Neurorestorative Effect of Urinary Bladder Matrix-Mediated Neural Stem Cell Transplantation Following Traumatic Brain Injury in Rats

Abstract

Traumatic brain injury (TBI) is a leading cause of cell death and disability among young adults and lacks a successful therapeutic strategy. The multiphasic injuries of TBI severely limit the success of conventional pharmacological approaches. Recent successes with transplantation of stem cells in bioactive scaffolds in other injury paradigms provide new hope for the treatment of TBI. In this study, we transplanted neural stem cells (0.5×105 cells/μl) cultured in a bioactive scaffold derived from porcine urinary bladder matrix (UBM; 4 injection sites, 2.5μl each) into the rat brain following controlled cortical impact (CCI, velocity, 4.0 m/sec; duration, 0.5 sec; depth, 3.2mm). We evaluated the effectiveness of this strategy to combat the loss of motor, memory and cognitive faculties. Before transplantation, compatibility experiments showed that UBM was able to support extended proliferation and differentiation of neural stem cells. Together with its reported anti-inflammatory properties and rapid degradation characteristics in vivo, UBM emerged to be an ideal scaffold. The transplants reduced neuron/tissue loss and white matter injury, and also significantly ameliorated motor, memory, and cognitive impairments. Furthermore, exposure to UBM alone was sufficient to decrease the loss of sensorimotor skills from TBI (examined 3–28 days post-CCI). However, only UBMs that contained proliferating neural stem cells helped attenuate memory and cognitive impairments (examined 26–28 days post-CCI). In summary, these results demonstrate the therapeutic efficacy of stem cells in bioactive scaffolds against TBI and show promise for translation into future clinical use.

Neural stem/progenitor cells differentiate into oligodendrocytes, reduce inflammation, and ameliorate learning deficits after transplantation in a mouse model of traumatic brain injury

“…Our results on rescue of mechanical injury‐related cognitive deficits are in line with previous studies showing that transplantation of NPCs isolated from various sources such as rat (Blaya et al, ) or human embryos (Gao et al, ) as well as immortalized cell lines from the early postnatal mouse cerebellum (Bakshi et al, ) have the potential to ameliorate cognitive decline caused by TBI. In conjunction with other reports indicating the potential of NPCs to ameliorate motor deficits induced by TBI (Li et al, ; Ma et al, ; Shear et al, ; Wang et al, ) or spinal cord injury (Hwang et al, ; Yan et al, ; Yasuda et al, ), our data suggest that NPCs would be useful as putative therapeutic agents for CNS trauma provided they can sustain a long‐term functional outcome (Makri et al, ; Skardelly et al, ). In our model early postnatal NPC grafts have lost their proliferative capacity by the second month after transplantation, indicating minimal risk of tumorigenesis if used as a potential therapeutic means in brain injuries.…”

Long-term retention of ECM hydrogel after implantation into a sub-acute stroke cavity reduces lesion volume

“…ECM implantation has been reported to promote behavioral improvements in animal models of TBI [23, 73, 74]. However, in these cases smaller volumes at lower concentrations of ECM were injected without retention of material within the tissue cavity.…”

“…UBM-ECM hydrogel also provides an excellent survival and differentiation of neural stem cells (NSCs) after transplantation into animals with traumatic brain injury [23]. A combination of UBM-ECM with 10% brain-ECM also resulted in the survival of NSCs implanted into stroke cavity, with evidence of some host invasion into hydrogel void of NSCs [24].…”

Biologic Scaffolds

“…A cryptic peptide derived from collagen IIIa showed chemotactic activity for many cells, including cortical neural stem cell and myoblasts in vitro and for cells showing stem-cell markers in vivo (Agrawal et al 2011b). Induction of both proliferation and differentiation of neural stem cells by UBM-ECM has been shown (Wang et al 2013a), and neural cell differentiation was later reproduced in neuroblastoma cells with MBVs isolated from UBM-ECM (Huleihel et al 2016). Primitive precursor cells seeded in decellularized kidney proliferated and expressed markers for site-appropriate differentiation (Ross et al 2009).…”