Springer Series in Translational Stroke Research Jun Chen John H. Zhang Xiaoming Hu Editors Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke Springer Series in Translational Stroke Research Series Editor John Zhang More information about this series at http://www.springer.com/series/10064 Jun Chen • John H Zhang • Xiaoming Hu Editors Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke Editors Jun Chen Department of Neurology University of Pittsburgh Pittsburgh, PA, USA Pittsburgh Institute of Brain Disorders and Recovery University of Pittsburgh Pittsburgh, PA, USA State Key laboratory of Medical Neurobiology Fudan University Shanghai, China Xiaoming Hu Department of Neurology University of Pittsburgh Pittsburgh, PA, USA John H Zhang Department of Anesthesiology Loma Linda University School of Medicine Loma Linda, CA, USA Department of Pharmacology Loma Linda University School of Medicine Loma Linda, CA, USA Department of Physiology Loma Linda University School of Medicine Loma Linda, CA, USA Center for Neuroscience Research Loma Linda University School of Medicine Loma Linda, CA, USA Pittsburgh Institute of Brain Disorders and Recovery University of Pittsburgh Pittsburgh, PA, USA State Key laboratory of Medical Neurobiology Fudan University Shanghai, China ISSN 2363-958X ISSN 2363-9598 (electronic) Springer Series in Translational Stroke Research ISBN 978-3-319-32335-0 ISBN 978-3-319-32337-4 (eBook) DOI 10.1007/978-3-319-32337-4 Library of Congress Control Number: 2016944470 © Springer International Publishing Switzerland 2016 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG Switzerland Introduction: Nonneuronal Mechanisms and Targets for Stroke For several decades now, clinically effective neuroprotection has been an elusive goal Although much progress has been made in terms of dissecting molecular pathways and cellular mechanisms, true translation has not succeeded for patients suffering from stroke, brain trauma, and neurodegeneration Excitotoxicity, oxidative stress, and programmed cell death all represent logical targets for preventing neuronal demise But it is now increasingly apparent that saving neurons alone may not be enough Based on these challenges, the neurovascular unit was proposed as a conceptual framework for reassessing neuroprotection, the fundamental premise being that central nervous system (CNS) function is not solely based on neuronal activity The brain is more than just action potentials! For neurotransmission to work, release– reuptake kinetics must be coordinated between neurons and astrocytes For myelinated signals to connect different brain networks, axons need to be in constant homeostatic communication with oligodendrocytes For the blood–brain barrier to be manifested, crosstalk is required between glial endfeet and cerebral endothelium Altogether, CNS function is based on cell–cell signaling between multiple cells Therefore, neuroprotection requires one to much more than just prevent neuronal death Rescuing function and cell–cell crosstalk between all cell types in neuronal, glial, and vascular compartments should be required It is in this context that this monograph Nonneuronal Mechanisms of Brain Damage and Repair After Stroke represents a significant addition to the literature and field This monograph is divided into five well-integrated sections The first section focuses on microvascular integrity Chapters here include analyses of the structural biology of tight junctions, the role of pericytes, glial regulation of barrier function, blood–brain barrier damage in neonatal stroke, and a reconsideration of angiogenesis after stroke The second section covers the complex actions of glial cells and includes chapters on astrocyte protection, biphasic effects of microglia, and crosstalk between cerebral endothelium and oligodendrocyte precursor cells The third section then goes on to examine the multifactorial pathways in stroke neuroinflammation, with analyses of peripheral immune activators, monocyte/macrophage responses, T cells, B cells, mast cells and neutrophils, and the web of cytokines that v vi Introduction: Nonneuronal Mechanisms and Targets for Stroke all contribute to stroke pathophysiology A critical part of stroke that is relatively less investigated comprises white matter response, and this is the focus of the fourth section of the monograph In this section, chapters are devoted to assessing the age dependence of white matter injury and subsequently investigating the role of oligodendrogenesis for white matter plasticity Finally, the last collection of chapters builds on the mechanistic themes explored thus far to develop potential therapeutic approaches In this final section, chapters span a comprehensive range, including the targeting of leukocyte–endothelial interactions, methods to repair the entire neurovascular unit, immune-based treatments, and cell-based therapies that all seek to achieve neuroprotection by restoring crosstalk amongst the nonneuronal population of CNS cells Taken together, the chapters here represent the very best in cutting-edge hypotheses and translational ideas The mechanisms dissected herein may eventually lead us to testable targets for stroke patients Curated by editors and authors who are experts in their field, this is an impressive collection of stroke science Eng H Lo, Ph.D Lo@helix.mgh.harvard.edu Neuroprotection Research Laboratory Department of Radiology Massachusetts General Hospital and Harvard Medical School 149 13th Street, Charlestown, MA, 02129, USA Contents Part I Microvascular Integrity in Stroke Structural Alterations to the Endothelial Tight Junction Complex During Stroke Anuska V Andjelkovic and Richard F Keep Role of Pericytes in Neurovascular Unit and Stroke Turgay Dalkara, Luis Alarcon-Martinez, and Muge Yemisci Glial Support of Blood–Brain Barrier Integrity: Molecular Targets for Novel Therapeutic Strategies in Stroke Patrick T Ronaldson and Thomas P Davis 25 45 Barrier Mechanisms in Neonatal Stroke Zinaida S Vexler 81 Angiogenesis: A Realistic Therapy for Ischemic Stroke Ke-Jie Yin and Xinxin Yang 93 Part II Glial Cells in Stroke Astrocytes as a Target for Ischemic Stroke 111 Shinghua Ding Microglia: A Double-Sided Sword in Stroke 133 Hong Shi, Mingyue Xu, Yejie Shi, Yanqin Gao, Jun Chen, and Xiaoming Hu Crosstalk Between Cerebral Endothelium and Oligodendrocyte After Stroke 151 Akihiro Shindo, Takakuni Maki, Kanako Itoh, Nobukazu Miyamoto, Naohiro Egawa, Anna C Liang, Takayuki Noro, Josephine Lok, Eng H Lo, and Ken Arai vii viii Part III Contents Peripheral Immune Cells in Stroke The Peripheral Immune Response to Stroke 173 Josef Anrather The Role of Spleen-Derived Immune Cells in Ischemic Brain Injury 189 Heng Zhao Regulatory T Cells in Ischemic Brain Injury 201 Arthur Liesz B-Cells in Stroke and Preconditioning-Induced Protection Against Stroke 217 Uma Maheswari Selvaraj, Katie Poinsatte, and Ann M Stowe Mast Cell as an Early Responder in Ischemic Brain Injury 255 Perttu J Lindsberg, Olli S Mattila, and Daniel Strbian Roles of Neutrophils in Stroke 273 Glen C Jickling and Frank R Sharp The Function of Cytokines in Ischemic Stroke 303 Christopher C Leonardo and Keith R Pennypacker Part IV White Matter Injury and Repair in Stroke Ischemic Injury to White Matter: An Age-Dependent Process 327 Sylvain Brunet, Chinthasagar Bastian, and Selva Baltan Part V Emerging Therapies to Target Non-neuronal Mechanisms After Stroke Neurovascular Repair After Stroke 347 Sherrefa R Burchell, Wing-Mann Ho, Jiping Tang, and John H Zhang The Role of Nonneuronal Nrf2 Pathway in Ischemic Stroke: Damage Control and Potential Tissue Repair 377 Tuo Yang, Yang Sun, and Feng Zhang Stem Cell Therapy for Ischemic Stroke 399 Hung Nguyen, Naoki Tajiri, and Cesar V Borlongan Contributors Luis Alarcon-Martinez, B.Sc., M.Sc., Ph.D Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey Anuska V Andjelkovic, M.D., Ph.D Department of Pathology, University of Michigan, Ann Arbor, MI, USA Department of Neurosurgery, University of Michigan Health System, Ann Arbor, MI, USA Josef Anrather Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA Ken Arai Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA Selva Baltan, M.D., Ph.D Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA Chinthasagar Bastian, M.B.B.S., Ph.D Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA Cesar V Borlongan Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA Sylvain Brunet, B.Sc., Ph.D Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University,, Cleveland, OH, USA Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA ix The Role of Nonneuronal Nrf2 Pathway in Ischemic Stroke: Damage Control… 393 50 Christensen T, Bruhn T, Balchen T, et al Evidence for formation of hydroxyl radicals during reperfusion after global cerebral ischaemia in rats using salicylate 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2015;133(1):144–52 143 De Simone R, Ajmone-Cat MA, Tirassa P, et al Apoptotic PC12 cells exposing phosphatidylserine promote the production of anti-inflammatory and neuroprotective molecules by microglial cells J Neuropathol Exp Neurol 2003;62(2):208–16 144 Ryu K-Y, Cho G-S, Piao HZ, et al Role of TGF-β in survival of phagocytizing microglia: autocrine suppression of TNF-α production and oxidative stress Exp Neurobiol 2012;21(4):151–7 145 Neher JJ, Emmrich JV, Fricker M, et al Phagocytosis executes delayed neuronal death after focal brain ischemia Proc Natl Acad Sci U S A 2013;110(43):E4098–107 Stem Cell Therapy for Ischemic Stroke Hung Nguyen, Naoki Tajiri, and Cesar V Borlongan Therapeutic Action of Stem Cell Transplantation in Stroke The therapeutic utility of stem cells for treating neurological disorders has been demonstrated either by stimulating these cells endogenously [1–4] as well as by transplanting them exogenously within injured brain tissues [5–11] Stem cell transplantation after a brain insult, such as stroke, is a major tenet of regenerative medicine [1–13] Stem cell therapy may offer a glimpse of hope for stroke patients because very scarce successful clinical trials have emerged from preclinical laboratory research in this area [14–16] Traditionally, the postulated therapeutic mechanism underlying stem cell repair for brain diseases implicates that the ensuing cellular regeneration occurs due to either the direct replacement of necrotizing cells with transplanted stem cells or the indirect repair of damaged tissue through the secretion of trophic factors by the stem cells [17, 18] That stem cells act via cell replacement and growth factor release regenerative processes have accompanied the translation of stem cell therapy for stroke from the laboratory to the clinic over the last 25 years Nonetheless, these two major mechanisms behind stem cells’ ability to restore the stroke brain only partially explain the paradoxical robust functional recovery in stroke animals despite low graft survival of transplanted stem cells Recent evidence from a relevant cerebrovascular disease, traumatic brain injury (TBI), suggests that transplanted stem cells are capable of forming a cellular migratory pathway as an active process for recruiting endogenous stem cells from the H Nguyen • N Tajiri • C.V Borlongan (*) Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA e-mail: cborlong@health.usf.edu © Springer International Publishing Switzerland 2016 J Chen et al (eds.), Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke, Springer Series in Translational Stroke Research, DOI 10.1007/978-3-319-32337-4_19 399 400 H Nguyen et al neurogenic niche to the damaged area within the cortex [19] This transplanted stem cell-generated “biobridge” has been visualized immunohistochemically and by laser capture microdissection to reside in the region between the neurogenic subventricular zone (SVZ) and the largely non-neurogenic TBI-damaged cortex Because endogenous stem cells have limited capacity to migrate long-distances, as in the case of traversing from the SVZ to the injured cortex of non-transplanted TBI animals, the recognition of this biobridge should facilitate the migration of endogenous stem cells to damaged brain areas that are remotely inaccessible from the neurogenic niche [19, 20] The overlapping pathologies between TBI and stroke indicate the potential of biobridge formation in stroke following stem cell transplantation We discuss below the progress of stem cell therapy for stroke, highlighting this possibility of extending the concept of transplanted stem cell-mediated biobridge as a therapeutic mechanism underlying stroke recovery Secondary Cell Death in Stroke as Therapeutic Target for Stem Cell Grafts Stroke is the consequence of blood flow restriction to a region of the brain Its signature pathological characteristic is a region of dead neuronal cells known as the infarct core, and this region is encased within a zone of injured and dying tissue called the penumbra This cardinal feature of vascular disablement associated with ischemic stroke results in a regional deficiency of glucose and oxygen, which then results in the stimulation of intricate secondary cell death processes [21] Such blood flow interruption to the brain is commonly referred to as ischemic stroke, whereas blood vessel bleeding is termed hemorrhagic stroke We focus our discussion of stem cell transplantation on ischemic stroke as this pathological condition, especially the secondary cell death, offers a far wide-ranging application of stem cell therapy than hemorrhagic stroke The wider therapeutic window, which can last for days, weeks, months, and even years, associated with the secondary cell death of ischemic stroke has been the target of stem cell therapy Within a matter of minutes after stroke onset, the primary necrotic core becomes fixed and unsalvageable In contrast, the secondary cell death that ensues in the tissue surrounding the core corresponds to the evolving ischemic penumbra [22], and may be resuscitated with proper treatment intervention such as stem cell therapy In view of the supracute window in the formation of the ischemic core, as opposed to the subacute and even chronic progression of the penumbra, a much better prognosis for arresting the secondary cell death seems to be indicated Sufficient circulation must be re-established in a very short amount of time, preferably less than h, in order to minimize the necrotic core and to limit the evolution of the penumbra In this regard, tPA needs to be initiated during the initial 4.5 h after Stem Cell Therapy for Ischemic Stroke 401 stroke onset, but beyond this acute window, the drug carries significant adverse effects in particular bleeding [23] Conversely, when targeting the evolving penumbra, treatment interventions over a much protracted window post-stroke should allow sequestration of secondary cell death events Indeed, stimulation of endogenous neurogenesis, angiogenesis, and neuroplasticity has been shown to minimize and even reverse penumbra-associated functional and neurostructural deficits Engaging the Endogenous Regenerative Process in Stroke The adult mammalian brain has long been considered to lack regenerative capacity, but scientific evidence has shown that neurogenesis occurs in discreet regions of the adult brain, namely in the SVZ of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus [24, 25] Such endogenous regeneration even in adulthood [21], which has been documented to be further stimulated during injury, suggests that the adult brain is able to mount a reparative process against stroke However, the proliferation level of newly formed cells, their neural lineage commitment, and their ability to migrate towards the injured brain areas may be limited, altogether indicating the insufficient regeneration by the host brain to exert clinically meaningful improvement after stroke Current investigations into finding strategies to enhance this endogenous neurogenesis following stroke has been a major research area of interest in the field of regenerative medicine Treatment regimens designed to boost proliferation, migration, and differentiation of neural progenitor cells by modifying the host microenvironment to be more conducive for synaptic integration of the newly generated neurons have been explored, but to date, compelling evidence suggests that the host neurogenesis remains relatively confined within the SVZ and SGZ, relegating most of the applications of this endogenous repair mechanism within these neurogenic niches or only to their neighboring tissues [25, 26] Because cerebrovascular diseases, such as stroke and TBI, present with major tissue damage to brain areas remote to the neurogenic niches, utilizing endogenous neurogenesis against these neurological disorders will need consideration Along the lines of mobilizing endogenous neurogenesis, ischemic stroke has been demonstrated to upregulate specific molecules that stimulate neurogenic niches, in particular increasing neural progenitor cell survival, proliferation, migration, and differentiation [21] Moreover, these mobilized neural progenitor cells (albeit a small population) have been shown to migrate from the SVZ to the postischemic striatum in rat stroke models [27, 28] In tandem, resident stem cells which remain quiescent during homeostasis, but are awakened after stroke, have been detected in the hippocampus and the cerebral cortex In the clinic, however, postmortem analysis of the stroke brain has not offered evidence of newly generated cortical neurons during the time period of days to 13 years after stroke onset [29] A rough estimate of host neurogenesis secondary to stroke has been calculated at 402 H Nguyen et al 0.1 %, or out of every 1000 neurons [29], suggesting that relying merely on the scarcity of newly born cells and their capacity to migrate from the neurogenic niche to the injured area may not be feasible when contemplating endogenous neurogenesis as a regenerative process against stroke Biobridge: A Migratory Pathway Between Neurogenic Niche and Non-neurogenic Brain Areas As noted in the preceding section, the two generally accepted mechanisms of action of stem cell transplantation which provides the therapeutic effects are cell replacement and modification of the microenvironment through trophic factors [17, 18] The new biobridge concept was first described in a study of transplanting modified mesenchymal stromal cells (MSCs) in TBI model [19] Adult rats were exposed to controlled cortical impact (CCI) TBI and were treated with MSCs The MSCs formed a biobridge between the neurogenic niche of the host and the injured site, and served as a highway for the host endogenous stem cells to travel to the injured area [19] The biobridge which spanned from the SVZ to the damaged cortex was visualized using immunohistochemistry and laser capture assay Upon closer examination of the biobridge, the levels of extracellular matrix metalloproteinases (MMPs) were significantly increased In particular, MMP-9 was found significantly increased within the biobridge, suggesting that this MMP may play an important role in facilitating the migration of neural progenitor cells in response to a brain insult, which likely released specific chemoattractant signals from the injured area This study further suggests that an inflammation-enriched (albeit cytokines, chemokines, MMPs) mechanism closely mediates that formation of biobridge Additional experiments are needed to better understand the effects of various inflammatory cues on the formation of biobridge Interestingly, the grafted MSCs are eventually replaced by the host cells after a period of time [19], which is a welcomed translational safety outcome because the prolonged and unregulated survival and proliferation of stem cells may be associated with tumor formation Moreover, that long-term graft survival per se is not a prerequisite robust and stable stroke recovery addresses the paradoxical dilemma on the reported studies demonstrating solid functional improvements despite mediocre engraftment A series of analyses to further characterize the biobridge reveals that MMPs assisted the grafted MSCs to form the biobridge Once the biobridge was formed, the transplanted cells were replaced by the endogenous neurogenic niche-derived stem cells [19] The biobridge guided the endogenous stem cells to successfully migrate from the SVZ and to home at the TBI injured site The stem cells then populated the peri-impacted area and exerted their effects in this area This novel concept of biobridge formation after transplantation is not limited to TBI but also can be extended to other neurological disorders, such as stroke The damage areas in stroke are generally larger compared to TBI thus it may be more challenging for endogenous stem cells to migrate across tissues toward the injured site The biobridge by Stem Cell Therapy for Ischemic Stroke 403 providing an extracellular matrix on which the endogenous stem cells could attach and migrate should improve in directed transport of neurogenic niche-derived cells to the remote injured areas [19] The Molecular Composition of the Biobridge The formation of the biobridge provides an alternative and complementary repair mechanism in stem cell therapy, in addition to the cell replacement and growth factor release regenerative processes The biobridge allows a favorable microenvironment for cell migration and axonal growth Three months after transplantation in the TBI brain, an increased level of proliferation and differentiation was observed at the peri-impacted area and a stream of cells labeled with nestin and DCX, markers for maturing neuron was maintained [19] In contrast, control animals which received vehicle did not express significantly, the level of migration nor differentiation In addition, the level of expression and activity of MMP-9 was upregulated ninefold which directly correlated with the endogenous stem cell migration compared with the animals that received the vehicle infusion [19] Recent studies have demonstrated the significance of MMPs and extracellular matrices (ECMs) in stroke pathology [2, 12] which further validates the importance of biobridge formation in stem cell therapy for stroke In the same vein, we envision that the grafted stem cells via a similar biobridge may promote the migration of stem cells from endogenous niche to the stroke core and infarct area Stem cells, such as peripheral blood, umbilical cord blood, and adult brain stem cells, are able to modulate the levels and functions of MMPs and ECMs [30–32] With MMPs and ECMs involved in stroke pathology, the ability of stem cells to generate a biobridge in stroke warrants investigations A study has shown that inhibition of MMPs sequestered the migration of endogenous stem cell from the niche to the damaged site [33], likely due to the depletion of neurovascular network remodeling On the other hand, the formation of a biobridge may stimulate the production of MMPs, which in turn can enhance the restoration of the neurovascular unit and the migration of host endogenous stem cells It is worth noting that the physiochemical homeostasis between cell deformation, tissue barrier restriction, and migration rates correspond to limiting factors that determine the capacity of cell migration In turn, this physiochemical homeostasis is regulated by the ability to degrade the ECM by proteolytic enzymes such as MMPs, and integrin- and actomyosin-mediated mechanocoupling [34] Based on the concept of biobridge in the TBI model [19], we hypothesize that a similar biobridge will be realized after an intracerebral stem cell transplantation in the stroke brain The biobridge will similarly guide the endogenous stem cells to migrate from the neurogenic niches, such as the SVZ and the SGZ, to the damaged areas in stroke brain, and eventually contributing to functional improvement [35] Of note, laboratory studies have reported that transplantation of MSCs aids in stroke recovery, with modulation of inflammation and immune response as a postulated 404 H Nguyen et al therapeutic mechanism [36] Indeed, it has been shown that transplanted stem cells can secrete transforming growth factor-beta (TGF-β) that can dampen the spreading of the inflammatory MPC-1 cells [36] To this end, transplanted MSCs via formation of the biobridge can also secrete anti-inflammatory or immunomodulatory cytokines, termed as MSC secretome, which can mediate the therapeutic benefits in the stroke brain [37] The MSC secretome may consist of insulin-like growth factor (IGF)-1, stromal cell-derived factor (SDF-1α), and glial cell-line-derived neurotrophic factor (GDNF) [38], which are growth factors that are elevated in the stroke brain after intracerebral transplantation of MSCs [38] Translational Caveats of Biobridge Application to the Clinic Despite the demonstration of the biobridge in mediating stem cell therapy TBI animal models, there are limitations in translating this concept to the clinic Additional studies are needed to further characterize the biobridge facilitation of endogenous stem cell migration In particular, the formation of such biobridge after peripheral transplantation of stem cells is a missing endeavor that will be of practical use in the clinic, as a minimally invasive procedure may be more preferred instead of a direct intracerebral transplantation approach when targeting the subacute phase of TBI and stroke models Another limitation of the biobridge is that the formation itself depends on the severity of the injury Severe TBI or chronic stage of stroke presumably presents with more extensive damage tissue which may influence the biobridge formation The pathology of TBI and stroke are also complicated and varied from patient to patient based on the severity of the insult, requiring tailoring of stem cell regimen, e.g., timing of cell transplant initiation, number of transplantations over the progressive period of secondary cell death, among others that may affect the creation of a biobridge Moreover, the formation of biobridge might be influenced by the nonconductive nature of the microenvironment in the brain, necessitating the need to treat the severe cases of TBI and stroke in the early and acute stage to immediately halt the progression of the disease and arrest the evolution of a non-favorable host microenvironment The inflammatory responses accompanying TBI and stroke also warrant investigations, in order to assess the effects of this secondary cell death on biobridge formation While prolonged inflammation has detrimental effect, acute inflammation may support the brain (i.e., biobridge) The timeline when inflammation produces beneficial effects then switches into a destructive mode remains debatable Arguably, transplanting at an earlier period post-insult may aid in the biobridge formation and may enhance the pro-survival over the pro-death properties of inflammation Additional studies are needed to understand the critical time point to maximize the therapeutic effect of inflammation on stem cell transplantation and its modulation of biobridge formation Stem Cell Therapy for Ischemic Stroke 405 Towards a Safe and Effective Stem Cell Therapy for Stroke According to the American Heart Association, approximately 800,000 Americans have stroke every year, with about 17 % mortality or in every 18 deaths in the US is a result of stroke [39] Stroke survivors also experience disability ranging from moderate to severe The total estimated healthcare costs due to disability related to stroke are $18.8 billion annually The number even approaches $34.3 billion if an additional $15.5 billion is added for loss of productivity and premature deaths [40] Despite the fact that the mortality rate of stroke has fallen 33.5 % in 10 years period from 1996 to 2006, the cost of healthcare associated with stroke increases significantly for the past decades [39] As the cost continues to increase, there is an urgent need for more effective treatment for neurological disorders such as TBI and stroke Regenerative medicine has put stem cell therapy as a promising treatment for CNS disorders The traditional mechanisms of action of stem cell therapy include cell replacement and bystander effects [41–44] Our recent study has shown another novel mechanism of stem cell transplantation therapy, the formation of biobridge, which provides a cellular pathway for the exogenous transplanted cells to attract endogenous stem cells to migrate from the neurogenic niche towards remote damaged brain areas This concept of biobridge may be extended in transplant studies to other CNS disorder, such as Parkinson’s disease and spinal cord injury, whereby endogenous stem cells may require long-distance migration from the neurogenic niche to the injured tissues In conclusion, the multi-pronged therapeutic actions of stem cell therapy, such as cell replacement, secretion of growth factors, and biobridge formation may work in concert to provide beneficial outcomes in cerebrovascular diseases [19] The formation of biobridge provides a cellular link between the exogenous repair mechanism and the endogenous regenerative processes That stem cell transplantation may involve different biological pathways in affording its therapeutic effects caters to the multiple cell death events associated with stroke In the end, an understanding of the mechanism of action that mediates stem cell transplantation may aid in optimizing the stem cell dose, timing of administration, and route of cell delivery, and the eventual laboratory-to-clinic translation of a safe and effective stem cell therapy for stroke Sources of Funding C.V.B is funded by NIH NINDS RO1 1R01NS071956-01, NIH NINDS 1R21NS089851-01, Department of Defense TATRC W811XWH-11-1-0634, Veterans Affairs BX001407-01, James and Esther King Biomedical Research Program 09KB-01-23123, and 1KG01-33966 References Barha CK, Ishrat T, Epp JR, Galea LAM, Stein DG Progesterone treatment normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus after traumatic brain injury Exp Neurol 2011;231(1):72–81 doi:10.1016/j.expneurol.2011.05.016 406 H Nguyen et al Borlongan CV Bone marrow stem cell mobilization in stroke: a ‘bonehead’ may be good after all! 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Switzerland 2016 J Chen et al (eds.), Non- Neuronal Mechanisms of Brain Damage and Repair After Stroke, Springer Series in Translational Stroke Research, DOI 10.1007/978-3-319-32337-4_1 A.V Andjelkovic... mast cells and neutrophils, and the web of cytokines that v vi Introduction: Nonneuronal Mechanisms and Targets for Stroke all contribute to stroke pathophysiology A critical part of stroke that... Brain Damage and Repair After Stroke Editors Jun Chen Department of Neurology University of Pittsburgh Pittsburgh, PA, USA Pittsburgh Institute of Brain Disorders and Recovery University of Pittsburgh