Survival of Neural Progenitors Allografted into the CNS of Immunocompetent Recipients is Highly Dependent on Transplantation Site

Abstract

Allografts continue to be used in clinical neurotransplantation studies, hence it is crucial to understand the mechanisms that govern allograft tolerance. We investigated the impact of transplantation site within the brain on graft survival. Mouse (FVB) glial precursors, transfected with luciferase have been injected (3×105) into the forceps minor (FM) or striatum (STR). Immunodeficient rag2−/− and immunocompetent BALB/c mice were used as recipients. Magnetic resonance imaging confirmed that cells were precisely deposited at the selected coordinates. The graft viability was assessed non-invasively with bioluminescent imaging for a period of 16 days. Regardless of implantation site all grafts (n=10) deposited in immunodeficient animals revealed excellent survival. In contrast, immunocompetent animals accepted all grafts only at STR site (n=10), while all FM grafts were rejected (n=10). To investigate the factors that led to rejection of FM grafts, with acceptance of STR grafts, another group of animals (n=19) was sacrificed during pre-rejection period, on day 5. Near-infrared fluorescence imaging with IRDye®800CW-PEG probe displayed similar blood-brain barrier disruption at both graft locations. The morphological distribution of FM grafts was cylindrical, parallel to the needle track, while cells transplanted into the STR accumulated along the border between the striatum and corpus callosum. There was a significantly less infiltration by both innate and adaptive immune cells in the STR grafts, especially along the calloso-striatal border. With allograft survival being dependent on the transplantation site, the anatomical coordinates of the graft target should always be taken into account as it may determine success or failure of therapy.

Prospects for polymer therapeutics in Parkinson's disease and other neurodegenerative disorders

“…For example, studies show immunosuppression to increase xenograft (human to rat) survival qualitatively [29] and quantitatively [30], but allograft transplantation into the striatum was not affected between immune-deficient/immuno-competent mice [31] other than to favor neuron differentiation [32]. The brain is now no longer considered a completely immuno-privileged region there is a degree of immune privilege, and the immune response is a major consideration for cell therapy [33].…”

Gaining Mechanistic Insights into Cell Therapy Using Magnetic Resonance Imaging

“…For instance, neural stem cells implanted into the periinfarct parenchyma of a stroke promote recovery, whereas cells injected into the lateral ventricle did not [11]. Considering the varied extent and topology of lesions caused by neurological conditions, such as stroke and traumatic brain injury, guidance of injection to the parenchyma is, hence, a crucial step to ensure that the transplanted cells can be efficacious [12]. Nevertheless, in other cases, direct targeting of the lesion cavity is important and MRI can provide the required guidance in terms of volume and location to perform a safe and efficient injection [13,14].…”

Seeing Stem Cells at Work In Vivo

“…This is because BL signal generation is ATP-dependent and BLI can be used to monitor cell survival post-transplantation. Transplantation site-dependent survival of neuronal progenitor allografts in the mouse brain [129] and neuronal progenitor cell survival within hydrogels can be determined in vivo by BLI (Fig. 5) [130].…”