Autotransplantation in the CNS
Autologous brain cell ecosystem
We optimized an appropriate process to obtain viable cells in vitro from human and non human primate cortical biopsies.
Neurological resections were dissected to separate white and grey matter. Fractions were mechanically dissociated, expanded in culture and characterized by immunochemistry. Through this specific process, brain cells were generated and formed adult brain cell ecosystems that consist in astrocytes surrounding quiescent and proliferative progenitors. These brain cell ecosystem that could be maintained in culture for up to 150 days.
In parallel a successful procedure for cryopreservation of adult human brain tissue has been established that might facilitate future autologous transplantation strategies
These cortical cells express doublecortin, a neural progenitor marker. Doublecortin-positive cells were present in the whole primate cerebral cortex and also expressed glial and/or neuronal markers such as GFAP or NeuN. Only doublecortin/GFAP positive cells were able to proliferate and originate progenitor cells in vitro.
We hypothesize that these doublecortin-positive cells in vivo have a role in cortical plasticity and brain reaction to injury. Moreover, in vitro, these doublecortin-positive cells have the potential to reacquire progenitor characteristics that confirm their potential for brain repair.
Transplantation in motor cortex lesion
Brain lesions in the adult have dramatic consequences as the spontaneous capacity of the brain to functionally recover is limited. Besides existing rehabilitative therapeutic ap-proaches (e.g. physiotherapy), several lines of research aim at developing treatments to promote and refine brain plasticity, in order to enhance functional recovery following brain injury. In stem cell research, which represents a promising strategy to treat several nervous diseases, many sources of cells have been studied. To bypass the caveats of allogenic stem cell transplantation, the feasibility and functional relevance of autologous adult neural cell ecosystem transplantation strategy in a non-human primate model of cerebral (motor) cortex lesion were demonstrated.
After lesion, there was a complete loss of manual dexterity in the contralesional hand. The ‘‘control’’ monkeys recovered progressively and spontaneously part of their manual dexterity, reaching a unique and definitive plateau of recovery. The ‘‘reimplanted’’ monkeys reached a first spontaneous recovery plateau at about 25 and 40 days postlesion, representing 35% and 61% of the prelesion performance, respectively. In contrast to the controls, a second recovery plateau took place 2 to 3 months after cell transplantation, corresponding to an additional enhancement of functional recovery, representing 24% and 37% improvement, respectively.
The preliminary data suggest that, after lesion of motor cortex, functional recovery in monkeys treated with autologous cell transplants is enhanced.
Transplantation in parkinsonian MPTP model
Autologous brain cell transplantation might be also useful for regenerating function in neurodegenerative diseases. Following MPTP treatment, primates were dopamine depleted and presented parkinsonian symptoms.
In a first phase, a low dose MPTP treatment was applied and a partial dopaminergic neuron depletion was observed in the substantia nigra. Autologous adult brain cell ecosystems were reimplanted into the right caudate nucleus of the donor monkey. Four months after reimplantation, histological analysis by stereology and TH immunolabeling showed that the reimplanted cells successfully survived, bilaterally migrated in the whole striatum, and seemed to have a neuroprotection effect over time since the number of dopaminergic neurons rise to normal value in reimplanted monkeys compare to MPTP-treated controls.
These results may add a new strategy to the field of brain neuroprotection or regeneration and could possibly lead to future clinical applications.