Combined Human Neural Stem Cell and Structured Treadmill Walking Therapy Enhances Recovery in a Pediatric Porcine
Sarah L Schantz1,2,3, Geffrey S Cosgrave1,3, Albino G Schifino1,4
1Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.
Insights
Combining induced pluripotent stem cell-derived neural stem cells (iNSCs) with treadmill exercise significantly improves recovery in pediatric traumatic brain injury (TBI) models. This novel therapy enhances neuroprotection, tissue repair, and motor function, offering a promising treatment for TBI patients.
Area of Science:
- Regenerative Medicine
- Neuroscience
- Pediatric Traumatology
Background:
- Traumatic brain injury (TBI) is a major global cause of death and disability, particularly affecting children, with no current FDA-approved therapeutics.
- Induced pluripotent stem cell-derived neural stem cells (iNSCs) show promise in preclinical TBI models by reducing tissue damage and functional deficits.
- Physical activity post-TBI is increasingly recognized for its potential to enhance neuroprotective and regenerative signaling.
Purpose of the Study:
- To evaluate the combined therapeutic efficacy of iNSCs and structured treadmill walking in a pediatric piglet model of TBI.
- To assess the synergistic effects of this combination therapy on cellular, tissue, and functional recovery following TBI.
Main Methods:
- One-month-old piglets underwent controlled cortical impact-induced TBI and were treated with iNSCs or placebo (PBS) via transplantation.
- Treadmill exercise was initiated 1 week post-transplantation and continued for 12 weeks.
- Assessments included motor function, open field behavior, MRI, and histological analysis of brain tissue.
Main Results:
- Transplanted iNSCs survived, engrafted, and differentiated into neurons, astrocytes, and oligodendrocytes.
- The iNSC + treadmill group exhibited enhanced endogenous neuron and oligodendrocyte survival, increased neuroblast proliferation, and reduced inflammation.
- MRI showed reduced lesion volume and white matter degradation, while functional tests indicated significant motor function and behavioral improvements.
Conclusions:
- The combination of iNSCs and structured treadmill walking significantly enhanced TBI recovery in a pediatric model.
- This synergistic approach improved cellular, tissue, and functional outcomes beyond monotherapy.
- This novel combination therapy warrants further investigation as a potential transformative treatment for pediatric TBI.
Abstract:
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, and is indiscriminate in who it affects, including children. Although there are currently no Food and Drug Administration-approved therapeutics, promising results from recent induced pluripotent stem cell-derived neural stem cell (iNSC) studies have demonstrated decreased tissue damage and functional deficits in pre-clinical TBI models. Moreover, while the rest has been traditionally identified as the standard of care following TBI, research now suggests that physical activity postinjury may significantly enhance neuroprotective and regenerative signaling in patients. Combining these two therapies may therefore synergistically improve recovery outcomes in TBI patients. In this study, we evaluated the combined therapeutic efficacy of iNSCs and structured treadmill walking on cellular, tissue, and functional recovery in a translational pediatric pig TBI model. One-month-old piglets received a controlled cortical impact-induced TBI and were randomly assigned to either a PBS (n = 4), PBS + treadmill (n = 4), iNSC (n = 4), or iNSC + treadmill (n = 4) treatment group. Piglets received intraparenchymal transplantations of either iNSCs or PBS 5 days post-TBI. At 1-week post-transplantation, piglets assigned to the treadmill treatment groups began a 12-week progressive walking regimen. Motor function and open field behavior assessments were performed pre-TBI and 12 weeks post-transplantation. Magnetic resonance imaging (MRI) and histological evaluation of collected brain tissue were performed 12 weeks post-transplantation. Immunohistochemistry revealed long-term survival, engraftment, and differentiation of transplanted iNSCs into neurons, astrocytes, and oligodendrocytes in treated piglets. Furthermore, iNSC + treadmill treatment showed increased endogenous neuron and oligodendrocyte survival, increased proliferation of neuroblasts, and decreased populations of reactive astrocytes and immune cells in TBI brain tissue. MRI analysis revealed a significant reduction in lesion volume, midline shift, and white matter degradation with preserved cerebral blood flow following both iNSC and iNSC + treadmill interventions. These cellular and tissue-level effects corresponded with significant motor function recovery as seen through increased step and stride length with decreased stance percentage and time. During open field behavioral assessments, iNSC and iNSC + treadmill-treated piglets demonstrated improved exploratory behaviors. These findings suggest that the combination of iNSCs with structured treadmill walking significantly enhanced TBI recovery beyond the therapeutic potential of iNSCs or exercise alone. Therefore, this novel combination therapy needs to be further explored as a potential transformative treatment option for pediatric TBI patients.
