Clinical Potential of Intravenous Neural Stem Cell Delivery for Treatment of Neuroinflammatory Disease in Mice?

Abstract

While neural stem cells (NSCs) are widely expected to become a therapeutic agent for treatment of severe injuries to the central nervous system (CNS), currently there are only few detailed preclinical studies linking cell fate with experimental outcome. In this study, we aimed to validate whether IV administration of allogeneic NSC can improve experimental autoimmune encephalomyelitis (EAE), a well-established animal model for human multiple sclerosis (MS). For this, we cultured adherently growing luciferase-expressing NSCs (NSC-Luc), which displayed a uniform morphology and expression profile of membrane and intracellular markers, and which displayed an in vitro differentiation potential into neurons and astrocytes. Following labeling with green fluorescent micron-sized iron oxide particles (f-MPIO-labeled NSC-Luc) or lentiviral transduction with the enhanced green fluorescent protein (eGFP) reporter gene (NSC-Luc/eGFP), cell implantation experiments demonstrated the intrinsic survival capacity of adherently cultured NSC in the CNS of syngeneic mice, as analyzed by real-time bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and histological analysis. Next, EAE was induced in C57BL/6 mice followed by IV administration of NSC-Luc/eGFP at day 7 postinduction with or without daily immunosuppressive therapy (cyclosporine A, CsA). During a follow-up period of 20 days, the observed clinical benefit could be attributed solely to CsA treatment. In addition, histological analysis demonstrated the absence of NSC-Luc/eGFP at sites of neuroinflammation. In order to investigate the absence of therapeutic potential, BLI biodistribution analysis of IV-administered NSC-Luc/eGFP revealed cell retention in lung capillaries as soon as 1-min postinjection, resulting in massive inflammation and apoptosis in lung tissue. In summary, we conclude that IV administration of NSCs currently has limited or no therapeutic potential for neuroinflammatory disease in mice, and presumably also for human MS. However, given the fact that grafted NSCs have an intrinsic survival capacity in the CNS, their therapeutic exploitation should be further investigated, and-in contrast to several other reports-will most likely be highly complex.

Intranasal Delivery of Neural Stem/Progenitor Cells: A Noninvasive Passage to Target Intracerebral Glioma

“…Ideally, alternative noninvasive strategies with minimal risks for the patient, high transplantation efficiency, and the possibility of a chronic treatment option are needed. Systemic intravascular application of cells could be another option, but major obstacles would be the entrapment and elimination of cells in peripheral organs and the risk of vascular and pulmonary embolization [10,14,29]. Although we detected NSPCs in the spleen after intranasal delivery indicating a systemic distribution we did not observe any NSPCs in lung or liver tissue at any time point.…”

RETRACTED ARTICLE: Targeted suicide gene therapy for glioma using human embryonic stem cell-derived neural stem cells genetically modified by baculoviral vectors

“…In the case of systemic injection of NSCtk for brain cancer therapy, the majority of intravenously injected cells became stuck in the lung and liver because of the narrow diameters of lung capillaries and liver sinusoids. 55 Damaging normal proliferating cells in these organs by the bystander effect of phosphorylated GCV is a major safety concern here. One possible way to alleviate this problem is to develop a new regulation system that triggers transgene expression in NSCs only after they home in on tumors.…”

Cell Size and Velocity of Injection are Major Determinants of the Safety of Intracarotid Stem Cell Transplantation

“…The evaluation of neural cell distribution after intravenous cell transplantation has shown that most of the cells are initially entrapped within the lungs and do not travel to the brain. 3 It has been hypothesized that an intraarterial approach would be a more efficient route of cell delivery to the brain, as this approach avoids the pulmonary circulation. This approach is particularly attractive when selecting and sorting cells for adhesion molecules, which can enhance cell homing and therapeutic outcome.…”