title: Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation.
abstract: Mesenchymal stromal stem cells (MSCs) isolated from adult tissues offer tangible potential for regenerative medicine, given their feasibility for autologous transplantation. MSC research shows encouraging results in experimental stroke, amyotrophic lateral sclerosis, and neurotrauma models. However, further translational progress has been hampered by poor MSC graft survival, jeopardizing cellular and molecular bases for neural repair in vivo. We have devised an adult human bone marrow MSC (hMSC) delivery formula by investigating molecular events involving hMSCs incorporated in a uniquely designed poly(lactic-co-glycolic) acid scaffold, a clinically safe polymer, following inflammatory exposures in a dorsal root ganglion organotypic coculture system. Also, in rat T9-T10 hemisection spinal cord injury (SCI), we demonstrated that the tailored scaffolding maintained hMSC stemness, engraftment, and led to robust motosensory improvement, neuropathic pain and tissue damage mitigation, and myelin preservation. The scaffolded nontransdifferentiated hMSCs exerted multimodal effects of neurotrophism, angiogenesis, neurogenesis, antiautoimmunity, and antiinflammation. Hindlimb locomotion was restored by reestablished integrity of submidbrain circuits of serotonergic reticulospinal innervation at lumbar levels, the propriospinal projection network, neuromuscular junction, and central pattern generator, providing a platform for investigating molecular events underlying the repair impact of nondifferentiated hMSCs. Our approach enabled investigation of recovery neurobiology components for injured adult mammalian spinal cord that are different from those involved in normal neural function. The uncovered neural circuits and their molecular and cellular targets offer a biological underpinning for development of clinical rehabilitation therapies to treat disabilities and complications of SCI.
authors.affiliation: Division of SCI Research, Veterans Affairs Boston Healthcare System, Boston, MA 02130.|Department of Physical Medicine & Rehabilitation, Harvard Medical School/Spaulding Rehabilitation Hospital, Charlestown, MA 02129.|Department of Neurosurgery, Harvard Medical School/Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Ropper
authors.affiliation: Division of SCI Research, Veterans Affairs Boston Healthcare System, Boston, MA 02130.|Department of Physical Medicine & Rehabilitation, Harvard Medical School/Spaulding Rehabilitation Hospital, Charlestown, MA 02129.|Department of Neurosurgery, Harvard Medical School/Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Devang K
authors.initials: DK
authors.lastname: Thakor
authors.affiliation: Division of SCI Research, Veterans Affairs Boston Healthcare System, Boston, MA 02130.|Department of Physical Medicine & Rehabilitation, Harvard Medical School/Spaulding Rehabilitation Hospital, Charlestown, MA 02129.|Department of Neurosurgery, Harvard Medical School/Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: InBo
authors.initials: I
authors.lastname: Han
authors.affiliation: Division of SCI Research, Veterans Affairs Boston Healthcare System, Boston, MA 02130.|Department of Physical Medicine & Rehabilitation, Harvard Medical School/Spaulding Rehabilitation Hospital, Charlestown, MA 02129.|Department of Neurosurgery, Harvard Medical School/Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Dou
authors.initials: D
authors.lastname: Yu
authors.affiliation: Division of SCI Research, Veterans Affairs Boston Healthcare System, Boston, MA 02130.|Department of Neurosurgery, Harvard Medical School/Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Division of SCI Research, Veterans Affairs Boston Healthcare System, Boston, MA 02130.|Department of Neurosurgery, Harvard Medical School/Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Anderson
authors.affiliation: Division of SCI Research, Veterans Affairs Boston Healthcare System, Boston, MA 02130.|Department of Neurosurgery, Harvard Medical School/Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Aljuboori
authors.affiliation: Division of SCI Research, Veterans Affairs Boston Healthcare System, Boston, MA 02130.
authors.forename: Soo-Woo
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Biomedical Engineering, Chemistry, and Biological Sciences, Stevens Institute of Technology, Hoboken, NJ 07030.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neurology, Harvard Medical School/Beth Israel Deaconess Medical Center, Boston, MA 02215 yang_teng@hms.harvard.edu richard_sidman@hms.harvard.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.affiliation: Department of Physical Medicine & Rehabilitation, Harvard Medical School/Spaulding Rehabilitation Hospital, Charlestown, MA 02129.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Zafonte
authors.affiliation: Division of SCI Research, Veterans Affairs Boston Healthcare System, Boston, MA 02130; yang_teng@hms.harvard.edu richard_sidman@hms.harvard.edu.|Department of Physical Medicine & Rehabilitation, Harvard Medical School/Spaulding Rehabilitation Hospital, Charlestown, MA 02129.|Department of Neurosurgery, Harvard Medical School/Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Yang D
authors.initials: YD
authors.lastname: Teng
mesh_terms: D000328:Adult; D000818:Animals; D018920:Coculture Techniques; D005260:Female; D005727:Ganglia, Spinal; D006614:Hindlimb; D006801:Humans; D019344:Lactic Acid; D008070:Lipopolysaccharides; D008124:Locomotion; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000628:therapy*; D054457:Tissue Scaffolds
chemical_list: D008070:Lipopolysaccharides; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: PLGA; locomotion; mesenchymal stromal stem cell; recovery neurobiology; spinal cord injury