Efficacy of NSCs in an EAE model of MS

Project Summary/Abstract
Multiple sclerosis (MS) is a degenerative disease, which affects the central nervous system (CNS). While most
neurodegenerative diseases affect older populations, the onset of MS generally occurs early in life. There is no
cure for MS. Currently used drugs have severe side effects. Past attempts to develop cell therapies to treat MS
have met with limited success. The major challenges in developing cell therapies include invasive isolation
techniques, limited growth and differentiation potential, as well as genetic instability of adult mesenchymal stem
cells (MSCs). We have isolated and differentiated highly proliferative and primitive (p) MSCs into neural stem
cells (NSCs). In our preliminary studies, transplantation of NSCs significantly reversed the clinical symptoms
when transplanted at an early stage of experimental autoimmune encephalomyelitis (EAE) in a mouse model.
These findings are very promising and provide a strong “proof of concept” for cell-based treatment of MS. Since
we saw substantial improvement in EAE disease with a single cell dose, we hypothesize that multiple doses
of NSCs will be more effective in ameliorating chronic EAE disease symptoms and promoting functional
recovery. We envision that this innovative approach using NSCs will enhanced the potency of cell therapy as
proposed in this study. The specific aims are: 1. To determine the therapeutic effects of repeated doses of
NSCs on chronic EAE in mice. We hypothesize that similar to repeated use of drugs, repeated cell therapy
treatments will be more efficacious. This hypothesis will be tested by injecting GFP-labeled NSCs in 3 doses to
counter chronic EAE induced by MOG immunization in mice. Changes in the disease symptoms and progression
will be monitored by performing neurobehavioral, neurological motor function, mechanical threshold response
and cold response analyses to assess the effect of cell therapy on the disease progression and remission. 2. To
investigate CNS pathology at cellular and molecular levels in NSC transplanted EAE mice. We
hypothesized that NSC treatments will reduce inflammation and restore CNS function. Histopathological analysis
of the CNS will be performed to access immune cell infiltrates. Composition of cell infiltrates will be assessed by
immunohistochemical analysis of CNS sections. Levels of pro- and anti-inflammatory cytokines will be carried to
assess the immunomodulatory properties of transplanted NSCs. NSCs are also likely to help in mitigating the
imbalance of immune regulatory cells, reduce astrogliosis, and improve myelination. This will be investigated
using appropriate cellular and molecular techniques. NSCs also express high level of neurotrophic factors, their
role in neuroprotection will be explored. The effect of NSCs on the global gene expression in the CNS of EAE
mice will be examined by RNA-seq and validated by qRT-PCR analysis. RNA-seq analysis should help in
determining the signaling pathways involved in potential functional recovery of damaged CNS in EAE mice. The
results of this research will provide fundamental insights into EAE and also help in developing cell therapies not
only for MS but also for other neurodegenerative diseases.

Grant Number: 5R16NS129748-04
NIH Institute/Center: NIH
Principal Investigator: G. CHAUDHRY