Bone marrow stromal cells reduce axonal loss in experimental autoimmune encephalomyelitis mice

Abstract

We investigated the ability of human bone marrow stromal cell (hBMSC) treatment to reduce axonal loss in experimental autoimmune encephalomyelitis (EAE) mice. EAE was induced in SJL/J mice by injection with proteolipid protein (PLP). Mice were injected intravenously with hBMSCs or PBS on the day of clinical onset, and neurological function was measured daily (score 0-5) until 45 weeks after onset. Mice were sacrificed at week 1, 10, 20, 34, and 45 after clinical onset. Bielshowsky silver was used to identify axons. Immunohistochemistry was performed to measure the expression of nerve growth factor (NGF) and MAB1281, a marker of hBMSCs. hBMSC treatment significantly reduced the mortality, the disease severity, and the number of relapses in EAE mice compared with PBS treatment. Axonal density and NGF(+) cells in the EAE brain were significantly increased in the hBMSC group compared with the PBS group at 1, 10, 20, 34, and 45 weeks. Disease severity was significantly correlated with decreased axonal density and decreased NGF, and increased axonal density was significantly correlated with reduced loss of NGF expression after hBMSC treatment. Most of the NGF(+) cells are brain parenchymal cells. Under 5% of MAB1281(+) cells colocalized with NG2(+), a marker of oligodendrocyte progenitor cells. Nearly 10% of MAB1281(+) cells colocalized with GFAP, a marker of astrocytes, and MAP-2, a marker of neurons. Our findings indicate that hBMSCs improve functional recovery and may provide a potential therapy aimed at axonal protection in EAE mice, in which NGF may play a vital role.

Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration

“…Recently, reports have appeared suggesting that bone marrow-derived cells can ameliorate toxic and inflammatory experimental demyelinating disease following intravenous delivery [1,3,5,7,[13][14][15][16]. However, whether this effect is achieved through cell replacement and…”

“…Others have previously reported the amelioration of EAE using bone marrow derived cells [1,3,5,7,[13][14][15][16]. Some studies propose and indeed help define systemic immune effects [3,5,7,13,14]; some find there to be CNS infiltration (following intravenous delivery of cells) [1,3,5,16] with certain groups proposing not immune 'therapeutic' activity but rather differentiation into microglia and/or oligodendrocyte lineage cells [1,5,16].…”

“…Some studies propose and indeed help define systemic immune effects [3,5,7,13,14]; some find there to be CNS infiltration (following intravenous delivery of cells) [1,3,5,16] with certain groups proposing not immune 'therapeutic' activity but rather differentiation into microglia and/or oligodendrocyte lineage cells [1,5,16]. Alternatively, local neuroprotective effects dependent on local infiltration also have been suggested as the therapeutic mechanism [5,16]. Any and all of these possible activities could of course be therapeutically relevant to MS [16], but whether one or other are more important functionally is a vital question if any cell therapy paradigm is to be optimised.…”

“…Alternatively, local neuroprotective effects dependent on local infiltration also have been suggested as the therapeutic mechanism [5,16]. Any and all of these possible activities could of course be therapeutically relevant to MS [16], but whether one or other are more important functionally is a vital question if any cell therapy paradigm is to be optimised.…”

Evaluation of corticospinal axon loss by fluorescent dye tracing in mice with experimental autoimmune encephalomyelitis

“…Moreover, neurological disability in patients with MS or animals with EAE has been correlated with the magnitude of degeneration of spinal cord axons (Bjartmar et al, 2000;Bjartmar et al, 2003;Medana and Esiri, 2003). Protective treatment for axonal degeneration also significantly reduces neurological deficit in the EAE model (Bechtold et al, 2006;Black et al, 2006;Kaneko et al, 2006;Zhang et al, 2006). The descending axons of the corticospinal tract (CST) are the only direct pathway from the motorsensory cortex to the spinal cord, and the major neural pathway for control of voluntary movement (Heffner and Masterton, 1983), and are often affected in MS (DeLuca et al, 2004).…”