title: 3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice.
abstract: Activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by the activation of protease-activated receptor 1 (F2R, also known as PAR1) and F2RL1 (also known as PAR3) via noncanonical cleavage. Recombinant variants of APC, such as the 3K3A-APC (Lys191-193Ala) mutant in which three Lys residues (KKK191-193) were replaced with alanine, and/or its other mutants with reduced (>90%) anticoagulant activity, engineered to reduce APC-associated bleeding risk while retaining normal cell-signaling activity, have shown benefits in preclinical models of ischemic stroke, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis, sepsis, ischemic and reperfusion injury of heart, kidney and liver, pulmonary, kidney and gastrointestinal inflammation, diabetes and lethal body radiation. On the basis of proof-of-concept studies and an excellent safety profile in humans, 3K3A-APC has advanced to clinical trials as a neuroprotectant in ischemic stroke. Recently, 3K3A-APC has been shown to stimulate neuronal production by human neural stem and progenitor cells (NSCs) in vitro via a PAR1-PAR3-sphingosine-1-phosphate-receptor 1-Akt pathway, which suggests the potential for APC-based treatment as a strategy for structural repair in the human central nervous (CNS) system. Here we report that late postischemic treatment of mice with 3K3A-APC stimulates neuronal production by transplanted human NSCs, promotes circuit restoration and improves functional recovery. Thus, 3K3A-APC-potentiated neuronal recruitment from engrafted NSCs might offer a new approach to the treatment of stroke and related neurological disorders.
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.|The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Yaoming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.|The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.|The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Sanket V
authors.initials: SV
authors.lastname: Rege
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.|The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.|The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Si
authors.affiliation: Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Shapingba District, Chongqing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA.|Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.|Center for Basic and Translational Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark.
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.|Division of Hematology/Oncology, Department of Medicine, University of California, San Diego, San Diego, California, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA.|Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.|Center for Basic and Translational Neuroscience, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark.
authors.forename: Steven A
authors.identifier: 0000-0002-5498-4303
authors.initials: SA
authors.lastname: Goldman
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.|The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
authors.forename: Berislav V
authors.identifier: 0000-0002-6802-8232
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia; D049109:Cell Proliferation / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D058953:Neural Stem Cells / Q000187:drug effects* / Q000637:transplantation; D011486:Protein C / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology*; D020127:Recovery of Function; D012038:Regeneration / Q000187:drug effects*; D013569:Synapses
chemical_list: C000591161:3K3A-APC protein; D011486:Protein C; D011994:Recombinant Proteins