Fibrin as a scaffold for delivery of GDNF overexpressing stem cells to the adult rat brain

Abstract

Treatment of neurodegenerative disease is entering a new era where direct intracerebral delivery of therapeutic factors aims to restore normality to dysfunctional circuits. Cell-based therapeutic approaches, where virally manipulated mesenchymal stem cells (MSCs) overexpressing glial cell line derived neurotrophic factor (GDNF) are utilized as vehicles to deliver neurotrophic support to the Parkinsonian brain, have shown promising preclinical results at preserving dopaminergic neuron integrity. However, poor cell survival following transplantation will hinder clinical progression. One approach to improve MSCs survival following transplantation is to couple the cell engraftment procedure with a scaffold thereby providing a physical substrate upon which to eventually complex pro-survival factors. Evaluation of commercially available, clinically accepted materials with an established safety profile will expedite clinical translation. Therefore, this study sought to determine if a clinically used fibrin scaffold can be utilized as an adjunct to intracerebral cell transplantation without evoking an adverse host or stem cell response. Sixteen male Sprague−Dawley rats received bilateral intrastriatal transplants of 30 000 GDNF-transduced MSCs delivered in either control transplantation medium or a fibrin scaffold. Rats were sacrificed 1, 4, 7, and 14 days post-transplantation. Brains were analyzed to determine in situ polymerization and biodegradability of the fibrin scaffold, GDNF release from transplanted GDNF-MSCs, survival of the GDNFMSC graft and the host s immune response to the transplant. This study found that fibrin scaffold was adaptable to intracerebral delivery with successful polymerization of the fibrin scaffold in situ. Inclusion of the fibrin scaffold was not detrimental to cell survival nor did it impede neurotrophin release from entrapped cells. Importantly, the inclusion of the fibrin scaffold was associated with a reduced host astroglial and microglial response compared to cells alone indicative of a favorable biocompatibility profile. Overall, fibrin represents an adaptable scaffold for inclusion in a minimally invasive cell-based therapeutic approach for neurodegenerative diseases.