title: Traumatic spinal cord injury in mice with human immune systems.
abstract: Mouse models have provided key insight into the cellular and molecular control of human immune system function. However, recent data indicate that extrapolating the functional capabilities of the murine immune system into humans can be misleading. Since immune cells significantly affect neuron survival and axon growth and also are required to defend the body against infection, it is important to determine the pathophysiological significance of spinal cord injury (SCI)-induced changes in human immune system function. Research projects using monkeys or humans would be ideal; however, logistical and ethical barriers preclude detailed mechanistic studies in either species. Humanized mice, i.e., immunocompromised mice reconstituted with human immune cells, can help overcome these barriers and can be applied in various experimental conditions that are of interest to the SCI community. Specifically, newborn NOD-SCID-IL2rg(null) (NSG) mice engrafted with human CD34(+) hematopoietic stem cells develop normally without neurological impairment. In this report, new data show that when mice with human immune systems receive a clinically-relevant spinal contusion injury, spontaneous functional recovery is indistinguishable from that achieved after SCI using conventional inbred mouse strains. Moreover, using routine immunohistochemical and flow cytometry techniques, one can easily phenotype circulating human immune cells and document the composition and distribution of these cells in the injured spinal cord. Lesion pathology in humanized mice is typical of mouse contusion injuries, producing a centralized lesion epicenter that becomes occupied by phagocytic macrophages and lymphocytes and enclosed by a dense astrocytic scar. Specific human immune cell types, including three distinct subsets of human monocytes, were readily detected in the blood, spleen and liver. Future studies that aim to understand the functional consequences of manipulating the neuro-immune axis after SCI should consider using the humanized mouse model. Humanized mice represent a powerful tool for improving the translational value of pre-clinical SCI data.
authors.affiliation: Neuroscience Graduate Studies Program, The Ohio State University, Columbus, OH, USA; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
authors.forename: Randall S
authors.initials: RS
authors.lastname: Carpenter
authors.affiliation: Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Kigerl
authors.affiliation: Neuroscience Graduate Studies Program, The Ohio State University, Columbus, OH, USA; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Marbourg
authors.affiliation: Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Gaudet
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.
authors.forename: Devra
authors.initials: D
authors.lastname: Huey
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Niewiesk
authors.affiliation: Neuroscience Graduate Studies Program, The Ohio State University, Columbus, OH, USA; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University, Columbus, OH, USA. Electronic address: phillip.popovich@osumc.edu.
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Popovich
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006614:Hindlimb / Q000503:physiopathology; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D007797:Laminin / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009000:Monocytes / Q000145:classification / Q000473:pathology; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020127:Recovery of Function / Q000276:immunology*; D013119:Spinal Cord Injuries / Q000276:immunology / Q000503:physiopathology / Q000601:surgery; D033581:Stem Cell Transplantation / Q000379:methods*
chemical_list: C112986:AIF1 protein, human; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C508594:IL2 protein, human; D007376:Interleukin-2; D007797:Laminin; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D017493:Leukocyte Common Antigens
keywords: Functional recovery; Hematopoiesis; Humanized mice; Inflammation; Lymphocytes; Macrophages; Neuroimmunology; Spinal cord injury; Stem cells