Biology subjects

Cummings, B. J.

Publications and source records attributed to Cummings, B. J..

5 recordsLinked to original sources

bioRxiv2026

Regenerative Neural Stem Cell Therapy Improves Multidomain Neurological Deficits after Traumatic Brain Injury in Nonhuman Primates

Traumatic brain injury (TBI) produces persistent multidomain disability spanning motor, cognitive, emotional and sleep-wake function, with no approved restorative therapy. Here, we tested pd.S6.133.hNSC, a cryopreserved, GMP-like human neural stem cell (hNSC) product derived from Shef-6 and FACS-sorted on CD133+/CD34-, in a randomized dose-ranging study in common marmosets subjected to controlled cortical impact (n = 18). Seven weeks after injury, animals received MRI-guided stereotactic transplantation into perilesional cortex bilaterally under tacrolimus immunosuppression, with either vehicle or pd.S6.133.hNSC at 1 million (1e6) or 5 million (5e6) cell dose. At 3 months post-transplantation, 5e6 dosage improved executive and problem-solving performances (Object Retrieval Task with Barrier Detour), gait dynamics (CatWalk assay), anxiety-like behavior (Human Intruder Test), and actigraphy-derived sleep-wake and circadian rhythm measures relative to vehicle and 1e6 dose. Longitudinal 7T MRI demonstrated a dose-dependent reduction in lesion volume and preservation of corpus callosum white matter volume in the 5e6 group. Transplantation was well tolerated, with no observed adverse events across 1,197 cumulative post-transplant animal-days. Histopathology at 3 months post-transplantation in NHPs showed engraftment without tumor formation or abnormal tissue overgrowth. These findings support the safety and multidomain efficacy of a cryopreserved hNSC product in a nonhuman primate TBI model and inform translational development toward first-in-human testing with clinically aligned endpoints.

neuroscience↗

bioRxiv2026

Aging reveals domain-specific vulnerability to the chronic behavioral consequences of repetitive mild traumatic brain injury

Older adults are among the fastest growing groups of traumatic brain injury (TBI) patients and sustain disproportionately poor chronic outcomes. Despite this, the preclinical aging-TBI literature is limited. Beyond the limited presence of aging TBI studies, most studies published in this domain use moderate-to-severe, open head models of TBI, rather than closed head models of mild TBI (mTBI) and repetitive mTBI (rmTBI), the most clinically prevalent presentation. Whether age modulates the chronic behavioral consequences of rmTBI is unknown. In the current study, young (3-4 months) and aged (18-19 months) male C57BL/6 mice received either five mTBIs on alternating days to model rmTBI or sham procedures and underwent behavioral testing in the chronic phase for spatial memory and anxiety-related behavior. Because cross-age behavioral comparisons are confounded by age-related declines in activity and by large sample sizes necessary to detection interaction effects, we applied a three-tier analytical framework combining within-age comparisons, sham-normalized inter-age comparisons, and factorial two-way ANOVA. Contrary to our hypothesis that aging would worsen rmTBI behavioral deficits, age produced domain-divergent effects. Spatial memory deficits were directionally consistent in both young and aged mice but was attenuated in the aged group. Conversely, anxiety-related behavior emerged selectively in the aged mice showing increased thigmotaxis. Locomotion was driven by age alone, with no injury effect, confirming that the aged anxiety signal was not a locomotor artifact. A post-hoc sensitivity analysis indicated that resolving the Age x Injury interaction effect would require at least 44 animals per group. These findings show that age shapes the affective, but not the cognitive, consequences of chronic rmTBI, and underscoring that statistical strategy is inseparable from design in factorial injury studies.

neuroscience↗

bioRxiv2026

Microtubule Stabilization and Biomaterial Guidance Synergize to Enhance CST Regeneration and Motor Recovery After Chronic SCI.

Spinal cord injury (SCI) results in loss of sensory and motor function below the level of damage, with chronic injuries presenting unique challenges for regenerative therapies. While multichannel biomaterial interventions have shown promise in promoting axonal regeneration, circuit restoration, and motor recovery in acute SCI, achieving similar outcomes in chronic injury models remains challenging due to a combination of intrinsic and extrinsic factors. These include the reduced capacity of the neuronal cell body to sustain a growth-activated state and the formation of a physical and chemical barrier at the injury site, preventing axonal growth. To address these challenges and promote motor recovery after chronic injury, we investigated the combinatorial effect of two regenerative approaches: 1) the implantation of poly (lactide-co-glycolide) (PLG) biomaterial bridge to guide axonal growth through the injury site, and 2) the delivery of Epothilone B (EpoB), a microtubule stabilizer that strengthens axons to promote regrowth. We used a transgenic mouse model that selectively expresses a red fluorescent protein variant (tdTomato) reporter throughout the corticospinal tract (CST) under control of the Crym promoter (Crym-tdTomato). We demonstrated that the combination of bridge implantation 60 days after surgical hemisection at C5 with EpoB improved locomotor function. At 12 weeks post-bridge implantation, immunohistology revealed axon regeneration in mice receiving implantation, but not EpoB or no-implant controls. The addition of EpoB significantly increased the volume of both total and CST axons regenerating through the biomaterial channels. Diffusion tensor magnetic resonance imaging (DTI) analysis identified enhanced fractional anisotropy (FA), axial diffusivity (AD), and mean diffusivity (MD) in the bridge region in the combination treatment group, consistent with new intact axons. Furthermore, EpoB enhanced the myelination of regenerated axons in the bridge. Finally, we investigated the proteomic profile of corticospinal neurons ipsilateral and contralateral to the SCI lesion and bridge, comparing the effect of EpoB treatment. Mass spectrometry-based analysis of laser-captured cells in this paradigm identified activation of a regeneration program by corticospinal neurons. These findings present a novel approach to enhance regenerative neural repair and locomotor recovery in chronic SCI.

neuroscience↗

bioRxiv2024

Minimally invasive serial collection of cerebrospinal fluid reveals sex-dependent differences in neuroinflammation in a rat model of mild traumatic brain injury

Traumatic brain injuries (TBI) are the seventh leading cause of disability globally with 48.99 million prevalent cases and 7.08 million years lived with diability. Approximately 80% of TBI patients are diagnosed with mild TBI (mTBI), or concussion, caused by nonpenetrating mechanical trauma to the head or body along with sudden rotational motion of the head. Studies investigating the temporal dynamics of neuroinflammation after mTBI are greatly needed. Without longitudinal studies, translating preclinical studies to clinical studies remains challenging as the difference in timing remains poorly understood. In this study, we describe a method of minimally invasive serial cerebrospinal fluid (CSF) collection that enables longitudinal investigation of CSF inflammation. The method described in this study can easily be adapted by any laboratory prepared for animal studies. Multiplex immunoassay of serially collected and singly collected CSF samples show collection frequency does not alter protein expression in the CSF. Further, sex-dependent differences in TBI have been reported, but remain poorly understood. This study establishes a framework for assessing sex difference in neuroinflammation after a concussion. We showed that results vary based on the framing of the statistical test. However, it is evident that males experience a more robust inflammatory response to a single concussion than females.

neuroscience↗

bioRxiv2020

Freshly Thawed Cryobanked Human Neural Stem Cells Engraft within Endogenous Neurogenic Niches and Restore Cognitive Function Following Chronic Traumatic Brain Injury

Human neural stem cells (hNSCs) have potential as a cell therapy following traumatic brain injury (TBI). While various studies have demonstrated the efficacy of NSCs from on-going culture, there is a significant gap in our understanding of freshly thawed cells from cryobanked stocks - a more clinically-relevant source. To address these shortfalls, the therapeutic potential of our previously validated Shef-6.0 human embryonic stem cell (hESC)-derived hNSC line was tested following long-term cryostorage and thawing prior to transplant. Immunodeficient athymic nude rats received a moderate unilateral controlled cortical impact (CCI) injury. At 4-weeks post-injury, 6x105 freshly thawed hNSCs were transplanted into six injection sites (2 ipsi- and 4 contra-lateral) with 53.4% of cells surviving three months post-transplant. Interestingly, most hNSCs were engrafted in the meninges and the lining of lateral ventricles, associated with high CXCR4 expression and a chemotactic response to SDF1alpha (CXCL12). While some expressed markers of neuron, astrocyte, and oligodendrocyte lineages, the majority remained progenitors, identified through doublecortin expression (78.1%). Importantly, transplantation resulted in improved spatial learning and memory in Morris water maze navigation and reduced risk-taking behavior in an elevated plus maze. Investigating potential mechanisms of action, we identified an increase in ipsilateral host hippocampus cornu ammonis (CA) neuron survival, contralateral dentate gyrus (DG) volume and DG neural progenitor morphology as well as a reduction in neuroinflammation. Together, these findings validate the potential of hNSCs to restore function after TBI and demonstrate that long-term bio-banking of cells and thawing aliquots prior to use may be suitable for clinical deployment. Significance StatementThere is no cure for chronic traumatic brain injury (TBI). While human neural stem cells (hNSCs) offer a potential treatment, no one has demonstrated efficacy of thawed hNSCs from long-term cryobanked stocks. Frozen aliquots are critical for multisite clinical trials, as this omission impacted the use of MSCs for graft versus host disease. This is the first study to demonstrate the efficacy of thawed hNSCs, while also providing support for novel mechanisms of action - linking meningeal and ventricular engraftment to reduced neuroinflammation and improved hippocampal neurogenesis. Importantly, these changes also led to clinically relevant effects on spatial learning/memory and risk-taking behavior. Together, this new understanding of hNSCs lays a foundation for future work and improved opportunities for patient care.

neuroscience↗