A Stepup Approach for Cell Therapy in Stroke Tra

Authors: Loren E Glover Naoki Tajiri Nathan L Weinbren Hiroto Ishikawa Kazutaka Shinozuka Yuji Kaneko D Martin Watterson Cesar V Borlongan

Publish Date: 2011/11/18

Volume: 3, Issue: 1, Pages: 90-98

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Abstract

Stroke remains a significant unmet condition in the USA and throughout the world To date only approximately 3 of the population suffering an ischemic stroke benefit from the thrombolytic drug tissue plasminogen activator largely due to the drug’s narrow therapeutic window The last decade has witnessed extensive laboratory studies suggesting the therapeutic potential of cellbased therapy for stroke Limited clinical trials of cell therapy in stroke patients are currently being pursued Bone marrowderived stem cells are an attractive novel transplantable cell source for stroke There remain many unanswered questions in the laboratory before cell therapy can be optimized for transplantation in the clinical setting Here we discuss the various translational hurdles encountered in bringing cell therapy from the laboratory to the clinic using stem cell therapeutics as an emerging paradigm for stroke as a guiding principle In particular we focus on the preclinical studies of cell transplantation in experimental stroke with emphasis on a better understanding of mechanisms of action in an effort to optimize efficacy and to build a safety profile for advancing cell therapy to the clinic A forward looking strategy of combination therapy involving stem cell transplantation and pharmacologic treatment is also discussedStroke continues to be a major cause of death in the USA and throughout the world Due to treatment options for stroke being limited to tissue plasminogen activator tPA a surge in novel therapies such as stem cell transplantation has been explored in the laboratory Over the last decade stem cell therapy has shown promise as an experimental treatment for stroke 1 2 3 The first clinical trial implementing cell therapy as a treatment for stroke occurred in 1998 4 In the last 2 years the US Food and Drug Administration FDA has approved limited clinical trials of cell therapy in stroke patients Bone marrowderived stem and progenitor cells represent a major donor cell source for transplantation Along the lines of stroke treatment academic industry roundtable STAIR recommendations for translating pharmacologics from the laboratory to the clinic the stem cell therapeutics as an emerging paradigm for stroke STEPS has been advanced as a guiding principle for cell therapy in stroke Here we discuss preclinical studies of cell transplantation in experimental stroke with emphasis on bone marrowderived stem cells using STEPS as a yardstick in building the efficacy and safety profile of this cell therapy for clinical applicationThe bone marrow consists of a heterogeneous population of stem cells namely hematopoietic stem cells HSCs and mesenchymal stem cells MSCs 5 Endothelial progenitor cells EPCs and very small embryoniclike stem cells VSELs have also been isolated from the bone marrow Previous studies have discussed the potential of bone marrowderived stem cells to differentiate into neurons in vitro 6 and their secretion of growth factors crucial to neuronal survival 7 8 9 Interest in utilizing bone marrowderived stem cells as a therapy for stroke has increased as researchers look to cell therapy as a treatment for strokeA central characteristic of HSCs is their ability to repopulate removed bone marrow 10 HSCs remain quiescent and low in number during homeostasis but can quickly proliferate and become mobile in response to injury 11 12 13 The SDF1/CXCR4 chemoattractant pathway is crucial for HSC mobilization and migration Activation of this pathway stimulates the migration of HSCs from the bone marrow into the circulation 14

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