Neuro-immune interactions of neural stem cell transplants: from animal disease models to human trials

Abstract

Stem cell technology is a promising branch of regenerative medicine that is aimed at developing new approaches for the treatment of severely debilitating human diseases, including those affecting the central nervous system (CNS). Despite the increasing understanding of the mechanisms governing their biology, the application of stem cell therapeutics remains challenging. The initial idea that stem cell transplants work in vivo via the replacement of endogenous cells lost or damaged owing to disease has been challenged by accumulating evidence of their therapeutic plasticity. This new concept covers the remarkable immune regulatory and tissue trophic effects that transplanted stem cells exert at the level of the neural microenvironment to promote tissue healing via combination of immune modulatory and tissue protective actions, while retaining predominantly undifferentiated features. Among a number of promising candidate stem cell sources, neural stem/precursor cells (NPCs) are under extensive investigation with regard to their therapeutic plasticity after transplantation. The significant impact in vivo of experimental NPC therapies in animal models of inflammatory CNS diseases has raised great expectations that these stem cells, or the manipulation of the mechanisms behind their therapeutic impact, could soon be translated to human studies. This review aims to provide an update on the most recent evidence of therapeutically-relevant neuro-immune interactions following NPC transplants in animal models of multiple sclerosis, cerebral stroke and traumas of the spinal cord, and consideration of the forthcoming challenges related to the early translation of some of these exciting experimental outcomes into clinical medicines.

Keywords: Clinical trials; Immune modulation; Neural stem cells; Neuro-immune interactions; Stem cell therapy.

Fig. 1

Overview diagram of the novel evidence of stem cell mediated effects – including neuro-immune interactions – that have inspired the present pipeline of neural stem cell therapeutic product development in multiple sclerosis, spinal cord injuries and brain stroke. In neurospheres, magenta is for Vimentin and green is for Phospho-Histone; in differentiated NPCs, red is for glial fibrillary acidic protein (GFAP) and green is for microtubule-associated protein 2 (MAP-2). Nuclei are stained with 4′,6-diamidino-2-phenylindole (DAPI). The magnetic resonance image (MRI) is a representative diffusion weighted image (DWI) coronal scan from the brain of a mouse 24 h after transient (45′) middle cerebral artery occlusion (MCAo).