Systemic Injection of Neural Stem/Progenitor Cells in Mice with Chronic EAE

Matteo Donegà; Elena Giusto; Chiara Cossetti; Julia Schaeffer; Stefano Pluchino

doi:10.3791/51154

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Method Article

Systemic Injection of Neural Stem/Progenitor Cells in Mice with Chronic EAE

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DOI:

10.3791/51154

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April 15th, 2014

Matteo Donegà¹ , Elena Giusto¹ , Chiara Cossetti¹ , Julia Schaeffer¹ , Stefano Pluchino¹^,²

¹Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, UK, ²NIHR Biomedical Research Center, University of Cambridge, UK

Summary

The transplantation of neural stem/progenitor cells (NPCs) holds great promises in regenerative neurology. The systemic delivery of NPCs has turned into effective, low invasive, and therapeutically very efficacious protocol to deliver stem cells in the brain and spinal cord of rodents and nonhuman primates affected by experimental chronic inflammatory damage of the central nervous system.

Abstract

Neural stem/precursor cells (NPCs) are a promising stem cell source for transplantation approaches aiming at brain repair or restoration in regenerative neurology. This directive has arisen from the extensive evidence that brain repair is achieved after focal or systemic NPC transplantation in several preclinical models of neurological diseases.

These experimental data have identified the cell delivery route as one of the main hurdles of restorative stem cell therapies for brain diseases that requires urgent assessment. Intraparenchymal stem cell grafting represents a logical approach to those pathologies characterized by isolated and accessible brain lesions such as spinal cord injuries and Parkinson's disease. Unfortunately, this principle is poorly applicable to conditions characterized by a multifocal, inflammatory and disseminated (both in time and space) nature, including multiple sclerosis (MS). As such, brain targeting by systemic NPC delivery has become a low invasive and therapeutically efficacious protocol to deliver cells to the brain and spinal cord of rodents and nonhuman primates affected by experimental chronic inflammatory damage of the central nervous system (CNS).

This alternative method of cell delivery relies on the NPC pathotropism, specifically their innate capacity to (i) sense the environment via functional cell adhesion molecules and inflammatory cytokine and chemokine receptors; (ii) cross the leaking anatomical barriers after intravenous (i.v.) or intracerebroventricular (i.c.v.) injection; (iii) accumulate at the level of multiple perivascular site(s) of inflammatory brain and spinal cord damage; and (i.v.) exert remarkable tissue trophic and immune regulatory effects onto different host target cells in vivo.

Here we describe the methods that we have developed for the i.v. and i.c.v. delivery of syngeneic NPCs in mice with experimental autoimmune encephalomyelitis (EAE), as model of chronic CNS inflammatory demyelination, and envisage the systemic stem cell delivery as a valuable technique for the selective targeting of the inflamed brain in regenerative neurology.

Introduction

Strong evidence has arisen from in vivo studies attesting to the therapeutic efficacy of the transplantation of somatic neural stem/precursor cells (NPCs) in animal models of CNS disorders^1-8. Nevertheless, a number of issues relating to the delivery of stem cells into the host require careful consideration before these experimental results can be translated into clinical applications. A particularly substantial hurdle towards the development of (nonhematopoietic) restorative stem cell therapies for multifocal, chronic inflammatory brain diseases is the identification of the ideal route of NPC injection. A firm understanding of the pathophysiology ....