Components critical for enhancing spinal cord regeneration identified
Researchers from the University of Texas Southwestern Medical Center (Dallas, TX, USA) have identified and manipulated key components of the regenerative mechanism within spinal cord neurons in order to successfully enhance the regeneration of mature nerve cells in the spinal cords of adult mice, laying the groundwork for potential regenerative medicines for spinal cord injuries in humans.
Spinal cord injuries can be fatal or severely debilitating, as the spinal cord has little capacity to regenerate, resulting in irreversible damage and subsequent scarring that can inhibit motor and sensory functions. A team from the University of Texas (UT) Southwestern Medical Center (Dallas, TX, USA) has elucidated critical components of the pathway involved in the regeneration of neurons, and has used this knowledge to successfully improve regeneration of the spinal cord after injury in a mouse model, in the hopes of eventually developing a therapy for spinal cord injury in humans.
“Spinal cord injuries can be fatal or cause severe disability. Many survivors experience paralysis, reduced quality of life, and enormous financial and emotional burdens,” commented lead author Dr Lei-Lei Wang. The team, working in the lab or Dr Chun-Li Zhang, Associate Professor of Molecular Biology at UT Southwestern, therefore aimed to help understand this process better, and have previously derived mature adult nerve cells from reprogrammed mouse glial cells.
In this new study, the team silenced parts of the p53–p21 protein pathway, which inhibits glial cells from being reprogrammed into the more primitive, stem-like types of cells. Despite removing this barrier, many cells failed to advance past the stem cell-like stage, so the mice were screened for specfic factors that could boost the number of induced adult neuroblasts that mature into adult neurons, thereby identifying critical components of the process. BDNF and Noggin were found to boost the successful reprogramming by tenfold.
“Silencing the p53–p21 pathway gave rise to progenitor (stem-like) cells, but only a few matured. When the two growth factors were added, the progenitors matured by the tens of thousands,” Dr Zhang said, senior author of the paper. “Because p53 activation is thought to safeguard cells from undergoing uncontrolled proliferation, as in cancer, we followed mice that had temporary inactivation of the p53 pathway for 15 months without observing any increased cancer risk in the spinal cord,” he added.
“This research lays the groundwork for regenerative medicine for spinal cord injuries. We have uncovered critical molecular and cellular checkpoints in a pathway involved in the regeneration process that may be manipulated to boost nerve cell regeneration after a spinal injury,” explained Dr Zhang.
They managed to successfully produce a large population of long-lived and diverse subtypes of new neurons in the adult spinal cord. Although the research is still in the early experimental stage and not ready for clinical translation, it is hoped that it could ultimately help provide a starting point for the development of autologous cell-based therapies for spinal cord injury.
Sources: Wang LL, Su Z, Tai W, Zou Y, Xu XM, Zhang CL. The p53 pathway controls SOX2-mediated reprogramming in the adult mouse spinal cord. Cell Rep. 17(3), 891–903 (2016); http://www.utsouthwestern.edu/newsroom/news-releases/year-2016/oct/spine-stem-cells.html