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) over-expressing glial cell line derived neurotrophic factor (GDNF) are utilised as vehicles to deliver neurotrophic support to the Parkinsonian brain, have shown promising pre-clinical 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 utilised as an adjunct to intra-cerebral cell transplantation without evoking an adverse host or stem cell response. Sixteen male SpragueDawley rats received bilateral intra-striatal 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 analysed to determine in situ polymerisation and biodegradability of the fibrin scaffold, GDNF release from transplanted GDNF-MSCs, survival of the GDNF-MSCs graft and the host's immune response to the transplant. This study found that fibrin scaffold was adaptable to intra-cerebral delivery with successful polymerisation 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 favourable biocompatibility profile. Overall, fibrin represents an adaptable scaffold for inclusion in a minimally invasive cell-based therapeutic approach for neurodegenerative diseases.TEXT Introduction:

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“…Normally, AD is hardly detected in the early stage and develops quickly, resulting in irreversible neuronal damage, dementia, and death . Currently, there is no effective clinical treatment for this disease . Due to the limitation of the blood–brain barrier (BBB), medicine cannot be effectively sent to the expected diseased region .…”

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“…7 ) [ 191 ]. The upregulation of GDNF expression in MSCs by either coculture or genetic overexpression has also been shown to enhance recovery in rat models of PD [ 192 , 193 ] and SCI [ 194 , 195 ]. Further, the simultaneous upregulation of BDNF, GDNF, and NGF in rat adipose-derived stem cell sheets using a hybrid baculovirus CRISPRa system improved Schwann cell migration, neuron regeneration, and neurite outgrowth in vitro , whereas the implantation of these ASC sheets into sciatic nerve injury sites enhanced reinnervation, axon regeneration, and remyelination [ 15 ].…”

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“…Another research group used in situ polymerization of a fibrin scaffold to engraft MSCs that overexpress GDNF; the biomaterial did not show adverse effects related to cell survival or GDNF release. The use of the scaffold was also associated with the modulation of reduced host microglial and astroglial response, which enhanced the therapeutic properties of these cells in adult rats [99]. In a more recent study, in 2019, Gómez-Pinedo et al [100] used scaffolds loaded with permissive olfactory sheathing glia to bridge the substantia nigra and striatum, promoting colonization and migration of TH+ axons between both ends of the graft.…”