ORIGINAL ARTICLE Protective Effects of Autologous Bone Marrow Mononuclear Cells After Administering t-PA in an Embolic Stroke Model Bing Yang 1 & Weilang Li 2 & Nikunj Satani 1 & Duyen M. Nghiem 1 & XiaoPei Xi 1 & Jaroslaw Aronowski 1 & Sean I. Savitz 1 Received: 6 June 2017 /Revised: 9 August 2017 /Accepted: 10 August 2017 # Springer Science+Business Media, LLC 2017 Abstract Tissue plasminogen activator (t-PA) is the only FDA-approved drug for acute ischemic stroke but poses risk for hemorrhagic transformation (HT). Cell therapy has been investigated as a potential therapy to improve recovery after stroke by the modulation of inflammatory responses and the improvement of blood-brain barrier (BBB) integrity, both of which are associated with HT after t-PA. In our present study, we studied the effect of autologous bone marrow mononuclear cells (MNCs) in an embolic stroke model. We administered MNCs in a rat embolic stroke 2 h after administering t-PA. We observed that even though autologous MNCs did not alter the incidence of HT, they decreased the severity of HT and reduced BBB permeability. One possible mechanism could be through the inhibition of MMP3 released by astrocytes via JAK/STAT pathway as shown by our in vitro cell interaction studies. Keywords Cellular therapy . Embolic stroke . Hemorrhagic transformation . Blood-brain barrier integrity . Reperfusion injury Introduction Tissue plasminogen activator (t-PA) is the only FDA- approved drug for acute ischemic stroke. Despite the narrow time window of 4.5 h after stroke onset, a frequent limitation for t-PA treatment is the complication of intracerebral hemor- rhagic transformation (HT). HT incidence occurs up to 40% after t-PA treatment. One possible reason for HT after t-PA is due to increased blood-brain barrier (BBB) permeability after early BBB disruption caused by cerebral ischemia in animal and clinical studies [1–4]. Cell therapy has demonstrated safety in both experimental animal stroke models as well as in stroke patients. However, questions remain on which cell type to administer and from which route for different types of stroke [5]. Autologous bone marrow-derived mononuclear cells (MNCs), as one type of cell-based therapy, have recently been shown to have potential benefits in the recovery after stroke by our team and other investigators [6–8] and is under active investigation as a po- tential new therapy in clinical trials [9–13]. Considering that most patients presenting in the first few hours after symptom onset to stroke centers are treated with t-PA, studying the effects of MNCs following t-PA treatment is clinically rele- vant. We previously reported that MNCs regulate serum in- flammatory cytokine levels, modulating free radicals and re- ducing brain edema [14, 15], which are all regarded as poten- tial factors associated with BBB disruption after stroke [16, 17]. In addition, MNCs have been found to reduce BBB dis- ruption in a model of traumatic brain injury [18] and ICH stroke model [15]. Thus, we hypothesized that MNC treat- ment might improve BBB permeability and reduce HT in- duced by t-PA in ischemic stroke. Challenge in using rodent model of stroke is the fact that results are not easily translatable clinically. More studies are re- quired for use of stroke model which encompasses t-PA-induced * Bing Yang Bing.Yang@uth.tmc.edu 1 Institute for Stroke and Cerebrovascular Disease and Department of Neurology, McGovern Medical School, University of Texas Health Science Center (UTHealth) at Houston, Houston 77030, TX, USA 2 Department of Neurology, Tongde Hospital of Zhejiang Province, Hangzhou, China Transl. Stroke Res. DOI 10.1007/s12975-017-0563-1