Cell therapy has emerged as a potential new treatment to reduce injury and improve outcome after ischemic stroke. Several studies have demonstrated that mononuclear cells (MNCs) from bone marrow are safe and enhance recovery in animal stroke models. This grant proposal aims to define specific mechanisms by which MNCs reduce neurological deficits using a variety of in vitro and in vivo models of ischemic stroke. Our preliminary data indicate that MNCs are cytoprotective and reduce pro-inflammatory responses in the post-ischemic brain.
In Specific Aim 1, we first will determine which cell populations within MNCs are critical to reduce neurological deficits, lesion size, and pro-inflammatory responses after stroke.
In Specific Aim 2, we will test the hypothesis that MNCs release the cytokines, IL-10 and IGF-1, which lead to neuroprotection and modulation of microglia.
Aim 2 A will focus on the hypothesis that both cytokines, secreted by MNCs, directly protect neurons in in vitro models of hypoxia and directly reduce injury in an animal model of stroke.
Aim 2 B addresses the hypothesis that MNCs activate and change microglia to become anti-inflammatory and neuroprotective after stroke. We hypothesize that IL-10 and IGF-1 are key factors in the capacity of MNCs to modulate the anti-inflammatory and neuroprotective effects of microglia after stroke. Our proposed studies would be the first step to elucidate specific pathways mediating the protective effects of MNCs in the post-ischemic brain and are critical to develop MNCs as a potential treatment for ischemic stroke, a condition for which there is an enormous public health need for more and improved therapies.
Stroke is the leading cause of adult disability but there is only one approved therapy with limited effectiveness for this devastating condition. Cellular therapy is a promising new approach to improve stroke recovery. This application proposes to define underlying mechanisms by which autologous bone marrow mononuclear cells improve outcome after stroke. The data from these proposed experiments are essential to better develop this new therapeutic approach to enhance recovery from stroke.
|Vahidy, Farhaan S; Rahbar, Mohammad H; Zhu, Hongjian et al. (2016) Systematic Review and Meta-Analysis of Bone Marrow-Derived Mononuclear Cells in Animal Models of Ischemic Stroke. Stroke 47:1632-9|
|Savitz, Sean I; Cox Jr, Charles S (2016) Concise Review: Cell Therapies for Stroke and Traumatic Brain Injury: Targeting Microglia. Stem Cells 34:537-42|
|Yang, Bing; Parsha, Kaushik; Schaar, Krystal et al. (2016) Cryopreservation of Bone Marrow Mononuclear Cells Alters Their Viability and Subpopulation Composition but Not Their Treatment Effects in a Rodent Stroke Model. Stem Cells Int 2016:5876836|
|Yang, Bing; Parsha, Kaushik; Schaar, Krystal et al. (2016) Various Cell Populations Within the Mononuclear Fraction of Bone Marrow Contribute to the Beneficial Effects of Autologous Bone Marrow Cell Therapy in a Rodent Stroke Model. Transl Stroke Res 7:322-30|
|Savitz, Sean I (2015) Developing Cellular Therapies for Stroke. Stroke 46:2026-31|
|Suda, Satoshi; Yang, Bing; Schaar, Krystal et al. (2015) Autologous Bone Marrow Mononuclear Cells Exert Broad Effects on Short- and Long-Term Biological and Functional Outcomes in Rodents with Intracerebral Hemorrhage. Stem Cells Dev 24:2756-66|
|Savitz, Sean I (2013) Cell therapies: careful translation from animals to patients. Stroke 44:S107-9|
|Yang, Bing; Migliati, Elton; Parsha, Kaushik et al. (2013) Intra-arterial delivery is not superior to intravenous delivery of autologous bone marrow mononuclear cells in acute ischemic stroke. Stroke 44:3463-72|
|Mir, Osman; Savitz, Sean I (2013) Stem cell therapy in stroke treatment: is it a viable option? Expert Rev Neurother 13:119-21|
|Yang, Bing; Xi, Xiaopei; Aronowski, Jaroslaw et al. (2012) Ischemic stroke may activate bone marrow mononuclear cells to enhance recovery after stroke. Stem Cells Dev 21:3332-40|