Elsevier

Experimental Neurology

Volume 260, October 2014, Pages 19-32
Experimental Neurology

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

https://doi.org/10.1016/j.expneurol.2013.03.009Get rights and content

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.

Introduction

The discovery of adult neurogenesis and the development of protocols that allow in vitro growth and significantly large scale-up of stem and precursor cells of the brain (Reynolds and Weiss, 1992) have fostered the development of innovative therapies aimed at stem cell transplantation for acute and chronic disorders of the nervous system (Cossetti et al., 2012). Motivated by the expectation of achieving CNS repair and/or regeneration via functional neural cell replacement, these studies have demonstrated a potential benefit of neural stem/precursor cell (NPC)-based experimental treatments in animal models of several neurological diseases (Martino et al., 2011). However, mounting evidence suggests that the effects orchestrated by transplanted NPCs are not only associated with the generation of new neurons or glial cells but also that the pathological setting in which these cells are transplanted critically determines the outcome (Cossetti et al., 2012). Cell replacement is therefore only one of the multiple ways in which transplanted NPCs promote tissue repair, and a much more complex therapeutic scenario should be foreseen. The concept of stem cell therapeutic plasticity (Martino and Pluchino, 2006) (or functional multipotency) (Teng et al., 2011) has therefore emerged, as it describes the multiple way(s) grafted NPCs which mediate systemic homeostasis, e.g. by the secretion of tissue trophic factors, as well as interaction with tissue-resident vs. -infiltrating immune cells, at the level of the inflammatory tissue context in which they are either transplanted or to which they migrate after transplantation.

The newest picture is therefore that stem cell therapies, contrary to single-molecule-based pharmaceutical interventions, hold the potential to deliver a complex series of information to a multitude of targets in the diseased microenvironment (Cossetti et al., 2012). While no final mechanisms (or direct evidence) of stem cell-to-host immune system interaction is yet available, a number of studies are now focussing on the cellular signalling that exists between grafted stem cells and endogenous target cells, with the aim of clarifying its physiological or circumstantial nature, and elucidating its molecular signature and therapeutic potential.

Here we will review the most recent evidence of immune modulation following syngeneic NPC transplants in animal models of multiple sclerosis, spinal cord injury and stroke, and discuss the next challenges related to the translation of some of these exciting experimental outcomes into clinical medicines.

Section snippets

Multiple sclerosis

Multiple sclerosis (MS) is a complex, highly debilitating CNS autoimmune disease that constitutes the most common cause of neurological disability in young adults (Compston and Coles, 2002). The main pathological hallmark of MS is the presence of highly heterogeneous, chronic inflammatory and demyelinating perivascular lesions within the CNS (Compston and Coles, 2002, Dyment and Ebers, 2002, Flugel et al., 2001, Lucchinetti et al., 2000, Noseworthy et al., 2000, Wingerchuk et al., 2001). Most

Spinal cord injuries

Spinal cord injuries (SCIs) are devastating and debilitating conditions affecting all regions of the world – predominantly in young adults – which are associated with severe physical, psychological, social and economic burdens on patients and their families [reviewed in Ho et al. (2007) and van den Berg et al. (2010)]. An important premise for the development of effective treatments for SCIs is the precise understanding of the main pathophysiological events following the acute injury and how

Stroke

Clinical recovery after stroke remains very poor despite advances in therapy, and stem cell treatment is considered a promising alternative (Lindvall and Kokaia, 2011). Transplantation of NPCs with different delivery strategies, intraparenchymal (ipc) or icv injection, as well as systemic administration, has been shown to improve clinical signs in experimental stroke models (Liu et al., 2009, Pluchino et al., 2010).

Irrespective of the route of administration, transplanted NPCs migrate towards

Towards clinical trials

Based on the encouraging results collected pre-clinically during the last 5–7 years (Table 1), phase I clinical trials have started to be conducted, both in fatal and non-fatal incurable neurological diseases where the risk/benefit ratio is in theory favourable (Aboody et al., 2011). Besides the unquestionable care regarding the characterisation and manufacture of the medicinal product (Rayment and Williams, 2010), one of the other important hurdles in the design of clinical study for (stem)

Conclusions and future directions

Stem cell-based therapies hold great promise in regenerative neuroscience (Park et al., 2010). The huge advances made over the last few years have enormously deepened our knowledge about the biology of stem cells, leading to global reconsideration of their therapeutic potential and mechanisms of action, as well as their intrinsic limitations (Martino et al., 2011). Importantly, the use of animal models that closely mimic different aspects of human pathologies has also contributed to increasing

Acknowledgments

The authors are grateful to Gianvito Martino for the vision and continuous inspiration, Jayden A. Smith for critically reviewing the article, Paula Francis for proof edits and Letterio Politi for the diffusion weighted image shown in Fig. 1. This work has received support from the National Multiple Sclerosis Society (NMSS, partial grant RG-4001-A1), the Italian Multiple Sclerosis Association (AISM, grant 2010/R/31), the Italian Ministry of Health (GR08-7), Wings for Life, Banca Agricola

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