Exogenous Adult Postmortem Neural Precursors Attenuate Secondary Degeneration and Promote Myelin Sparing and Functional Recovery following Experimental Spinal Cord Injury

Abstract

Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neurological dysfunctions. Neural stem cells from the subventricular zone of the forebrain have been considered a potential tool for cell replacement therapies. We recently isolated a subclass of neural progenitors from the cadaver of mouse donors. These cells, named postmortem neural precursor cells (PM-NPCs), express both erythropoietin (EPO) and its receptor. Their EPO-dependent differentiation abilities produce a significantly higher percentage of neurons than regular NSCs. The cholinergic yield is also higher. The aim of the present study was to evaluate the potential repair properties of PM-NPCs in a mouse model of traumatic SCI. Labeled PM-NPCs were administered intravenously; then the functional recovery and the fate of transplanted cells were studied. Animals transplanted with PM-NPCs showed a remarkable improved recovery of hindlimb function that was evaluated up to 90 days after lesion. This was accompanied by reduced myelin loss, counteraction of the invasion of the lesion site by the inflammatory cells, and an attenuation of secondary degeneration. PM-NPCs migrate mostly at the injury site, where they survive at a significantly higher extent than classical NSCs. These cells accumulate at the edges of the lesion, where a reach neuropile is formed by MAP2- and β-tubulin III-positive transplanted cells that are also mostly labeled by anti-ChAT antibodies.

Grafted Neural Precursors Integrate Into Mouse Striatum, Differentiate and Promote Recovery of Function Through Release of Erythropoietin in MPTP-Treated Mice

“…A similar effect was observed after a septo-hippocampal lesion, where septal neurons recovered ChAT positivity following NGF or BDNF infusion (Morse et al., 1993). Our previous work in experimental traumatic spinal cord injury reported the reduction of inflammatory cytokines levels, reactive GFAP-positive gliosis, and macrophage infiltration after the treatment with rhEPO (Gorio et al., 2002) or administration of Er-NPCs (Carelli et al., 2014, 2015). This seems to happen also in the present work by the counteraction of inflammation events caused by MPTP, particularly ipsilateral to the injection site.…”

“…IL-6 mRNA analyses were performed at 7 days after transplant ( n  = 3 mice for each group) in striatum homogenates as described in Carelli et al., 2015. Briefly, left and right striatum regions were dissected out rapidly, frozen on dry ice, and stored at −80℃ for further analyses.…”

Brain adaptation to hypoxia and hyperoxia in mice

“…Immunofluorescence analysis was performed as previously reported [11]. Briefly, cryostat coronal sections (15 µm) were collected onto glass slides and processed for immunocytochemistry.…”

HuR interacts with lincBRN1a and lincBRN1b during neuronal stem cells differentiation

“…Neural stem cells (NSCs) are multipotent stem cells present in the central nervous system (CNS) with self-renewing capabilities and the ability to generate all the main cellular phenotypes present in the nervous system, including neurons, astrocytes and oligodendrocytes [1]. NSCs were first observed as resident progenitors in the sub-ventricular zone (SVZ) and dentate gyrus of the mouse brain [2], and have later found a strong use in regenerative medicine [3][4][5][6][7][8][9]. In that context, NSCs are described to act both by releasing anti-inflammatory soluble factors and by differentiating into cellular components of the CNS [4][5][6][7][8][9][10][11][12].…”

“…NSCs were first observed as resident progenitors in the sub-ventricular zone (SVZ) and dentate gyrus of the mouse brain [2], and have later found a strong use in regenerative medicine [3][4][5][6][7][8][9]. In that context, NSCs are described to act both by releasing anti-inflammatory soluble factors and by differentiating into cellular components of the CNS [4][5][6][7][8][9][10][11][12]. Many progresses have been made in understanding the factors that regulate adult NSCs' specification, proliferation and differentiation, but much remains to be understood, especially the potential involvement of RNA-binding proteins (RBPs) and long non-coding RNAs (lncRNAs) in these processes [13].…”