cesar V (2017) When friend turns foe: central and peripheral neuroinflammation in central nervous system injury. Neuroimmunol Neuroinflamm 4:82-92|
|Tajiri, Naoki; Quach, David M; Kaneko, Yuji et al. (2017) NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats. J Cell Physiol 232:2731-2740|
|Napoli, Eleonora; Borlongan, Cesar V (2017) Stem Cell Recipes of Bone Marrow and Fish: Just What the Stroke Doctors Ordered. Stem Cell Rev 13:192-197|
|Stonesifer, Connor; Corey, Sydney; Ghanekar, Shaila et al. (2017) Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms. Prog Neurobiol 158:94-131|
|Uchida, Hiroki; Niizuma, Kuniyasu; Kushida, Yoshihiro et al. (2017) Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model. Stroke 48:428-435|
|Napoli, Eleonora; Borlongan, Cesar V (2017) Cell Therapy in Parkinson's Disease: Host Brain Repair Machinery Gets a Boost From Stem Cell Grafts. Stem Cells 35:1443-1445|
|Shojo, Hideki; Borlongan, Cesario V; Mabuchi, Tadashi (2017) Genetic and Histological Alterations Reveal Key Role of Prostaglandin Synthase and Cyclooxygenase 1 and 2 in Traumatic Brain Injury-Induced Neuroinflammation in the Cerebral Cortex of Rats Exposed to Moderate Fluid Percussion Injury. Cell Transplant 26:1301-1313|
|Liska, Michael G; Crowley, Marci G; Borlongan, Cesar V (2017) Regulated and Unregulated Clinical Trials of Stem Cell Therapies for Stroke. Transl Stroke Res 8:93-103|
Showing the most recent 10 out of 25 publications