Literature Review

A Review of Stem Cell Therapy for Spinal Cord Injury: Large Animal Models and the

Frontier in Humans

Brandon C. Gabel, Erik I. Curtis, Martin Marsala, Joseph D. Ciacci

-OBJECTIVE: To review the literature of spinal cord injury and stem celltherapy for large animal models and incorporate those results into an under-standing of stem cell therapy for human cord injury.

-METHODS: Review of the literature.

-RESULTS: Eleven canine studies were identified and 3 sub-human primatestudies were identified showing variable results.

-CONCLUSIONS: Stem cell therapy is a promising therapeutic option for pa-tients with spinal cord injury; however, the technology has many un-answeredquestions and further research is needed.

Key words- Direct injection- Mesenchymal- Neuron- Spinal cord injury- Stem cell

Abbreviations and AcronymsMRI: Magnetic resonance imaging

Department of Neurosurgery, University of California, SanDiego, San Diego, California, USA

To whom correspondence should be addressed:Brandon C. Gabel, M.D.[E-mail: bgabel@ucsd.edu; brandoncgabel@gmail.com]

Citation: World Neurosurg. (2017) 98:438-443.http://dx.doi.org/10.1016/j.wneu.2016.11.053

Journal homepage: www.WORLDNEUROSURGERY.org

Available online: www.sciencedirect.com

1878-8750/$ - see front matter ª 2016 Elsevier Inc. All

INTRODUCTION

Spinal cord injury is a devastating con-dition with a large medical and socio-economic impact. Acute and chronicmedical conditions associated with cordinjury are a large source of medicalmorbidity and mortality. Neurogenicshock, pneumonia, decubitus ulcers,osteoporosis, urinary tract infections,spasticity, and pain syndromes are a fewof the many problems that plague cord-injured patients.1 These medicalproblems, combined with lost workpotential, have a large socioeconomicimpact throughout the world.2 Giventhese concerns, it is not surprising thatconsiderable research has looked forways to cure, or at least improve thefunctioning of patients with cord injury;much of this research has been directedtoward stem cell therapy.Despite the theoretic benefits of stem

cells, there are still many undeterminedfactors associated with their use as atherapy for cord injury. The best source forstem cells has yet to be determined. Bothautogenic and allogenic stem cells havebeen tried for spinal cord injuries andother neurological conditions with varying

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results.2-5 Autogenous stem cells arebeneficial because they are not immuno-genic and are harvested directly from thepatient, but may not be as potent as fetal-derived cells. Allogenic cells carry the riskof rejection and the need for potentiallong-term immunosuppression, but whenharvested from certain sources (i.e., um-bilical cord blood, fetal tissue) may havebetter potency.There are numerous stem cell sources.

Bone marrow and adipose-derivedmesenchymal stem cells, hematopoieticstem cells, neural precursor cells, olfactorymucosa, and embryonic cord blood haveall been used as sources of cells for spinalcord injury in animal models.6-10 Each ofthese sources has benefits and drawbacks;the ideal source, both in terms of thequality of the cell and the ethical consid-erations surrounding certain types of cells,remains elusive.As the biochemistry associated with

stem cells becomes more advanced, thebenefit they may provide becomes salientin modern medicine. This article willreview studies of direct parenchymal in-jection large animal models that have beenperformed, and their relevance to spinalcord injury in humans.

METHODS

A literature search using the followingsearch terms was performed on PubMed:stem cell(s), spinal cord injury, swine,

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monkey, canine, dog, primate, pig. Anyarticle between 1980 and 2015 thatincluded direct parenchymal injections ofstem cells into injured spinal cord wasincluded in the study. Injury-only articleswere not included, nor were stem-cellinjection-only models without antecedentspinal cord injury.

RESULTS

Canine StudiesThere are numerous canine studies thathave shown efficacy for stem cell thera-pies. Our review of the literature found 11studies that used a canine model. The typeof stem cell used, the type of injury,timing of stem cell injection, and numberof animals studied varied between groups(Table 1).Despite the heterogeneity of the studies,

numerous interesting conclusions can bedrawn. In most, there was a significantimprovement in functional outcomes. Astudy by Jung et al,9 which comparedallogenous, autogenous, and controlgroups, found that pelvic limb functionscores were improved in dogs receivingeither allogenous or autogenous stemcells compared with the control group.In addition, the animals who receivedautologous stem cells had higher Olbyscores (i.e., a gait scoring scale used indogs) compared with the allogenic stemcell group.11 Lee et al8,11 performed 2

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Table 1. Canine Models of Spinal Cord Injury

Author Injury ModelLevel ofInjury

Length of Time fromInjury to Injection

Stem CellSource

Stem CellDosage

Number ofAnimals Studied

Outcome Metric(s)Studied

Grangeret al.,20127

Natural injuries T10 to L4 >3 months Olfactory epithelium 5 � 106 cells 20 in stem cell group; 11in control group

Gait analysisSSEPsMEP

Urodynamics

Junget al.,20099

Balloon catheter L2 7 days Autologous andallogenous bone marrow

derived

1 � 107 cells 10 in autologous group;10 in allogenic group; 10

in control group

Olby scoreNeurotrophic factorexpression in the SCI

lesionMRI

Histology andimmunohistochemical

analysis

Lee et al.,20118

Balloon catheter L1-L2L2-L3L3-L4

(3 injectionsites peranimal)

7 days Human umbilical cordblood

1-2 � 106 cells 6 in stem cell group; 4 incontrol group

Basso, Beattie, andBresnahan scale (BBB)Deep pain perception

MRIHistology

Lee et al.,200911

Balloon catheter L2 7 days Human umbilical cordblood

1 � 107 cells 7 in stem cell group; 3 incontrol group

Canine hindlimblocomotor scale

Histology

Lee et al.,200912

Surgical incision oncord (hemicordectomy)

L1-L2 Injection at time ofinjury

Human neural stem cellswith Matrigel

1 � 106 cells 5 dogs in injectiongroup; 7 in control group

Hindlimb movementHistology and

immunohistochemistry

Lim et al.,200713

Balloon catheter L1 7 days Canine umbilical cordblood; some groups alsoreceived rhGCS factor

1.0 � 106 cells 5 in rhGCS group only; 5in stem cell group only;5 in stem cell group þrhGCS; 5 injured only; 5with cell injection media

only (no cells)

- Olby score- SSEP- MRI

- Histology

Park et al.,201114

Balloon catheter L1 Various (ranged from12 hours to 2 weeks)

Canine umbilical cordblood

1 � 106 cells 9 in stem cell group(various time pointsfrom injury); 12 incontrol group

Olby scoreTarlov scoreHistology

Park et al.,201215

Balloon catheter L1 7 days Adipose-derived cellswith Matrigel

1 � 107 cells 12 dogs total; 4 inphosphate-buffered

saline group (control); 4in Matrigel only group; 4in Matrigel þ stem cell

BBB scoreTarlov scoreHistology

Penhaet al.,201416

Natural cord injuries T12-L5 Roughly 8 monthsafter injury

Autologous bonemarrow-derived cells

1 � 106 cells 4 dogs in cell group; nocontrol animals

Tail movementPanicculi reflex

Urinary continenceProprioception reflexWeight bearing

MRI

Ryu et al.,201217

Balloon catheter L1 7 days Allogenic adiposederived cells

6 � 106 total cellsdivide at 3 sites

5 in stem cell group; 6 incontrol group

Olby scoreRevised Tarlov score

Histology

Ryu et al.,200918

Balloon catheter L1 7 days Allogenic and autogenicbone marrow-derivedcells; canine umbilicalcord blood; Wharton’s

jelly stem cells

1 � 106 cells 4 animals in each of thestem cell groups (16

animals total); 4 dogs incontrol group

Olby scoreSSEPsMRI

Histology

SSEP, somatosensory-evoked potential; MEP, motor evoked potentials; SCI, spinal cord injury; MRI, magnetic resonance imaging; BBB, Basso, Beattie, and Bresnahan; rhGCS, recombinanthuman granulocytic colony stimulating factor.

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LITERATURE REVIEW

BRANDON C. GABEL ET AL. A REVIEW OF STEM CELL THERAPY FOR CORD INJURY

LITERATURE REVIEW

BRANDON C. GABEL ET AL. A REVIEW OF STEM CELL THERAPY FOR CORD INJURY

studies using human embryonic cordblood cells and found improvement inTarlov scores and the Basso, Beattie, andBresnahan scores in the animals treatedwith stem cells. A third study by Leeet al12 using human-derived neural stemcells combined with Matrigel versusMatrigel alone showed significantly betterfunctional recovery in the animals whoreceived cells. Lim et al13 reportedimproved Olby scores and restoration ofsomatosensory-evoked potentials in ani-mals receiving canine umbilical cordblood compared with control groups. Parket al14,15 performed 2 studies using canineumbilical cord blood cells and adipose-derived stem cells. In each study,improved functional outcome, asmeasured by Olby, Tarlov, or Basso,Beattie, and Bresnahan scales, were higherin the stem cell groups compared withcontrol groups. Penha et al16 reportedsome improvement in bowel and bladderfunction, tail control, and pain responsesin some animals receiving autologousbone marrow-derived mesenchymal stemcells. In addition, another group showedimprovement in Olby scores,somatosensory-evoked potentials, andlocomotion in animals receiving stem celltherapy compared to control groups.17,19

Only 1 study12 of the 11, which usedolfactory epithelial cells, showed nofunctional improvements.Histopathologic and radiographic anal-

ysis in canine models has also beenencouraging. The study by Jung et al9

showed significantly fewer cavitationsand smaller injury areas as measured bymagnetic resonance imaging (MRI) indogs receiving either autogenous orallogenous bone marrow derived stemcells. In the series by Lee et al,7-9 controlanimals had increased cavitationcompared with the stem cell group. BothRyu and Lim’s cohort of dogs showedsignificantly higher areas of Luxol fastblue positivity in the stem cell groupscompared with control animals. In theLim et al study,13 the greatest area ofcavitation was seen in the sham group(no injection of any kind), and in theRyu et al studies,17,18 lesion sizes weresmaller and more nerve regeneration wasseen in stem cell-treated animalscompared with controls. Fibrosis washigher in control animals compared withthose receiving canine-derived umbilical

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cord blood cells.14,15 In addition, animalswho received Matrigel and stem cellsshowed decreased fibrosis, improvedneuronal markers, decreased expression ofinflammation and astrogliosis, as well asincreased neurotrophic factors comparedwith control animals.14,15

Although these studies are encouraging,it remains difficult to draw strong con-clusions for several reasons. First, thenumber of animals is relatively small ineach study. In addition, the cell types varyfrom study to study, which makes com-parison of the best cell type difficult. Only2 studies used “natural” cord injuries.7,16

One of these studies showed no differ-ence in functional outcome comparedwith control groups, but they also usedolfactory epithelial cells.12 The secondstudy had a small cohort of dogs and didnot include a control group, making theresults difficult to interpret.16 Most of theremaining models used a ballooncompression model of injury, whichalthough it creates a reproducible injury,it may not reliably reproduce naturalinjuries (i.e., falls, motor vehicleaccidents) seen in humans.

Sub-Human Primate StudiesThere are not as many studies that haveevaluated stem cell therapy for spinal cordinjury in sub-human primates because ofthe high cost associated with caring forthese animals.20 Sub-human primatestudies are important because unlike manyother small animal models, sub-humanprimates have spinal cord tracts that aremore similar to humans. Our review of theliterature returned 3 articles that met in-clusion criteria (Table 2). Similar to thecanine studies, the type of injury, time ofstem cell injection, and type of cells usedvaried.Like the canine studies, the primate

studies showed positive outcomes associ-ated with stem cell use. Using adultmonkey neural stem cells, Nemati et al21

showed that sensory and motor functionimproved more rapidly compared withcontrols. In addition, control animalsonly showed perceptible jointmovements, whereas the stem cell-injected animals showed active limbmovements. In line with this, the controlanimals developed bed sores and muscleatrophy, but the stem cell animals did not.Another study23 showed that stem cell-

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injected monkeys demonstrated improvedbar grip, spontaneous motor activity, andtreadmill tests compared with control an-imals. This same group of investigatorsalso demonstrated that human neuralstem cells modified with galectin-1showed even greater improvement inbehavioral scores compared with non-modified human neural stem cells. Thethird study22 we assessed was notdesigned to test the efficacy of stemcells, but did show a trend towardimproved hind limb function in stemcell-treated animals.Some of these studies also showed

interesting histopathologic correlates. Thestudy by Pritchard et al22 showed thatscaffold material was nearly fullyresorbed by 82 days after injury. Yamaneet al.23 showed that in stem cell-treatedanimals cavity areas were smaller onboth MRI and histologic analysis.Furthermore, myelin sheath and cortico-spinal fibers were increased in stem cell-treated animals compared with controlgroups. These two findings were furtherenhanced by cells modified to containgalectin-1. Galectin-1 containing cells thathad differentiated into neurons were alsoshown to have longer processes comparedwith unmodified stem cells.Similar to the canine studies, these

studies have shown improved outcomewith stem cell therapy. Interestingly, thedrop weight mechanism of injury used in 2of the 3 studies may better approximatetraumatic cord injuries in humans.

FUTURE DIRECTIONS IN HUMANS

The large animal studies have illustratedthat stem cell therapy has potential ther-apeutic benefit. The relationship of stemcell therapy to human cord injuries ispromising as well. Several studies haveshown beneficial effects in the treatmentof complete spinal cord injuries usingautologous bone marrow-derived mesen-chymal stem cells.3-5,24

The best way to deliver the cells is yet tobe determined. Several groups of in-vestigators have used direct injectionmodels, similar to the animal studiesdiscussed.3,5 Others have used intrathecallumbar injections of stem cells.4 Anotherstudy used intra-arterial and intravenousroutes of stem cell delivery.24 Both modelshave been validated as safe and effective at

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Table 2. Sub-human Primate Studies of Spinal Cord Injury

AuthorInjuryModel

Level ofInjury

Length of Time fromInjury to Injection Stem Cell Source

Stem CellDosage Number of Animals Studied

OutcomeMetricsStudied

Nemati et al.,201421

Drop weight T9-T10 10 days Adult monkey neural stem cells 1 � 106

cells/kg4 in stem cell group; 2 in control

groupSpontaneousmotor activityTarlov’s scaleTail movementsStimulatorymotor activity

Pinch

Pritchardet al., 201022

Surgicalhemisection

T9-T10 At time of injury PLGA scaffold with embeddedneural stem cells

1 � 106

cells2 in stem cell group; 1 in scaffold

alone; 1 in control groupLocomotionHistology

Yamaneet al., 201023

Drop weight C5 9 days Human neural stem cells with andwithout galectin-1 modification

1 � 106

cells21 animals total; 7 animals injectedwith cells and no growth factor; 7animals injected with cells þ

growth factor; 7 animals served ascontrol

Spontaneousmovement

Bar grip strengthTreadmill test

MRIHistology

PLGA, polylactide-co-glycolide; MRI, magnetic resonance imaging.

LITERATURE REVIEW

BRANDON C. GABEL ET AL. A REVIEW OF STEM CELL THERAPY FOR CORD INJURY

improving sensory and motor function.Furthermore, the best type of cell has yetto be determined. The studies by Dai,3

Mendonca,5 and El-kheir4 and theircolleagues all used autologous bonemarrow-derived stem cells. At present, aphase 1 clinical trial using embryonic stemcells is underway. A case report25 showedthe development of a spinal cord massafter implantation of olfactory mucosalcells. Further studies assessing the safetyof different types of stem cells inhumans is necessary before conclusionscan be drawn.The best timing for stem cell therapy is

also relatively undefined. Most animal andhuman studies wait a specified period oftime before injecting cells. The acutelyinjured cord is a hostile environment tostem cells.6,7,20 However, as time pro-gresses the fibrosis and cystic changes thatoccur in the cord can also hinder the effectof stem cells injected in the subacute orchronic stage of cord injury. Furthermore,natural improvement in neurologicalfunction is often seen after cord injury andthe use of stem cells during this periodmay falsely show a benefit to cell therapythat may not actually be present. This isone reason why studies in humans havebeen done in chronically injured patientswith complete cord injuries based onAmerican Spinal Injury Associationscoring.3-5 Ultimately, further studies are

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needed to address the issue of optimaltiming for stem cell implantation.Comparative neuroanatomy may limit

some conclusions from the animalstudies. It is well known that rodents havedifferent cord anatomy compared withhumans and sub-human primates. How-ever, there are also anatomic differencesbetween humans and large animals. Forexample, ependymal regions in adulthuman spinal cords may differ from otherspecies, including sub-human primates.26

On the other hand, studies have shownmany similarities between the spinalcords of humans and primates.27 Overall,large animal studies remain the best wayto assess the safety of different cell types,delivery mechanisms, and outcomesbecause of relative similarity of spinalcord anatomy compared with humans.Advances in neuroimaging will also be

of paramount importance in the use ofstem cell therapy for spinal cord injuries.Although improvement in clinical condi-tion is the sine-qua-non of stem celltherapy, it is also important to understandthe mechanisms associated with stem cellin-growth and fiber connectivity. Onestudy28 showed that cells labeled withsuperparamagnetic iron oxidenanoparticles could be seen on MRI upto 7 months after intrathecal injectioninto the subarachnoid space. Advances indiffusion tensor imaging will also allow

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clinicians to better assess theradiographic effect that stem cells haveon cord injury.Modification of stem cells to further

improve outcome remains a fascinatingarea for future study. In the animalstudies, only one was identified that usedmodified cells. In that study23 galectin-1,which is a carbohydrate-binding proteinwith roles in cell growth and differentia-tion, was shown to improve outcomescompared with nonmodified stem cells.Whether or not modifications to cells willimprove human cord injury is an inter-esting and potentially powerful way tofurther improve outcomes.It is important to consider alternative

options other than stem cell therapies. Forexample, neural prosthetic devices havebecome a potential alternative to stem celltherapy.29,30 Gene therapy has alsoemerged as a possible method of restoringfunction. For example, there are manyneurotrophic factors that play a significantrole in spinal cord injury.31 Harnessing thepower of the genes that code for thesefactors will be paramount to ensuring thegrowth of functional neural tissue atinjured segments of the cord. It is mostlikely that stem cells, when combinedwith alternative therapies, such as neuralprosthetics and gene therapy, will resultin the best outcome for patients withcord injuries. Therapies that combine

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LITERATURE REVIEW

BRANDON C. GABEL ET AL. A REVIEW OF STEM CELL THERAPY FOR CORD INJURY

neurotrophic factors with stem cells willlikely improve tissue integration.However, the best combination of factorsand stem cells remains elusive at thistime and requires further research.Ethics play a vital role in the future of

stem cell therapy. Given the often devas-tating consequences of cord injury, pa-tients often fall prey to practitioners whoclaim to be able to help them with stemcell therapies. Many nonregulated stemcell “clinics” exist and frequently chargeexuberant amounts of money for stem cell“therapy.” Often times these clinics boastof false results, which provides patientsunfounded hope. Stem cell therapy, at thistime, should be considered experimentaluntil randomized controlled trials canprove clinical benefit.

CONCLUSIONS

Stem cell therapies for spinal cord injuryhave shown significant promise, but thescience remains in its infancy. Furtherstudies in humans and large animalsaddressing the best type of cell, optimaltiming for implantation, cellular modifi-cations, and functional outcomes willimprove our understanding of this up-and-coming treatment.

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Conflict of interest statement: The authors declare that thearticle content was composed in the absence of any

WORLD NEUROSURGERY 98: 438-443, F

commercial or financial relationships that could be construedas a potential conflict of interest.

Received 4 August 2016; accepted 10 November 2016

Citation: World Neurosurg. (2017) 98:438-443.http://dx.doi.org/10.1016/j.wneu.2016.11.053

EBRUARY 2017 ww

Journal homepage: www.WORLDNEUROSURGERY.org

Available online: www.sciencedirect.com

1878-8750/$ - see front matter ª 2016 Elsevier Inc. Allrights reserved.

w.WORLDNEUROSURGERY.org 443