title: Activated spinal cord ependymal stem cells rescue neurological function.
abstract: Spinal cord injury (SCI) is a major cause of paralysis. Currently, there are no effective therapies to reverse this disabling condition. The presence of ependymal stem/progenitor cells (epSPCs) in the adult spinal cord suggests that endogenous stem cell-associated mechanisms might be exploited to repair spinal cord lesions. epSPC cells that proliferate after SCI are recruited by the injured zone, and can be modulated by innate and adaptive immune responses. Here we demonstrate that when epSPCs are cultured from rats with a SCI (ependymal stem/progenitor cells injury [epSPCi]), these cells proliferate 10 times faster in vitro than epSPC derived from control animals and display enhanced self renewal. Genetic profile analysis revealed an important influence of inflammation on signaling pathways in epSPCi after injury, including the upregulation of Jak/Stat and mitogen activated protein kinase pathways. Although neurospheres derived from either epSPCs or epSPCi differentiated efficiently to oligodendrocites and functional spinal motoneurons, a better yield of differentiated cells was consistently obtained from epSPCi cultures. Acute transplantation of undifferentiated epSPCi or the resulting oligodendrocyte precursor cells into a rat model of severe spinal cord contusion produced a significant recovery of motor activity 1 week after injury. These transplanted cells migrated long distances from the rostral and caudal regions of the transplant to the neurofilament-labeled axons in and around the lesion zone. Our findings demonstrate that modulation of endogenous epSPCs represents a viable cell-based strategy for restoring neuronal dysfunction in patients with spinal cord damage.
authors.affiliation: Cellular Reprogramming Laboratory, Valencia, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Moreno-Manzano
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Rodríguez-Jiménez
authors.forename: Mireia
authors.initials: M
authors.lastname: García-Roselló
authors.forename: Sergio
authors.initials: S
authors.lastname: Laínez
authors.forename: Slaven
authors.initials: S
authors.lastname: Erceg
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Calvo
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ronaghi
authors.forename: Maria
authors.initials: M
authors.lastname: Lloret
authors.forename: Rosa
authors.initials: R
authors.lastname: Planells-Cases
authors.forename: Jose María
authors.initials: JM
authors.lastname: Sánchez-Puelles
authors.forename: Miodrag
authors.initials: M
authors.lastname: Stojkovic
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival; D004594:Electrophysiology; D004805:Ependyma / Q000166:cytology*; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D009836:Oligodendroglia / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000166:cytology* / Q000473:pathology*; D013119:Spinal Cord Injuries / Q000628:therapy*; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000502:physiology