Oligodendrocyte fate after spinal cord injury

Abstract

Oligodendrocytes (OLs) are particularly susceptible to the toxicity of the acute lesion environment after spinal cord injury (SCI). They undergo both necrosis and apoptosis acutely, with apoptosis continuing at chronic time points. Loss of OLs causes demyelination and impairs axon function and survival. In parallel, a rapid and protracted OL progenitor cell proliferative response occurs, especially at the lesion borders. Proliferating and migrating OL progenitor cells differentiate into myelinating OLs, which remyelinate demyelinated axons starting at 2 weeks post-injury. The progression of OL lineage cells into mature OLs in the adult after injury recapitulates development to some degree, owing to the plethora of factors within the injury milieu. Although robust, this endogenous oligogenic response is insufficient against OL loss and demyelination. First, in this review we analyze the major spatial-temporal mechanisms of OL loss, replacement, and myelination, with the purpose of highlighting potential areas of intervention after SCI. We then discuss studies on OL protection and replacement. Growth factors have been used both to boost the endogenous progenitor response, and in conjunction with progenitor transplantation to facilitate survival and OL fate. Considerable progress has been made with embryonic stem cell-derived cells and adult neural progenitor cells. For therapies targeting oligogenesis to be successful, endogenous responses and the effects of the acute and chronic lesion environment on OL lineage cells must be understood in detail, and in relation, the optimal therapeutic window for such strategies must also be determined.

FIG. 1

Intraspinal histone deacetylase (HDAC) messenger RNA (mRNA) expression is altered after moderate spinal cord injury (SCI) in rats. A temporal gene expression profile using real-time polymerase chain reaction (PCR) was conducted for HDAC 1, 2, 3, and 11 after spinal contusion injury at T8 in rats. HDAC1 was not altered after SCI; HDAC-2 and 3 were significantly down-regulated by 1 week postinjury and remained low at 14 dpi (a–c). HDAC-11 mRNA levels decreased at 3 dpi then returned to naïve levels by 14 dpi (d). *p < 0.05 vs naïve; **p < 0.01 vs naïve; ^^p < 0.01 vs 3 dpi, , #p < 0.05 vs 28 dpi.

FIG. 2

Schematic of events involved in oligogenesis after injury to the spinal cord. This schematic represents that the normal spinal cord has axons myelinated by the oligodendrocytes (OL); however, after spinal cord injury (SCI), a series of events ensues that contribute to OL loss (see black) and formation. There is dramatic loss of OLs due to necrotic and apoptotic cell death resulting in axonal demyelination. Acute OL protective strategies (blue) after injury may help salvage OLs and prevent further loss. Oligodendrocyte progenitor cells (OPC) present in the spinal cord react to injury with extensive proliferation in the presence of numerous growth factors and cytokines. Once the OPCs proliferate, environmental and axonal cues regulate OPC migration to denuded axons. After reaching their destination, OPCs differentiate into mature OLs due to axonal signals and/or environmental factors, resulting in remyelination of the axons. Supplementing with stimulatory (green) and inhibitory (red) factors involved in each of the steps can further enhance endogenous OL formation. A common approach to increase OL numbers is subacute cell transplantation (blue), which is another therapeutic intervention that bolsters remyelination of axons after SCI. FGF-2 = fibroblast growth factor-2; IGF = insulin-like growth factor; PDGF-A = platelet-derived growth factor-A; CNTF = ciliary neurotrophic factor; LINGO = leucine rich repeat and Ig domain containing; PSA-NCAM = polysialylated form of the neural cell adhesion molecule; NOGO = neurite outgrowth inhibitor; SEMA3F = Semaphorin-3F.