Nerve growth factor-hypersecreting Schwann cell grafts augment and guide spinal cord axonal growth and remyelinate central nervous system axons in a phenotypically appropriate manner that correlates with expression of L1.
Schwann cells contribute to efficient axonal regeneration after peripheral nerve injury and, when grafted to the central nervous system (CNS), also support a modest degree of central axonal regeneration. This study examined (1) whether Schwann cells grafted to the CNS exhibit normal patterns of differentiation and association with spinal axons and what signals putatively modulate these interactions, and (2) whether Schwann cells overexpressing neurotrophic factors enhance axonal regeneration. Thus, primary Schwann cells were transduced to hypersecrete human nerve growth factor (NGF) and were grafted to spinal cord injury sites in adult rats. Comparisons were made to nontransfected Schwann cells. From 3 days to 6 months later, grafted Schwann cells exhibited a phenotypic and temporal course of differentiation that matched patterns normally observed after peripheral nerve injury. Schwann cells spontaneously aligned into regular spatial arrays within the cord, appropriately remyelinated coerulospinal axons that regenerated into grafts, and appropriately ensheathed but did not myelinate sensory axons extending into grafts. Coordinate expression of the cell adhesion molecule L1 on Schwann cells and axons correlated with establishment of appropriate patterns of axon-Schwann cell ensheathment. Transduction of Schwann cells to overexpress NGF robustly increased axonal growth but did not otherwise alter the nature of interactions with growing axons. These findings suggest that signals expressed on Schwann cells that modulate peripheral axonal regeneration and myelination are also recognized in the CNS and that the modification of Schwann cells to overexpress growth factors significantly augments their capacity to support extensive axonal growth in models of CNS injury.
Weidner
N
N
Department of Neurosciences, University of California-San Diego, La Jolla, California 92093-0626, USA.
Blesch
A
A
Grill
R J
RJ
Tuszynski
M H
MH
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D015870:Gene Expression / Q000502:physiology; D015316:Genetic Therapy; D006085:Graft Survival / Q000502:physiology; D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins / Q000235:genetics*; D009413:Nerve Fibers, Myelinated / Q000737:chemistry / Q000201:enzymology; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D019006:Neural Cell Adhesion Molecules / Q000235:genetics*; D009475:Neurons, Afferent / Q000166:cytology / Q000648:ultrastructure; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000601:surgery; D013119:Spinal Cord Injuries / Q000628:therapy*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D012333:RNA, Messenger; D020932:Nerve Growth Factor; D014446:Tyrosine 3-Monooxygenase; D015740:Calcitonin Gene-Related Peptide