The Potential of Mesenchymal Stem Cells for Neural Repair.pdf

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The Potential of Mesenchymal Stem Cells for Neural

Repair

Published on March 17, 2010

Author:Robert H. Miller

Specialty:Stem Cells,Neuroscience

Institution: Centers for Stem Cells and Regenerative Medicine, Translational Neuroscience,

Department of Neurosciences, Case Western Reserve University School of Medicine

Address: 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States

Author:Lianhua Bai

Specialty:Neurology,NeuroscienceInstitution: Centers for Stem Cells and Regenerative Medicine, Translational Neuroscience,

Department of Neurosciences, Case Western Reserve University School of Medicine

Address: Cleveland, Ohio, 44106, United States

Author:Donald P. Lennon

Specialty:Stem Cells,Biology

Institution: The Skeletal Research Center, Case Western Reserve University School of

Medicine


Author:Arnold I. Caplan

Specialty:Stem Cells,Biology

Institution: The Skeletal Research Center, Case Western Reserve University School of

Medicine


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Abstract: Developing effective therapies for serious neurological insults remains a major

challenge for biomedical research. Despite intense efforts, the ability to promote functional

recovery after contusion injuries, ischemic insults, or the onset of neurodegenerative diseases

in the brain and spinal cord remains very limited even while the need for such therapies is

increasing with an aging population. Recent studies suggest that cellular therapies utilizing

mesenchymal stem cells (MSCs) may provide a functional benefit in a wide range of
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neurological insults. MSCs derived from a variety of tissue sources have been therapeutically

evaluated in animal models of stroke, spinal cord injury, and multiple sclerosis. In each

situation, treatment with MSCs results in substantial functional benefit and these pre-clinical

studies have led to the initiation of a number of clinical trials worldwide in neural repair.

Introduction

Cell based therapies are emerging as innovative approaches for the treatment of neurological

disorders that currently lack effective therapies. Critical to the success of cell therapies is the

selection and mode of delivery of cell populations. A leading candidate population for

neurological applications is mesenchymal stem cells (MSCs). Here we briefly review the data

supporting the clinical application of MSCs in three distinct neural insults and review the

current thinking on the mechanisms of action of MSCs in the setting of neural injury. Several

lines of evidence support the hypothesis that transplanted MSCs modulate both the host

immune response to injury as well as direct neural stem cells and progenitors to differentiatealong lineages that support rather than inhibit regeneration. It seems likely that the

therapeutic efficacy of MSCs is a consequence of their capacity to localize to areas of insult

and release a broad spectrum of trophic factors that guide endogenous neural cell repair. The

ability to identify the spectrum of signals involved in neural repair will allow for engineering

of MSCs that will potentially enhance the hosts capacities to promote functional recovery.

Origins and Potential of MSCs

Adult mesenchymal stem cells can be isolated from a range of tissues includingbone marrow

or bone marrow aspirates, fat, and other somatic tissues (Caplan, 2007). The multiple sources

of MSCs and their relative ease of isolation have resulted in them becoming a preferred

therapeutic cell population in a variety of therapeutic settings (Caplan, 2007). Our

understanding of the biology of MSCs has developed rapidly as a result of the ability to grow

them in vitro while maintaining their capacity to give rise to multiple cell lineages as well as

direct their differentiation down specific pathways (Lennon and Caplan, 2006). The most

common MSC differentiation pathways are along mesodermal lineages to form muscle, bone,

cartilage, fat, andtendon(Pittenger et al., 1999) and these can be modulated depending upon

local cues. There is considerable evidence suggesting that MSCs are also capable of

differentiating into non-mesenchymal lineages including endothelial cells (Oswald et al.,

2004) and neural cells (Jiang et al., 2002) although in the case of neural cells, it is unclear

whether this reflects trans-differentiation, ectopic marker expression, orcell fusion(Rutenberg et al., 2004).

The capacity to engineer specific cell types from MSCs has facilitated their use in rebuilding

damaged mesenchymal tissues; however, the utility of MSCs is not restricted to cell or tissue

replacement. Mesenchymal stem cells also release signals that modulate host tissue

responses. For example, MSCs have a strong immunosuppressive effect on the host immune

system and alter the relative level of pro- and anti-inflammatory cytokine expression by T

cells. Similarly, through the release of trophic factors MSCs are capable of enhancing the

endogenous repair potential of many tissues. The augmentation of host MSC responses by the

treatment with exogenous MSCs has emerged as a therapeutic approach to a range of tissue

insults. Currently clinical trials are ongoing to use MSCs in the treatment ofgraft-versus-hostdisease,heart failure,stroke,spinal cord injury,andmultiple sclerosis.
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Neural Applications of MSCs

Common features of neural insul ts

Regardless of the precise mechanism of damage, insults to the adult CNS provoke a similar

range of responses in the damaged tissue. For example,ischemiaresulting fromblood vesselocclusion or damage leads to functional deficits reflecting local death of neurons,

demyelination followingoligodendrocyteloss, and stimulation of a glial scar generated by

astrocytehypertrophy and proliferation (Beck et al., 2008). Likewise contusion or penetrating

injuries to the brain orspinal cordgenerate a similar spectrum of responses withneuronal cell

death and demyelination spreading from the original site of injury. Neurodegenerative

diseases including Alzheimers disease and multiple sclerosis also provoke similar responses

since neuronal cell death in Alzheimers disease, which is correlated with the deposition of

betaamyloidplaques, generates a local inflammatory response and glialscar formation(Yan

et al., 2009). In multiple sclerosis patients, the infiltrating activated immune cells attack

oligodendrocytes, the myelinating cells of the CNS, and generate focal demyelinated lesions

or plaques in which naked axons are surrounded by reactive astrocytes (Stadelmann et al.,2008). The demyelinated axons fail to conduct electrical signals with resulting functional

deficits (Waxman, 1991).

Two major themes emerge from analyses of these different types of CNS insult. One is that

they all result in the loss of neurons and oligodendrocytes concomitant with the generation of

reactive astrocytes and the formation of a glial scar. Second, a significant component of the

overall damage to the CNS is a result of either primary or secondary inflammatory attack on

the host tissue. This suggests that therapeutic strategies targeted at promoting the genesis of

neurons and oligodendrocytes while suppressing reactive astrocyte responses and modulating

pro- to anti-inflammatory immune responses would provide an ideal approach to treating a

spectrum of neural insults. The current literature provides strong support for the hypothesis

that MSCs are uniquely suited to fulfill these roles through the release of bioactive trophic

factors (Caplan, 2007).

MSCs in stroke

Stoke is the third leading cause of neurological injury in the USA and can be caused by the

occlusion of small vessels in the brain that result in a localized loss of blood supply and

subsequent neuronal death. This neuronal loss triggers a cascade of events including

inflammatory response that leads to a spreading of the affected area. Current therapies for

ischemic insults include relief of the vessel blockage through treatment withtissueplasminogen activator(tPA)that, while releasing blood flow, may stimulate further injury on

reperfusion. A standard animal model of stroke involves occlusion of the middle cerebral

artery (MCAO). Treatment of these rodents with MSCs delivered either directly into the brain

or intravenously resulted in a significant reduction of the extent of the damaged area and

improved neurological outcome (Li and Chopp, 2009).

The basis of MSC-induced functional improvement is not well understood. It has been

proposed that MSCs regulate the levels of cell death through the release of trophic factors as

well as alter the gap junction coupling between astrocytes that allows these cells to respond

more effectively to control damage (Li and Chopp, 2009). Recent studies suggest that MSCs

may also locally increase the levels of tPA in astrocytes around the stroke lesion and that thisincreasesneuroprotectionand enhances neurite outgrowth (Xin et al., 2010).
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MSCs inspinal cord injury

Spinal cord injuries result in long-term functional deficits as a result of the failure of severed

adult CNS neurons to regrow long distances, connect to their original targets, and restore

circuitry. Several factors are thought to contribute to the lack of regeneration of spinal cord

axons. These include a reduction in the intrinsic growth capacity of adult CNS projectionneurons, the presence of inhibitory cues derived from damaged CNS myelin, and the

formation of a glial scar by local astrocytes in response to inflammatory stimuli (Fitch and

Silver, 2008). Attempts to negate any single inhibitory mechanism have not resulted in a

significant enhancement of axonal regeneration, suggesting that multiple approaches will be

required to generate functional recovery. This hypothesis has recently received strong support

from the use of combinatorial therapies directed at intrinsic and environmental regulators of

regeneration (Kadoya et al., 2009). Remarkably, treatment with MSCs appears to enhance

functional recovery in the absence of combinatorial treatments. The underlying mechanisms

responsible for MSC-stimulated spinal cord regeneration are currently unclear. Studies with

otherstem cellpopulations suggest that they antagonize the negative effects of immune cells

(Busch et al., 2010) while MSCs appear to release trophic factors that promote axonalregeneration and may also enhance the survival of damaged neurons (Cho et al., 2009).

MSCs in mul tiple sclerosis

Perhaps the most advanced application for MSCs in the neurological clinical arena is in

multiple sclerosis (MS). Multiple sclerosis is an inflammatory disease of the CNS

characterized by extensive mononuclear cell infiltration and demyelination. MS is generally

considered to be a T-cell mediated disease based on local inflammation, response to immune

modulation orimmunosuppression(Stuve et al., 2006; Perini et al., 2007), and the genetic

association with themajor histocompatibility complex(Haines et al., 1996). The best

characterized model of MS is experimental allergic encephalomyelitis (EAE)(Martin, 1997)

induced byimmunizationof susceptible host animals with specific myelin proteins. This

animal model has formed the basis for the development of therapeutic approaches to MS. The

ultimate goal of such therapies is the restoration of function. Long-term functional recovery

requires regulation of the pathogenic process, which may be modulated by MSCs. For

example, in EAE, treatment with mouse MSCs reduces disease burden (Gerdoni et al., 2007;

Kassis et al., 2008). While animal models are essential for identifying potential therapeutic

approaches, the development of MSC-based clinical programs requires demonstration that

human MSCs have similar functional properties.
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Figure 1. Treatment of animals at the peak of disease with human MSCs rapidly results in a

reduction in functional deficits and sustains a long-term recovery. These data suggest that

MSCs may prove to be highly effective in the treatment of relapsing remitting MS.

We and others have shown that human MSCs have similar disease regulatory characteristics

to murine cells (Aggarwal and Pittenger, 2005; Zhang et al., 2005; Bai et al., 2007; Bai et al.,2009). Injection of bone marrow derived human MSCs into animals with either chronic or

relapsing remitting EAE resulted in a rapid reduction in functional deficits and led to long

term recovery (Figure 1). This recovery was correlated with the migration of the transplanted

MSCs into the CNS and their accumulation in regions of demyelination. Histological

characterization of the demyelinated lesions in the spinal cord of control and MSC treated

animals showed a number of significant changes. For example, the extent of astrogliosis was

reduced in the presence of MSCs, and the number of oligodendrocytes and their progenitors

was substantially increased. Treated animals demonstrated a significant reduction in the size

of the lesions and a dramatic increase in the number of myelinated axons. Together these

studies suggest a localized effect of the MSCs on the cell fate influenced by host endogenous

neural stem cells or progenitors in the area of lesions.

Consistent with the notion that MSCs alter neural cell fate in EAE, culture studies indicate

that neural stem cells (or neurospheres) grown in the presence of MSCs generate more

neurons and oligodendrocytes while giving rise to fewer astrocytes than controls. This effect

is seen in neurospheres derived from both developing and adult animals. More importantly,

neurospheres derived from EAE animals also show a pronounced potential to generate

neurons and oligodendrocytes when grown from animals treated with MSCs.

Mechanisms of Action of MSCs

It seems likely that common molecular mechanisms underlie the therapeutic benefit of MSCs

in the different neurological conditions. Although currently there is not a clear understanding

of the detailed mechanisms by which MSCs mediate neural recovery, several possibilities

exist. First, MSCs that infiltrate lesion areas may differentiate directly into neural cells. Early

studies suggested that MSCs injected into the lateral ventricles of developing animals

differentiated into astrocytes and other neural cell types (Woodbury et al., 2000; Deng et al.,

2001). This seems unlikely to account for the histological changes seen in the EAE studies,

however, since when labeled MSCs were injected into nave or EAE animals no evidence of

them adopting a neural fate was detected based on their expression of neuronal (TuJ1) or glial

(GFAP, CC1) antigens. Furthermore, even when grown in highly neuralizing conditions in

vitro, the proportion of neuralized MSC progeny remains relatively small and theirfunctional properties are not well known (Alexanian, 2007; Bai et al., 2007). One likely

explanation for the appearance of GFAP+MSCs in other models of neural damage is cell

fusion (Terada et al., 2002; Weimann et al., 2003). Indeed, intravenously injected bone

marrow-derived cells are known to fuse with hepatocytes in liver, Purkinje neurons in the

cerebellum, and cardiac muscle in the heart. However, the notion of MSCtransdifferentiation

into non-mesenchymal phenotypes is poorly supported by the current data.

The rapid and sustained functional recovery seen in animals with EAE after treatment with

MSCs suggests that these cells alter several aspects of disease progression. First, treatment

with MSCs suppressed T-lymphocyte activities thereby exerting an immunoregulatory

capacity (Di Nicola et al., 2002; Gerdoni et al., 2007; Nauta and Fibbe, 2007). The cytokineprofile of spleen was biased away fromTH1pro-inflammatory signals such asinterferon
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gamma,IL-17,andIL-2and towardsTh2anti-inflammatory signals such asIL-4andIL-5.

Though the mechanisms mediating such effects are still only partially understood, it is likely

that they involve both cell-to-cell contact and soluble factors. Second, endogenous neural

stem or progenitor cells are activated by MSCs (Munoz et al., 2005). Neural stem cells exist

in the developing and adult mammalian nervous system including that of humans. They are

capable of undergoing expansion and differentiation into neurons, astrocytes, andoligodendrocytes in vitro (Reynolds and Weiss, 1992) and aftertransplantationin vivo

(Svendsen et al., 1997). Although their restricted locations in the brain may limit their clinical

effectiveness, stimulation by MSCs may enhance their response and facilitate endogenous

CNS repair. In the EAE studies, it is likely that the recovery of myelination is a reflection of

suppression of the autoimmune responses in combination with induced proliferation or

enhanced differentiation of endogenous progenitor cells. Consistent with this hypothesis, an

increase in the density of NG2+cells and oligodendrocytes was seen in MSC-treated animals

presumably reflecting the release of multiple bioactive factors by MSCs (Caplan and Dennis,

2006). Indeed earlier studies have suggested that bone marrow stromal cells can promote

neurogenesisin the hippocampus (Munoz et al., 2005). Whether the functional improvement

seen in EAE reflects remyelination or neuroprotection derived from oligodendrocyteprecursor cells (OPCs) is currently unclear. A similar combination of anti-inflammatory

signals and modulation of neural cell fate may underlie the efficacy of MSCs in stroke and

spinal cord injury.

Conclusions and Future Directions

In conclusion, MSCs are emerging as an effective therapeutic approach to a wide range of

neural insults. Studies in demyelinating diseases have highlighted the importance of both the

immunoregulatory actions of MSCs and their neuromodulatory properties. These properties

are a reflection of several unique characteristics of MSCs. Specifically, these cells home to

areas of insults, they release a wide range of trophic signals that influence surrounding tissues

and they have immunosuppressive properties that allow their long term survival in non-

immunocompatible hosts. While MSCs are currently being utilized in the setting of a number

of neural injuries, in the future their potential may be enhanced by more effective targeting to

injury sites as well as augmenting or enhancing the spectrum of trophic factors they deliver.

Such studies offer a new perspective for the treatment of demyelinating diseases such as MS

and neurodegenerative diseases like Alzheimers disease and Parkinsons disease.

(Corresponding author: Robert H. Miller, Ph.D., Center for Translational Neurosciences,

Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106,

USA.)
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The Potential of Mesenchymal Stem Cells for Neural Repair.pdf

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