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

Abstract

Erythropoietin-releasing neural precursor cells (Er-NPCs) are a subclass of subventricular zone-derived neural progenitors, capable of surviving for 6 hr after death of donor. They present higher neural differentiation. Here, Er-NPCs were studied in animal model of Parkinson’s disease. Dopaminergic degeneration was caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intraperitoneal administration in C57BL/6 mice. The loss of function was evaluated by specific behavioral tests. Er-NPCs (2.5 × 105) expressing the green fluorescent protein were administered by stereotaxic injection unilaterally in the left striatum. At the end of observational research period (2 weeks), most of the transplanted Er-NPCs were located in the striatum, while several had migrated ventrally and caudally from the injection site, up to ipsilateral and contralateral substantia nigra. Most of transplanted cells had differentiated into dopaminergic, cholinergic, or GABAergic neurons. Er-NPCs administration also promoted a rapid functional improvement that was already evident at the third day after cells administration. This was accompanied by enhanced survival of nigral neurons. These effects were likely promoted by Er-NPCs-released erythropoietin (EPO), since the injection of Er-NPCs in association with anti-EPO or anti-EPOR antibodies had completely neutralized the recovery of function. In addition, intrastriatal administration of recombinant EPO mimics the effects of Er-NPCs. We suggest that Er-NPCs, and cells with similar properties, may represent good candidates for cellular therapy in neurodegenerative disorders of this kind.

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].…”

Counteracting neuroinflammation in experimental Parkinson’s disease favors recovery of function: effects of Er-NPCs administration

“…In this sense, adult neural stem cells grafting into animal experimental models of neurodegenerative diseases have shown beneficial effects promoting both trophic and anti-inflammatory actions [ 25 – 31 ]. Recently, we reported the therapeutic potential of erythropoietin-releasing neural precursors cells (Er-NPCs) intrastriatally infused in a preclinical model of PD, obtained upon the administration of MPTP [ 30 , 32 ]. After the unilateral transplantation into the striatum of MPTP-treated C57BL/6 mice, Er-NPCs were vital and capable of engrafting into the recipient’s brain.…”

Photoreceptor Therapy: Generation of Neurosphere-Like Cells from Human Mesenchymal Stem Cells Expressing Erythropoietin

“…It is noteworthy that EPO has long been recognized to also participate in neurogenesis and anti-apoptotic activities (Eckardt & Kurtz 2005;Lv et al 2015;Zhang et al 2007) to maintain various tissue functions (Chung et al 2009;Shirley Ding et al 2016). For example, EPO was found to be released in an autocrine manner from neural progenitor cells in a mouse model of spinal cord injury to sustain neural progenitor cell survivability under apoptotic microenvironment and upregulate neurogenesis (Carelli et al 2016). Meanwhile, administration of EPO were demonstrated to increase precursor and mature neuronal cell differentiation in healthy young mouse models (Hassouna et al 2016).…”