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Figure 1: FLuc loaded PEG tubes sustained expression over a course of 12 weeks. Qualitatively, (A) bioluminescence was detected in highest concentrations at the injured spinal cord. (B) Bioluminescent signal of lentivirus-laden hydrogel tubes was assessed over a course of 12 weeks with higher expression compared to background across all times evaluated. n=6 per condition, * p<0.05, ** p<0.01, **** p<0.001.
Figure 2: Macrophage infiltration is not exacerbated by tube implantation or E14 spinal progenitor transplantation. Macrophage densities in (A) SCI only, (B) Tubes only, (C)Tubes+IL-10, (D) E14 spinal progenitors only, (E) Tubes+E14, and (F) Tubes+E14+IL-10 in transverse tissue cross sections exhibit both M1 macrophages (F4/80+, red) denoted by ^ and M2 macrophages (F4/80+arginase+, red and green) denoted by *. At 4 weeks after implantation, there were no differences in (G) total macrophage density, (H) M2 macrophage density, and (I) M2 percent across all conditions. Data are presented as mean ± SEM. n=4 per condition, 50 µm scale bars.
Figure 3: (A) Experimental timeline detailed with major interventions. Delayed EGFP+ spinal progenitor transplantation into IL-10 encoding lentivirus loaded tubes 2 weeks post-injury improves survival. Five hydrogel tubes, either blank or IL-10 lentivirus loaded, were implanted directly after lateral C5 hemisection injury, and EGFP+ spinal progenitors were transplanted 2 weeks post-injury into (B) SCI only, (C) blank tubes, or (D) IL-10 lentivirus loaded tubes. Quantitatively, survival was assessed 4 weeks post-injury (2 weeks post-transplantation), and IL-10 lentivirus loaded tubes exhibited an increase in (E) cell density and (F) percent survival over the other two conditions. Data are presented as mean ± SEM. n=4 per condition, * p<0.05, ** p<0.01, 50 µm scale bars.
Figure 4: Neuron formation at 12 weeks post-injury is increased when hydrogel tubes are implanted. (A) Formed neurons were observed at 12 weeks post-injury arising from both exogenous (EGFP+NeuN+|green+gray+, green arrow) and endogenous (BrdU+NeuN+|red+gray+, pink arrow) sources. (B) No statistically significant differences was observed in exogenous-sourced neuron density. (C) A significant increase in NeuN+ cells as a percent of total EGFP+ cells was observed when E14 spinal progenitors were transplanted into either blank tubes or IL-10 lentivirus-loaded tubes. (D) There were no statistically significant differences observed in endogenous-sourced neuron formation. Data are represented as mean ± SEM, n = 4-7 animals per conditions, * p<0.05, ** p<0.01, 50 µm scale bars.
Figure 5: E14 spinal progenitor transplants into IL-10 lentivirus-laden tubes improve new axon formation at 12 weeks post-injury. Axon expression (NF-200+) in (A) SCI only, (B) Tubes only, (C) Tubes+IL-10, (D) E14 spinal progenitors only, (E) Tubes+E14, and (F) Tubes+E14+IL-10. Examples of (G) bundles and (H) elongated axons observed in the ipsilateral tissue. Quantitatively, animals receiving Tubes+E14+IL-10 exhibited a higher elongated axon density (I) in the ipsilateral tissue. Data are presented as mean ± SEM. n=6 animals per condition, * p<0.05, ** p<0.01, *** p<0.005, 200 µm scale bars (A-F), 50 µm scale bars (G-H).
Figure 6: E14 spinal progenitor delivery increases axon remyelination 12 weeks post-injury. Axon (NF-200+, red) co-localization with myelin (MBP+, green) was assessed in (A) SCI only, (B) Tubes only, (C) Tubes+IL-10, (D) E14 spinal progenitors only, (E) Tubes+E14, and (F) Tubes+E14+IL-10. (G) E14 only transplants and Tubes+E14+IL-10 exhibited an increase in overall myelinated axon density compared to the SCI only condition. (H) As a percent, myelination was significantly increased in the E14 only condition compared to all other conditions. Data are represented as mean ± SEM, n = 4-7 animals per condition, * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001, 20 µm scale bars.
Figure 7: Animals receiving E14 spinal progenitors transplanted into IL-10 lentivirus-laden tubes exhibited a quicker return of forelimb motor function. To assess mobility, a horizontal ladder beam test was used. Mice were trained on walking across the ladder prior to injury. Mobility was assessed through successful placements as a score out of 50 possible rungs. By 4 weeks post-injury Tubes+E14+IL-10 (a, p<0.005) had improved stepping compared to SCI only. At 8 weeks all conditions with tubes had improved stepping compared to (Tubes+E14, b, p<0.005; Tubes+IL-10, c, p<0.05; Tubes, d, p<0.05). At 12 weeks all conditions exhibited improved stepping (E14 only, e, p<0.01).