Cell transplantation offers the potential to treat central nervous system injuries, largely because multiple mechanisms can be targeted in a sustained fashion. It is crucial that cells are transplanted into an environment that is favourable for extended survival and integration within the host tissue. Given the success of using fetal tissue grafts for traumatic brain injury, it may be beneficial to mimic key aspects of these grafts (e.g. three-dimensionality, cell-cell and cell-matrix support) to deliver cells. Extracellular matrix proteins such as fibronectin and laminin are involved in neural development and may provide adhesive support for donor cells and mediate subsequent cell signalling events. In this study, neural stem cells were transplanted into the traumatically injured mouse brain within a tissue-engineered construct containing either a laminin- or fibronectin-based scaffold. Cells delivered within the scaffolds were more widely distributed in the injured brain compared to cells delivered in media alone. There were no differences in donor cell survival at 1 week post-transplant; however, by 8 weeks post-transplant, cells delivered within the scaffolds showed improved survival compared to those transplanted in media alone. Survival was more enhanced with the laminin-based scaffold compared to the fibronectin-based scaffold. Furthermore, behavioural analyses indicated that mice receiving neural stem cells within the laminin-based scaffold performed significantly better than untreated mice on a spatial learning task, supporting the notion that functional recovery correlates positively with donor cell survival. Together these results suggest that the use of appropriate extracellular matrix-based scaffolds can be exploited to improve cell transplantation therapy.

Host responses to biomaterials control the biological performance of implanted medical devices. Upon implantation, synthetic materials adsorb biomolecules which trigger an inflammatory cascade comprising coagulation, leukocyte recruitment/adhesion, and foreign body reaction. The foreign body reaction and ensuing fibrous encapsulation severely limit the in vivo performance of numerous biomedical devices. While it is well established that plasma fibrinogen and secreted cytokines modulate leukocyte recruitment and maturation into foreign body giant cells, mediators of chronic inflammation and fibrous encapsulation of implanted biomaterials remain poorly understood. Using plasma fibronectin conditional knock-out mice, we demonstrate that plasma fibronectin modulates the foreign body response to polyethylene terephthalate discs implanted subcutaneously. Fibrous collagenous capsules were two-fold thicker in mice depleted of plasma fibronectin compared to controls. In contrast, deletion of plasma fibronectin did not alter acute leukocyte recruitment to the biomaterial, indicating that plasma fibronectin modulates chronic fibrotic responses. The number of foreign body giant cells associated with the implant was three times higher in the absence of plasma fibronectin while macrophage numbers were not different, suggesting that plasma fibronectin regulates the formation of biomaterial-associated foreign body giant cells. Interestingly, cellular fibronectin was present in the capsules of both normal and plasma fibronectin-depleted mice, suggesting that cellular fibronectin could not compensate for the loss of plasma fibronectin. These results implicate plasma fibronectin in the host response to implanted materials and identify a potential target for therapeutic intervention to enhance the biological performance of biomedical devices.

Several studies have shown the benefits of transplanting bone marrow-derived multipotent mesenchymal stromal cells (MSC) into neurodegenerative lesions of the central nervous system, despite a low engraftment rate and the poor persistence of grafts. It is known that the extracellular matrix (ECM) modulates neuritogenesis and glial growth, but little is known about effects of MSC-derived ECM on neural cells. In this study, we demonstrate in vitro that the ECM produced by MSC can support neural cell attachment and growth. We also compare the neurosupportive properties of MSC to the MSC derivative, SB623 cells, which is being developed as a cell therapy for stroke. Embryonic rat brain cortical cells cultured for 3 weeks on human MSC- and SB623 cell-derived ECM exhibit about a 1.5 and 3 times higher metabolic activity, respectively, compared with the cultures grown on poly-D-lysine (PDL), although the initial neural cell adhesion to cell-derived ECM and PDL is similar. The MSC- and SB623 cell-derived ECM protects neural cells from nutrient and growth factor deprivation. Under the conditions used, only neurons grow on PDL. In contrast, both MSC- and SB623 cell-derived ECMs support the growth of neurons, astrocytes, and oligodendrocytes, as demonstrated by immunostaining. Morphologically, neurons on cell-derived ECM form more complex and extended neurite networks than those cultured on PDL. Together, these data indicate that the beneficial effect of MSC and SB623 cells in neurotransplantation could be explained in part by the neurosupportive properties of the ECM produced by these cells.

Cell transplantation is a promising treatment strategy for many neurological disorders, including stroke, which can target multiple therapeutic mechanisms in a sustained fashion. We investigated the ability of human mesenchymal stromal cells (MSCs) and MSC-derived SB623 cells to rescue neural cells via trophic support following an in vitro stroke model. Following oxygen glucose deprivation, cortical neurons or hippocampal slices were cocultured with either MSCs or SB623 cells separated by a semiporous membrane (prohibits cell-cell contact) or with MSC- or SB623 cell-conditioned medium. MSCs, SB623 cells, MSC-conditioned media, and SB623 cell-conditioned media all significantly reduced neural cell damage/death compared to untreated conditions, and the rescue effect of the conditioned media was dose dependent. We identified 11 neurotrophic factors secreted by MSCs and/or SB623 cells. This study emphasizes the importance of trophic support provided by marrow-derived cells, which likely contributes to the efficacy of cell therapy for brain injury.