Death resistant neural stem cell regenerate neuronal tissue and promote functional recovery after transplantation in a spinal cord injury model

Traumatic injuries in central nervous system lead to severe and permanent neurological deficit. In particularly acute traumatic spinal cord injury often results in a devastating loss of neurological function below the injury. Since the loss of CNS neurons may not be replaced by the proliferation of the surviving ones, intraspinal transplantation of exogenous neuronal cells or tissue has been accepted for a long time as a way to obtain a partial reconstruction of the lost cord tissue and to promote recovery of neurological function. Regeneration or replacement of dead or damaged cells is the primary goal of regenerative medicine and one of the prime motivations for the study of stem cells. NSCs can participate in repair of damage and may be useful in the treatment of degenerative brain conditions. Adult stem cells have been isolated from numerous adult tissues and other non-embryonic sources, and have demonstrated a surprising in vitro ability for transformation into other tissue or cell types and for repair of damaged tissues. Unfortunately when administrated on a spinal cord injury model they modulate the inflammatory response but do not differentiate into mature cells and are quickly engulfed by macrophages present at lesion site whitin 3 weeks after transplantation. Recently we isolated a new class of neural stem cell from the subventricular zone of mice forebrain named Death resistant neural stem cells (DR-NSCs), that are capable of surviving after a powerful ischemic insult. DR-NSCs for their potentiality in terms of proliferation and differentiation capabilities, are a good tool for tissue replacement therapies. In this study we focused on transplantation of DR-NSCs in a murine model of spinal cord injury by endovenous injection within 2 hours after injury. After administration, cells migrate specifically to the site of injury and significantly improve the rate of hind limb function evaluated by Basso Mouse Scale compared with animals treated with placebo. Intrestingly DR-NSCs survive at the injury site and differentiate predominantly into cholinergic neurons , reconstitute a rich axonal and dendritic network and promote a marked axonal regeneration across the injury site of monoaminergic fibers within 30 days from their administration. Moreover the molecular analysis of the lesion site show that DR-NSCs induce a remodulation of inflammatory response through the expression of proinflammatory cytokines and release of neurotrophic factors. Proinflammatory cytokines (IL-6, MIP-2 and TNF alpha levels significantly decrease after 48 hours from spinal cord injury and DR-NSCs transplantation, while after 7 days we observe an increase of IL-6 and TNF alpha probably because at longer time those cytokines are necessary to support the regenerative process according to the literature. These data suggest that DR-NSCs may represent a good source for cellular therapy in neurodegenerative disorders, specially on spinal cord injury