title: Biotherapies in stroke.
abstract: Stroke is the second leading cause of death worldwide and the most common cause of severe disability. Neuroprotection and repair mechanisms supporting endogenous brain plasticity are often insufficient to allow complete recovery. While numerous neuroprotective drugs trials have failed to demonstrate benefits for patients, they have provided interesting translational research lessons related to neurorestorative therapy mechanisms in stroke. Stroke damage is not limited to neurons but involve all brain cell type including the extracellular matrix in a "glio-neurovascular niche". Targeting a range of host brain cells, biotherapies such as growth factors and therapeutic cells, currently hold great promise as a regenerative medical strategy for stroke. These techniques can promote both neuroprotection and delayed neural repair through neuro-synaptogenesis, angiogenesis, oligodendrogliogenesis, axonal sprouting and immunomodulatory effects. Their complex mechanisms of action are interdependent and vary according to the particular growth factor or grafted cell type. For example, while "peripheral" stem or stromal cells can provide paracrine trophic support, neural stem/progenitor cells (NSC) or mature neurons can act as more direct neural replacements. With a wide therapeutic time window after stroke, biotherapies could be used to treat many patients. However, guidelines for selecting the optimal time window, and the best delivery routes and doses are still debated and the answers may depend on the chosen product and its expected mechanism including early neuroprotection, delayed neural repair, trophic systemic transient effects or graft survival and integration. Currently, the great variety of growth factors, cell sources and cell therapy products form a therapeutic arsenal that is available for stroke treatment. Their effective clinical use will require prior careful considerations regarding safety (e.g. tumorgenicity, immunogenicity), potential efficacy, cell characterization, delivery route and in vivo biodistribution. Bone marrow-derived cell populations such as mesenchymal stromal/stem cells (MSC) or mononuclear cells (MNC), umbilical cord stem cells and NSC are most investigated notably in clinical trials. Finally, we discuss perspectives concerning potential novel biotherapies such as combinatorial approaches (growth factor combined with cell therapy, in vitro optimization of cell products, or co-transplantation) and the development of biomaterials, which could be used as injectable hydrogel scaffold matrices that could protect a cell graft or selectively deliver drugs and growth factors into the post-stroke cavity at chronic stages. Considering the remaining questions about the best procedure and the safety cautions, we can hope that future translational research about biotherapies will bring more efficient treatments that will decrease post-stroke disability for many patients.
authors.affiliation: University Hospital of Grenoble, Stroke Unit, Department of Neurology, CS 10217, boulevard de la Chantourne, 38700 La Tronche, France; Inserm, U 836, BP 170, 38042 Grenoble cedex 9, France; Grenoble University, Grenoble Institute of Neurosciences (Team 5), BP 170, 38042 Grenoble cedex 9, France; Kyoto University, Institute for Frontier Medical Sciences, Department of Reparative Materials, 606-8507 Kyoto, Japan. Electronic address: ODetante@chu-grenoble.fr.
authors.forename: O
authors.initials: O
authors.lastname: Detante
authors.affiliation: 3T-MRI Research Unit, Department of Neuroradiology, CHU de Grenoble, boulevard de la Chantourne, 38700 La Tronche, France.
authors.forename: A
authors.initials: A
authors.lastname: Jaillard
authors.affiliation: Inserm, U 836, BP 170, 38042 Grenoble cedex 9, France; Grenoble University, Grenoble Institute of Neurosciences (Team 5), BP 170, 38042 Grenoble cedex 9, France; Cell Therapy and Engineering Unit, EFS Rhône-Alpes, 464, route de Lancey, 38330 Saint-Ismier, France.
authors.forename: A
authors.initials: A
authors.lastname: Moisan
authors.affiliation: University Hospital of Grenoble, Stroke Unit, Department of Neurology, CS 10217, boulevard de la Chantourne, 38700 La Tronche, France; Inserm, U 836, BP 170, 38042 Grenoble cedex 9, France; Grenoble University, Grenoble Institute of Neurosciences (Team 5), BP 170, 38042 Grenoble cedex 9, France.
authors.forename: M
authors.initials: M
authors.lastname: Barbieux
authors.affiliation: University Hospital of Grenoble, Stroke Unit, Department of Neurology, CS 10217, boulevard de la Chantourne, 38700 La Tronche, France; Inserm, U 836, BP 170, 38042 Grenoble cedex 9, France; Grenoble University, Grenoble Institute of Neurosciences (Team 5), BP 170, 38042 Grenoble cedex 9, France.
authors.forename: I M
authors.initials: IM
authors.lastname: Favre
authors.affiliation: University Hospital of Grenoble, Stroke Unit, Department of Neurology, CS 10217, boulevard de la Chantourne, 38700 La Tronche, France.
authors.forename: K
authors.initials: K
authors.lastname: Garambois
authors.affiliation: Department of Clinical Research, CHU de Grenoble, boulevard de la Chantourne, 38700 La Tronche, France.
authors.forename: M
authors.initials: M
authors.lastname: Hommel
authors.affiliation: Inserm, U 836, BP 170, 38042 Grenoble cedex 9, France; Grenoble University, Grenoble Institute of Neurosciences (Team 5), BP 170, 38042 Grenoble cedex 9, France.
authors.forename: C
authors.initials: C
authors.lastname: Remy
mesh_terms: D000818:Animals; D001691:Biological Therapy / Q000379:methods*; D064987:Cell- and Tissue-Based Therapy / Q000009:adverse effects / Q000379:methods; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000627:therapeutic use; D058953:Neural Stem Cells / Q000166:cytology / Q000637:transplantation; D018696:Neuroprotective Agents / Q000627:therapeutic use; D033581:Stem Cell Transplantation / Q000009:adverse effects; D013234:Stem Cells / Q000166:cytology; D020521:Stroke / Q000628:therapy*; D057170:Translational Research, Biomedical
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents
keywords: Cell therapy; Cellule souche; Neural repair; Plasticity; Plasticité; Régénération; Stem cells; Thérapie cellulaire; Transplantation