Transplantation of human neural stem cells restores cognition in an immunodeficient rodent model of traumatic brain injury

Abstract

Traumatic brain injury (TBI) in humans can result in permanent tissue damage and has been linked to cognitive impairment that lasts years beyond the initial insult. Clinically effective treatment strategies have yet to be developed. Transplantation of human neural stem cells (hNSCs) has the potential to restore cognition lost due to injury, however, the vast majority of rodent TBI/hNSC studies to date have evaluated cognition only at early time points, typically <1month post-injury and cell transplantation. Additionally, human cell engraftment and long-term survival in rodent models of TBI has been difficult to achieve due to host immunorejection of the transplanted human cells, which confounds conclusions pertaining to transplant-mediated behavioral improvement. To overcome these shortfalls, we have developed a novel TBI xenotransplantation model that utilizes immunodeficient athymic nude (ATN) rats as the host recipient for the post-TBI transplantation of human embryonic stem cell (hESC) derived NSCs and have evaluated cognition in these animals at long-term (≥2months) time points post-injury. We report that immunodeficient ATN rats demonstrate hippocampal-dependent spatial memory deficits (Novel Place, Morris Water Maze), but not non-spatial (Novel Object) or emotional/anxiety-related (Elevated Plus Maze, Conditioned Taste Aversion) deficits, at 2-3months post-TBI, confirming that ATN rats recapitulate some of the cognitive deficits found in immunosufficient animal strains. Approximately 9-25% of transplanted hNSCs survived for at least 5months post-transplantation and differentiated into mature neurons (NeuN, 18-38%), astrocytes (GFAP, 13-16%), and oligodendrocytes (Olig2, 11-13%). Furthermore, while this model of TBI (cortical impact) targets primarily cortex and the underlying hippocampus and generates a large lesion cavity, hNSC transplantation facilitated cognitive recovery without affecting either lesion volume or total spared cortical or hippocampal tissue volume. Instead, we have found an overall increase in host hippocampal neuron survival in hNSC transplanted animals and demonstrate that a correlation exists between hippocampal neuron survival and cognitive performance. Together, these findings support the use of immunodeficient rodents in models of TBI that involve the transplantation of human cells, and suggest that hNSC transplantation may be a viable, long-term therapy to restore cognition after brain injury.

One Step at a Time, Stem Cell Therapy for Traumatic Brain Injury Needs Two More Breakthroughs

“…[70][71][72][73] A recent study with athymic rat TBI and hNSCs ~38% of the transplanted cells expressed NeuN. 74 The duration of differentiation of hNSCs into NeuN positive cells is consistent with a published report that showed ~6-8 weeks were sufficient to induce transplant derived neurogenesis. …”

“…[70][71][72][73] A recent study with athymic rat TBI and hNSCs ~38% of the transplanted cells expressed NeuN. 74 The duration of differentiation of hNSCs into NeuN positive cells is consistent with a published report that showed ~6-8 weeks were sufficient to induce transplant derived neurogenesis. 1,75 Transplantation of viable fetal neural progenitor cells (as early as 24h post TBI) attenuated host neuronal degeneration (as assessed on day 6 post transplantation), also guided host microglia/macrophages towards an anti-inflammation phenotype indicating that a potentially beneficial effect of progenitor cell transplantation on adjacent host cells.…”

Traumatic Brain Injury: Current Treatment Strategies and Future Endeavors

“…In the past few decades, stem cell-based therapy opened a new therapeutic avenue for neurological disorders and Central Nervous System (CNS) injuries. Preclinical studies utilizing stem cells and progenitor cells as treatment for spinal cord injury, [89][90][91] stroke, 92,93 and brain injury 94,95 have shown beneficial effects in improving recovery. Currently, different cell types have been used as putative therapies for TBI recovery.…”

Safety of Neural Stem Cell Therapy for Traumatic Brain Injury

“…There is an urgent need to explore additional treatment options to address long-term TBI related disabilities. Since the demonstration of ability to culture, expand human fetal neural stem in vitro, their genetic modification and engraftment in rodents post transplantation [12][13][14][15] multiple insights into how embryonic transplant derived neurons integrate into adult circuits (Gotz 2016) and technical advances studies have supported clinically relevant studies in immunocompromised or immunosuppressed animal [16,17]. Athymic rats with TBI (Haus 2016), or Parkinson disease (Snyder 2016) have been used with neural stem cells derived from induced human pluripotent stem cells to demonstrate the viability of the approach.…”