The therapeutic effect of mesenchymal stem cell transplantation in experimental autoimmune encephalomyelitis is mediated by peripheral and central mechanisms
- Sara Morando†1, 2,
- Tiziana Vigo†1, 2,
- Marianna Esposito3,
- Simona Casazza1, 2,
- Giovanni Novi1,
- Maria Cristina Principato1, 2,
- Roberto Furlan3 and
- Antonio Uccelli1, 2, 4Email author
© BioMed Central Ltd 2012
Received: 6 July 2011
Accepted: 18 January 2012
Published: 26 January 2012
Stem cells are currently seen as a treatment for tissue regeneration in neurological diseases such as multiple sclerosis, anticipating that they integrate and differentiate into neural cells. Mesenchymal stem cells (MSCs), a subset of adult progenitor cells, differentiate into cells of the mesodermal lineage but also, under certain experimental circumstances, into cells of the neuronal and glial lineage. Their clinical development, however, has been significantly boosted by the demonstration that MSCs display significant therapeutic plasticity mainly occurring through bystander mechanisms. These features have been exploited in the effective treatment of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis where the inhibition of the autoimmune response resulted in a significant amelioration of disease and decrease of demyelination, immune infiltrates and axonal loss. Surprisingly, these effects do not require MSCs to engraft in the central nervous system but depend on the cells' ability to inhibit pathogenic immune responses both in the periphery and inside the central nervous system and to release neuroprotective and pro-oligodendrogenic molecules favoring tissue repair. These results paved the road for the utilization of MSCs for the treatment of multiple sclerosis.
Mesenchymal stem cells are stromal progenitors of the mesodermal lineage
Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells that can be isolated from many adult connective tissues. The cells grow as plastic-adherent fibroblast-like cells that proliferate in vitro, maintaining pluripotency after prolonged culture. Under appropriate stimulus, MSCs can differentiate in vitro and in vivo into cells of the mesodermal lineage, such as bone, fat and cartilage cells.
MSCs have mainly been characterized after isolation from the bone marrow, where they are likely to represent the precursor cells for stromal tissue in close physical association with hematopoietic stem cells involved in hematopoiesis and maintenance of the homeostasis of the hematopoietic stem cell niche . In the bone marrow the existence of a population of neural-crest-derived stem cells was also shown, thus providing an explanation for the reported ability of bone-marrow-derived stem cells to also generate, to some extent, neural cells .
Despite evidence showing that MSCs can transdifferentiate into multiple cell types in vitro and in vivo, the real contribution of MSCs to tissue repair - through significant engraftment and differentiation into biologically and functionally relevant tissue-specific cell types - is still elusive . In the bone marrow, MSCs provide a sheltering microenvironment contributing to the preservation of hematopoietic stem cells by shielding them from differentiation and apoptotic stimuli and regulating their quiescence, proliferation and differentiation. Owing to their ability to support hematopoiesis, MSCs were first utilized to enhance immune reconstitution when transplanted together with hematopoietic stem cells. The translation of the capacity of MSCs to differentiate into other tissues was first exploited for reparative purposes, for example, in bone and heart diseases. The observation that bone-marrow-derived MSCs suppressed T-cell proliferation in vitro  and in vivo , however, unexpectedly drove attention to their exploitation for the treatment of immune-mediated diseases; for example, in those diseases where their ability of modulating the immune response could combine with the ability to integrate into damaged tissues and foster repair. Experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, has been the first experimental autoimmune disease successfully treated with MSCs .
Experimental autoimmune encephalomyelitis is an example of immune-mediated disease
EAE can be actively induced in susceptible inbred rodents by immunization with different neural antigens mainly derived from myelin, including myelin basic protein, proteolipid protein (PLP) and myelin oligo-dendrocyte protein (MOG) in complete Freud's adjuvant. Disease induction with PLP in SJL mice, and likewise MOG in C57BL/6 mice, requires the use of pertussis toxin that facilitates immune cell entry into the central nervous system (CNS) and contributes to T-cell tolerance breaking. EAE can be also induced in naïve mice by the intravenous passive transfer of encephalitogenic myelin-specific T cells. In fact, EAE is considered a prototypical MHC class-II-restricted CD4+ T-cell-mediated disease. During the induction phase, myelin-reactive CD4+ T cells are primed and expanded in the peripheral lymphoid organs. The effector phase involves migration of activated myelin-specific T cells to the CNS, where they cross the blood-brain barrier and require myelin peptides presented by local antigen-presenting cells and dendritic cells for full reactivation .
Several lines of evidence indicate that many subsets of T cells play different roles in the onset, maintenance and recovery of EAE, T-helper-type 17 cells and regulatory T cells being among the main contributors to the final outcome . Not only T cells but also B cells producing demyelinating antibodies and macrophages are key effector cells in EAE pathogenesis. Typical EAE lesions resemble patterns of demyelination, inflammatory cell perivascular infiltrates, reactive microgliosis and astro-cytosis, observed in multiple sclerosis lesions .
Systemic effect of the intravenous delivery of mesenchymal stem cells in experimental autoimmune encephalomyelitis
In the study by Zappia and colleagues we demonstrated that intravenous injection of syngeneic MSCs into C57BL/6 mice immunized with peptide 35 to 55 of MOG significantly improved the clinical severity of EAE, in parallel decreasing CNS inflammation and demyelination . More importantly, we demonstrated that one injection of MSCs at disease onset or at the peak of disease suffices to induce peripheral tolerance, as demonstrated by the inability of T cells isolated from lymph nodes of MSC-treated mice, but not from control animals, to proliferate when stimulated with the immunizing antigen MOG. We also observed a dose-dependent effect that reached maximum efficacy and negligible mortality at the dose of 1 × 106 MSCs. No clinical effect was observed when MSCs were infused during the chronic phase of EAE, suggesting that multiple injections may not provide further advantages if permanent tissue damage has occurred . In another study, Zhang and colleagues demonstrated that intra-venous administration of human MSCs could improve the clinical course of PLP-induced EAE in SJL mice through some level of engraftment in the CNS and subsequent release of neurotrophic factors promoting oligo-dendrogenesis . These results highlighted that MSCs can cross MHC boundaries and exert their therapeutic effect also in the CNS, regardless of a very limited engraftment. Following these pioneer works, in the last years several studies have focused on the mechanisms underlying the therapeutic effect of MSC transplantation on EAE.
The concept that MSCs ameliorate EAE through the induction of peripheral immune tolerance was further nourished by the demonstration that intravenous administration of allogeneic MSCs in PLP-immunized mice inhibits the production of myelin-specific antibodies compared with controls . In addition, the exposition of encephalitogenic T cells to MSCs in vitro significantly decreases their ability to passively transfer EAE to healthy syngeneic mice . Many other studies have confirmed that MSCs can modulate the peripheral immune response to myelin antigens [12–19]. These in vivo results have been corroborated by detailed in vitro studies dissecting the mechanisms of action of MSCs on T lymphocytes, B lymphocytes, dendritic cells, natural killer cells and other immune cells .
Mesenchymal stem cells are neuroprotective
It is important to underline that effects of MSCs on EAE are not exclusively due to their immunomodulatory activity, as many groups have shown that MSCs can also protect neurons and spare axons with no or very limited evidence of engraftment and/or transdifferentiation into neural cells [11–13, 15, 16, 21]. These findings posed the question of whether the observed neuroprotection in EAE is due to the peripheral effects suppressing the immune response that damages myelin or to a direct protective and reparative activity that follows their engraftment in the CNS.
Several lines of evidence suggest that, somehow, MSCs have a direct effect on neural cells. They have been shown to enhance remyelination in vivo [15, 16], provide in vitro soluble cues that influence fate determination of neural cells [16, 22], display a potent antioxidant effect in vivo [23, 24] and display a neuroprotective effect  mediated by the release of antiapoptotic molecules in vitro  and in vivo . These neuroprotective effects may well explain the remarkable effect obtained with the administration of MSCs in experimental models of stroke  and spinal cord injury . There is uncertainty, however, regarding the ability of MSCs to colonize the CNS after peripheral delivery due to their scarce ability to pass the lung filter following intravenous administration  and due to the lack of reliable labels or definitive markers for MSCs .
Irrespective of these aspects, the current view suggests that MSCs may exert their neuroprotective effect at distance through the release of trophic molecules, possibly affecting microglia activation  and inducing local neurogenesis [15, 16, 32].
Does local administration provide significant advantage compared with systemic infusion?
To enhance the possibility for MSCs to engraft in the CNS and provide optimal therapeutic effects locally, Kassis and colleagues demonstrated, following intra-ventricular injection of MSCs, the expression of neural markers by a few transplanted labeled cells mainly in the proximity of inflammatory lesions - suggesting that some level of transdifferentiation was achieved . Similarly, Barhum and colleagues showed that intraventricular administration in vitro of MSCs modified to produce neurotrophins successfully attenuated EAE .
Clinical features of experimental autoimmune encephalomyelitis-affected mice
Disease onset, days after immunization
Mean maximum neurologic score
Cumulative disease score
EAE control i.v.
12 ± 0.8
3 ± 0.5
84.4 ± 13
EAE + MSCs i.v.
11.5 ± 0.5
2.5 ± 0.9
67.6 ± 28.7*
EAE control i.t.
11.6 ± 0.6
3 ± 0.5
85.2 ± 15.3
EAE + MSCs i.t.
12.3 ± 1
2.4 ± 0.7*
63.7 ± 25.7*
Intravenous injection of mesenchymal stem cells also modulates the immune response in the CNS
A major issue still unsolved by the above-described studies was whether intravenously injected MSCs could also impact the immune response inside the CNS. It is well known that, following intravenous administration, MSCs inhibit infiltration of T cells and macrophages in mice with EAE . These results, however, are likely to be an effect of the cells' tolerogenic ability exerted in the periphery on encephalitogenic T cells, as demonstrated by the inhibition of EAE following passive transfer of myelin-specific T cells .
Overall, many studies have confirmed that MSCs, either from syngenic or xenogeneic sources, are effective in the treatment of EAE and dissected their mechanisms of action, probably in a much deeper fashion than in any other experimental disease. The results discussed in the present article demonstrate that MSCs can repair neural tissues as they display a broad therapeutic activity that acts both on immune and neural cells but feebly involves their transdifferentiation. Interestingly, despite a limited ability to engraft in the nervous system, MSCs can clearly modulate the immune response not only in the peripheral lymphoid organs  but also within the CNS.
Based on these studies and the available clinical experience obtained in several human conditions, MSCs can be considered an appealing therapeutic option for multiple sclerosis individuals with ongoing inflammatory disease refractory to conventional therapies [37, 38].
This article is part of a review series on Immunology and stem cells, edited by Christian Jorgensen. Other articles in the series can be found online at http://stemcellres.com/series/immunology
central nervous system
experimental autoimmune encephalomyelitis
major histocompatibility complex
myelin oligodendrocyte glycoprotein
mesenchymal stem cell
polymerase chain reaction
Some of the studies discussed in this article were supported by grants from the Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health (Ricerca Finalizzata), the Italian Ministry of the University and Scientific Research (MIUR-PRIN), the Progetto LIMONTE, and the Fondazione CARIGE. The authors thank Tiziana Ferrando for technical assistance on histological analysis. The skillful secretarial assistance of Tiziana Poggio is gratefully acknowledged.
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