Patients suffering from spinal cord injury and from neurodegenerative disorders such as Parkinson’s disease and amyotrophic lateral sclerosis have high hopes for cell transplantation therapy. However, survival and integration of transplanted cells is often poor and thought to be inhibited by scar tissue that is produced by non-neuronal supporting cells called glial cells. Thus the glial scar is believed to be a major barrier to successful cell transplantation to the nervous system. The current practice is to deliver cells directly into nerve tissue through a fine tube, the idea being to place cells as close as possible to their desired location. This delivery method is called intra-neural cell transplantation.
However, we noticed that some cells that had spilled onto the surface of the glial scar appeared to have migrated into the nerve by themselves and survived. This chance observation led us to repeat the experiment but to change the delivery by leaving the glial scar intact and by placing the cells onto the surface. We called this method “surface transplantation”. Many cells subsequently entered the nerve tissue, apparently recapitulating elements of their behavior during development. To our surprise they formed functional connections with auditory sensory cells in the ear and to the cells in the hindbrain. Restoration of responses to sound within the brain provided evidence that the auditory pathway had been reconnected. Our results provide hope for patients who might benefit from nerve cell transplantation. They show not only that the glial scar contains critical structural and chemical cues for nerve regeneration but also that cells can be transplanted with minimal further damage to the nerve tissue. Such a breakthrough could impact, for example, on patients with amyotrophic lateral sclerosis, for whom suitable donor cells may be applied to the surface of degenerated anterior roots of the spinal cord to restore lost motor function.
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.
By:Sekiya, T (Sekiya, Tetsuji)[ 1 ] ; Holley, MC (Holley, Matthew C.)[ 2 ] ; Hashido, K (Hashido, Kento)[ 1 ] ; Ono, K (Ono, Kazuya)[ 1 ] ; Shimomura, K (Shimomura, Koichiro)[ 3 ] ; Horie, RT (Horie, Rie T.)[ 1 ] ; Hamaguchi, K (Hamaguchi, Kiyomi)[ 1 ] ; Yoshida, A (Yoshida, Atsuhiro)[ 1 ] ; Sakamoto, T (Sakamoto, Tatsunori)[ 1 ] ; Ito, J (Ito, Juichi)[ 1 ]
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume: 112 Issue: 26 Pages: E3431-E3440
Published: JUN 30 2015