Long distance selective fiber outgrowth of transplanted hNT neurons in white matter tracts of the adult rat brain

Abstract

Terminally differentiated neurons derived from a human teratocarcinoma cell line (NT2N or hNT neurons) are promising as a cell source for transplantation, as they have been shown to be safe for transplantation in humans. We have shown previously that hNT neurons can express a catecholaminergic phenotype in a rat Parkinson model. In this study, we investigated the long-term survival and ability of hNT neurons to express tyrosine hydroxylase and reconstruct the dopamine-denervated nigrostriatal pathway. Hemiparkinsonian rats received grafts of 400,000 viable hNT neurons into each of the denervated striatum and substantia nigra. Robust hNT grafts were detected up to 24 weeks posttransplantation, although few cells expressed tyrosine hydroxylase. Many hNT fibers were often associated with ipsilateral and contralateral white matter tracts--corpus callosum, rostral migratory stream, optic tract, and external capsule. Fewer fibers were associated with the superior cerebellar peduncle, medial lemniscus, and nigrostriatal pathway. Axons also projected into the frontal cortex and extended parallel to the surface of the brain in the superficial cortical layers. These pathways were seen in all grafted animals, suggesting that specific guidance cues exist in the adult brain governing hNT fiber outgrowth. Injured adult axons and transplanted embryonic neuronal axons rarely extend for such distances in the adult nervous system. We propose that elucidating the factors promoting and guiding hNT axonal outgrowth could provide important clues to enhancing regeneration and target reinnervation in the adult brain, two factors of critical importance for cell restoration strategies aimed at brain repair.

Stroke alters behavior of human skin-derived neural progenitors after transplantation adjacent to neurogenic area in rat brain

“…A similar outgrowth was previously shown from human tertocarcinoma cells transplanted into the striatum of adult rat brain [7], suggesting guidance cues in the adult brain that govern fiber outgrowth (e.g., ADAM21 metalloprotease; [35]). The same signals that regulate neuronal migration also mediate neurite outgrowth [36].…”

“…Several cues have been identified which take part in this process [4–6] and may regulate the behavior also of cells transplanted close to the SVZ into the adult rodent brain. For example, differentiated neurons from a human teratocarcinoma send their axons through the RMS and in association with ipsilateral and contralateral white matter pathways [7]. When implanting human skin-derived iPSCs close to the SVZ in adult intact brains, most of the grafted cells migrate via the RMS.…”

Restorative approaches in Parkinson's Disease: Which cell type wins the race?

“…The nigro-striatal dopaminergic pathway would have to be reconstructed to enable the grafted neurons to integrate into the basal ganglia circuitries. Intranigral grafting has been shown to be technically possible and safe in rodents [183][184][185][186] and humans [187,188]. Graft integration, survival and partial functional recovery have been demonstrated and provide the impetus for the existence of factors guiding targeted nerve fiber outgrowth from the substantia nigra to the striatum [183][184][185][186].…”

Human Model Neurons in Studies of Brain Cell Damage and Neural Repair

“…In the following, Baker and Mendez [132] tried to reconstruct the dopamine-denervated nigrostriatal pathway by intrastriatal and intranigral grafts of NT-2 neurons to hemiparkinsonian rats, using immunocytochemistry to monitor expression of TH and testing for recovery in rotational behavioral testing. The study evaluated three groups of animals, which received unilateral 6-hydroxydopamine (6-OHDA) lesions of the right nigrostriatal pathway and subsequent grafts of NT-2 neurons 2 weeks after lesioning.…”

“…Since injured axons and also transplanted embryonic neurons rarely extend for such distances in the adult nervous system, unknown guidance factors seem to promote the outgrowth of NT-2 neurons in the host tissue. The authors suggest that the analysis of growth promoting and guidance factors for the transplanted NT-2 neurons could provide clues for enhancing target reinnervation in the adult brain [132].…”