Combination Therapy With Fingolimod and Neural Stem Cells Promotes Functional Myelination in vivo Through a Non-immunomodulatory Mechanism.

Yuan Zhang,Abdolmohamad Rostami,Bogoljub Ciric,Xing Li,Guang-Xian Zhang,Ze-Qin Ye,Xin-Yu Lu,Cun-Gen Ma

doi:10.3389/fncel.2019.00014

Abstract

Myelination, which occurs predominantly postnatally and continues throughout life, is important for proper neurologic function of the mammalian central nervous system (CNS). We have previously demonstrated that the combination therapy of fingolimod (FTY720) and transplanted neural stem cells (NSCs) had a significantly enhanced therapeutic effect on the chronic stage of experimental autoimmune encephalomyelitis, an animal model of CNS autoimmunity, compared to using either one of them alone. However, reduced disease severity may be secondary to the immunomodulatory effects of FTY720 and NSCs, while whether this therapy directly affects myelinogenesis remains unknown. To investigate this important question, we used three myelination models under minimal or non-inflammatory microenvironments. Our results showed that FTY720 drives NSCs to differentiate into oligodendrocytes and promotes myelination in an ex vivo brain slice culture model, and in the developing CNS of healthy postnatal mice in vivo. Elevated levels of neurotrophic factors, e.g., brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, were observed in the CNS of the treated infant mice. Further, FTY720 and NSCs efficiently prolonged the survival and improved sensorimotor function of shiverer mice. Together, these data demonstrate a direct effect of FTY720, beyond its known immunomodulatory capacity, in NSC differentiation and myelin development as a novel mechanism underlying its therapeutic effect in demyelinating diseases.

Highlights

Inflammatory demyelination and axonal damage in the central nervous system (CNS) are pathological hallmarks of the chronic stage of multiple sclerosis (MS), an autoimmune demyelinating disorder that leads to severe neurological dysfunction (Plemel et al, 2017; Scolding et al, 2017)
The beneficial effects of FTY720 on neural stem cells (NSCs) differentiation into oligodendrocytes in vitro (Zhang et al, 2017) prompted us to investigate whether FTY720 could enhance myelination and myelin maintenance under nonpathological conditions in an ex-vivo culture of brain slices, which maintain the true three-dimensional structure of the tissue (Humpel, 2015)
After 14 days, some exogenous GFP-positive NSCs were attached on the surface, or the edge of the slice, but others penetrated into the tissue slice structure, matured and myelinated (Figure 1B)

Summary

Introduction

Inflammatory demyelination and axonal damage in the central nervous system (CNS) are pathological hallmarks of the chronic stage of multiple sclerosis (MS), an autoimmune demyelinating disorder that leads to severe neurological dysfunction (Plemel et al, 2017; Scolding et al, 2017). Considerable progress has been made in MS therapies to reduce disease severity and progression, these therapies are only partially effective in the acute, but not the chronic state of disease (Bramow et al, 2010; Bible, 2013). This may be because they are Fingolimod and NSCs Promote Myelination mainly immunomodulatory but lack the neuroregenerative capacity to repair already damaged CNS tissue (Plemel et al, 2017). One major goal in therapeutic repair is the remyelination of demyelinated axons. A therapeutic strategy that has both immunomodulatory and (re)myelination effects is required to overcome the deficiency of current MS treatments (Grossman et al, 2017)

Methods

Results

Conclusion