Intraspinal transplantation of subventricular zone-derived neural progenitor cells improves phrenic motor output after high cervical spinal cord injury.
Following spinal cord injury (SCI), intraspinal transplantation of neural progenitor cells (NPCs) harvested from the forebrain sub-ventricular zone (SVZ) can improve locomotor outcomes. Cervical SCI often results in respiratory-related impairments, and here we used an established model cervical SCI (C2 hemisection, C2Hx) to confirm the feasibility of mid-cervical transplantation of SVZ-derived NPCs and the hypothesis that that this procedure would improve spontaneous respiratory motor recovery. NPCs were isolated from the SVZ of enhanced green fluorescent protein (GFP) expressing neonatal rats, and then intraspinally delivered immediately caudal to an acute C2Hx lesion in adult non-GFP rats. Whole body plethysmography conducted at 4 and 8wks post-transplant demonstrated increased inspiratory tidal volume in SVZ vs. sham transplants during hypoxic (P=0.003) or hypercapnic respiratory challenge (P=0.019). Phrenic nerve output was assessed at 8wks post-transplant; burst amplitude recorded ipsilateral to C2Hx was greater in SVZ vs. sham rats across a wide range of conditions (e.g., quiet breathing through maximal chemoreceptor stimulation; P<0.001). Stereological analyses at 8wks post-injury indicated survival of ~50% of transplanted NPCs with ~90% of cells distributed in ipsilateral white matter at or near the injection site. Peak inspiratory phrenic bursting after NPC transplant was positively correlated with the total number of surviving cells (P<0.001). Immunohistochemistry confirmed an astrocytic phenotype in a subset of the transplanted cells with no evidence for neuronal differentiation. We conclude that intraspinal transplantation of SVZ-derived NPCs can improve respiratory recovery following high cervical SCI.
University of Florida, Department of Physical Therapy, P.O. Box 100154, Gainesville, FL 32610-0154, United States.
M S
MS
Sandhu
University of Florida, Department of Physical Therapy, P.O. Box 100154, Gainesville, FL 32610-0154, United States.
H H
HH
Ross
University of Florida, Department of Physical Therapy, P.O. Box 100154, Gainesville, FL 32610-0154, United States.
K Z
KZ
Lee
University of Florida, Department of Biomedical Engineering, P.O. Box 116131, Gainesville, FL 32611-6131, United States.
B K
BK
Ormerod
University of Florida, Department of Neuroscience, P.O. Box 100244, Gainesville, FL 32610-0244, United States.
P J
PJ
Reier
University of Florida, Department of Physical Therapy, P.O. Box 100154, Gainesville, FL 32610-0154, United States. Electronic address: ddf@phhp.ufl.edu.
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DD
Fuller
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D039481:CD11b Antigen / Q000378:metabolism; D002574:Cervical Vertebrae; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia; D020547:Lateral Ventricles / Q000166:cytology*; D008297:Male; D004676:Myelin Basic Protein / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology; D010791:Phrenic Nerve / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D020127:Recovery of Function / Q000502:physiology; D012120:Respiration Disorders / Q000209:etiology* / Q000601:surgery; D013119:Spinal Cord Injuries / Q000150:complications* / Q000601:surgery*
D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D004676:Myelin Basic Protein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases
Astrocyte; Neural precursor cells; Phrenic; Plasticity