Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration

Abstract

Cell transplantation therapy has long been investigated as a therapeutic intervention for neurodegenerative disorders, including spinal cord injury, Parkinson’s disease, and amyotrophic lateral sclerosis. Indeed, patients have high hopes for a cell-based therapy. However, there are numerous practical challenges for clinical translation. One major problem is that only very low numbers of donor cells survive and achieve functional integration into the host. Glial scar tissue in chronic neurodegenerative disorders strongly inhibits regeneration, and this inhibition must be overcome to accomplish successful cell transplantation. Intraneural cell transplantation is considered to be the best way to deliver cells to the host. We questioned this view with experiments in vivo on a rat glial scar model of the auditory system. Our results show that intraneural transplantation to the auditory nerve, preceded by chondroitinase ABC (ChABC)-treatment, is ineffective. There is no functional recovery, and almost all transplanted cells die within a few weeks. However, when donor cells are placed on the surface of a ChABC-treated gliotic auditory nerve, they autonomously migrate into it and recapitulate glia- and neuron-guided cell migration modes to repair the auditory pathway and recover auditory function. Surface transplantation may thus pave the way for improved functional integration of donor cells into host tissue, providing a less invasive approach to rescue clinically important neural tracts.

Immunization with neural derived peptides plus scar removal induces a permissive microenvironment, and improves locomotor recovery after chronic spinal cord injury

“…A number of reports supporting the role of scar tissue as a barrier have shown that its removal facilitates neural restoration [16–18]. However, recent studies have also suggested that scar tissue is not necessarily an obstacle for regeneration and may even be necessary for neural restoration [19]. In the present work, we demonstrated that INDP alone promotes motor recovery, although this effect is augmented with glial scar removal.…”

Neural stem/progenitor cells are activated during tail regeneration in the leopard gecko (Eublepharis macularius)

“…Whereas glial scars are neuroprotective (against severe inflammation) they also inhibit axon regrowth (Frisén et al, ; Liu et al, ; Rowland, Hawryluk, Kwon, & Fehlings, ). Despite numerous efforts to reduce the negative impact of the glial scar, improvements to functional recovery remain limited (Sekiya et al, ; Shen, Wang, & Gu, ; Zhao & Fawcett, ).…”

The glial scar is more than just astrocytes

“…Given the abundance of data showing that reactive astrocytes can, indeed, form a barrier to highly invasive glioblastoma as well as oligodendrocyte progenitor cells (Lau et al, 2012;Keough et al, 2016), macrophages (Wanner et al, 2013), neural precursor cells (Karimi-Abdolrezaee et al, 2010), auditory neuroblasts (Sekiya et al, 2015), fibroblasts (Wanner et al, 2008), Schwann cells (Fouad et al, 2005;Kanno et al, 2014) and regenerating olfactory sensory and other axons (Anders and Hurlock, 1996;Silver and Miller, 2004;Zhang et al, 2006;Schachtrup et al, 2010;Cregg et al, 2014), it seems likely that they could at least participate in the formation of an additional constraint to severed axons after spinal cord injury as they encircle the lesion core.…”

“…In the special case of a very narrow lesion when core cells are lacking and there is less need to "corral" them (Wanner et al, 2013), scar forming astrocytes may be made permissive in response to the presence of an abundance of robustly growing axons . It was also made clear beginning long ago that reactive astrocytes can be a substrate for axonal outgrowth under the right circumstances (Reier, 1979;Silver and Ogawa, 1983;Smith et al, 1986;Hoke et al, 1994;McKeon et al, 1995;East et al, 2010;Sekiya et al, 2015) and, therefore, it should have been no surprise that they could serve as a permissive substrate into the lesion (which is clinically irrelevant) when axons were highly stimulated and especially before the glia became hyper dense. Thus, in the fashion of a drawbridge, reactive scar astrocytes can be either a barrier or, on occasion, a roadway depending on the conditions present normally or created experimentally inside or outside of the lesion penumbra.…”