alzheimers research e-journal issue 10 2012

7/30/2019 Alzheimers Research e-journal Issue 10 2012

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Stem Cells

The value of stem cells as a research tool in the study of neurodegenerativediseaseDr Emma Jones

Adult stem cells for stem cell therapies: progress and perspectivesStephanie Strohbueker

Stem cell research update: Report from a Stem Cell Research ForumDr Anne Corbett

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June 2010Issue 10alzheimers.org.uk/research

Alzheimers Society scientific journal with lay versions of every article

Research e-journal


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EditorialProfessor Clive Ballard,Academic Editor

There is fantastic appeal about the idea ofregenerating lost brain cells in order to treatdiseases such as Alzheimers disease and vasculardementia. Stem cell research has consistently beenvoted as the highest research priority by theAlzheimer Societys Quality Research in Dementiavolunteer network and basic stem cell research hasattracted substantial funding in the UK andinternationally.

The current edition reviews several key areas ofstem cell research. The critical questions to ask arewhether we have genuinely made significantprogress and whether we can begin to see theopportunities of a therapy emerging from thisresearch that is science fact not science fiction.

I believe that this offers genuine hope and not justhype, and that it is one of the most exciting areas ofcurrent research. We are now seeing amazingprogress in our scientific understanding of stem cellbiology and our ability to manipulate stem cells for

therapeutic purposes. For example we are now ableto guide the development of stem cells fromdifferent body systems and turn them into nervecells, to change fibroblast skin cells into nerve cellsand to grow neural stem cells in the laboratory thatare of sufficient quality to enable them to betransplanted into humans these are allphenomenal hallmarks of progress, and all achievedwithin the last 5 yeas! Perhaps most importantly,we are now seeing the beginning of realistictherapies that can be taken forward for people withdementia. We cant yet control the full

development of these cells into new nerve networks,and we dont always even understand why thetherapies appear to work, but they neverthelessprovide realistic therapeutic opportunities. I offersome further personal thoughts regarding stem celltreatments in one of the articles.

It is timely that the current edition of theAlzheimers Society e-journal provides an overview ofkey developments in this exciting area of research.

Each article in this e-journal is accompanied bya lay version which summarises the scientificversions without any technical language orneed for any previous scientific knowledge.

The lay versions are contributed by sciencewriter Caroline Bradley, to whom we are verygrateful for her expertise and hard work.

Quick-read summaries are also included toprovide the main points of each article.


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Stem cells are able to self-renew and differentiateinto a wide range of cell types. For example,neural stem cells (NSCs) have the capacity todevelop into neurons, as well as glial cells. Forsome time NSCs were thought to be only ofembryonic origin, but it is now known that adultNSCs also exist [1] and can go on to differentiate,providing a mechanism of neuroreplacementfollowing brain injury [2]. So far, the majority ofthis research has been carried out using animal

models, but there is also evidence of theseprocesses occurring in human neurodegenerativediseases, such as Alzheimers disease (AD) [3],dementia with Lewy bodies [4] and vasculardementia [5]. Much research has now focussed onthis regenerative potential as a therapeuticopportunity, but what else can these cells tell usabout the processes involved in neurogenesis andthe mechanisms occurring in degeneratingneurons? In this article, we discuss how these stemcells can be used as a research tool for theanalysis of neurodegenerative diseases.

Animal models have been invaluable for the studyof many human diseases, but the generation ofthese models can be difficult in some cases andthey might not fully model the human disease. Forexample, Downs syndrome (DS) is caused by anextra copy of chromosome 21. Mouse models ofDS are available, but there are some issues withtheir use for analysis of the development of classicDS characteristics, such as differences betweenthe genes triplicated in humans and those in themouse models. These problems can be managed

by producing a model using human DS cells, sothat all three copies of the triplicated genes arehuman in origin and all of the triplicated humanchromosome 21 genes are present. By applyingvarious growth factors to primary fetal tissue,neurospheres can be formed [6, 7]. Neurospheresare clusters of cells, containing stem and neuralprogenitor cells (NPCs). Progenitor cells have somecapacity for further differentiation but havealready progressed towards a particular celllineage. These neurospheres allow thedevelopment of neuronal tissue to be monitored,

rather than only examining primary neuronaltissue which has been taken at a particulardevelopmental time point. DS is characterised byaltered neuronal development, a predisposition todevelop Alzheimers disease (AD) and accelerated

aging, therefore neurospheres originating fromindividuals with DS can be used to examine any ofthese mechanisms.

For example, decreases in the proliferativefunctioning of stem cells have been found to beassociated with aging [8] and the acceleratedaging noted in DS does affect DS NSCs. Geneexpression changes seen in these cells includechanges in pathways associated with DNA repair,apoptosis, cell cycle and inflammation. In thisway, the generation of NSCs to analyse theimpact of chromosome 21 trisomy has alsoprovided a model to examine the aging of stemcells. In fact, such studies, using NSCs which all

have similar properties and are changing at thesame time, have allowed the detection ofexpression profiles associated with stem cell aging[9].

The amyloid precursor protein (APP) is processedinto beta-amyloid, the characteristic protein foundin the plaques which develop in the brains ofpeople with AD. Analysis of the impact upon APPprocessing upon human embryonic stem celldifferentiation into neural progenitor cells hasshown that amyloidogenic processing favours

human embryonic stem cell (hESC) proliferation,whilst non-amyloidogenic processing promotesNPC production. Thus the use of stem cellsprovides a clue as to the impact of dysfunctional

The value of stem cells as a research tool in thestudy of neurodegenerative diseaseDr Emma JonesWolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1ULCorrespondence: [email protected]

A rosette of neural progenitor cells(Image courtesy of Dr Antigioni Ekonumou,Kingsa College Liondon)


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APP processing upon neurogenesis in AD and DSbrain [10].

The effects of different forms of amyloid(monomeric, oligomeric, fibrillar) on NSCs havealso been studied [11], which allows theexamination of how these cells may respond inthe pathological environment. Similarly, the

effects of hypoxia upon NSC proliferation anddifferentiation have also been studied [12].Neuroreplacement is being progressed as atreatment for neurodegenerative conditions.Although stem cell therapies appear promising,the pathological environment present must beconsidered as this may prevent NSCdifferentiation and proliferation in the requiredlocations. NSCs at different development stagesmay already be committed to differentiate intoparticular types of neuron or glia, and further workon adult stem is required to examine their

capacity to replace the appropriate type of cell ina variety of neurodegenerative diseases. A studyof NSCs labelled with BrdU allows their trackinginto the locations where their progeny are finallyincorporated. Using this method the effects ofdrugs such as MS-818, which increase proliferationand differentiation, can be determined [13, 14].

Injection of hNSCs into rat brain has been shownto improve cognitive function [15] in agedanimals. As previously stated, the levels of beta-amyloid present in the AD brain may regulate

with the proliferation and differentiation of stemcells. In fact it appears that secreted APP favoursglial rather than neural differentiation, and thusthe environment of the AD brain may beunsuitable as a location for neuroreplacement,and may lead to gliosis. The APP gene is presenton chromosome 21, and therefore there is anextra copy in the genome of people with DS, andthis is thought to be responsible for thepredisposition to developing AD. Concurrent withthis is the finding that stem cells derived frompeople with DS are also more likely to develop into

glial cells than neurons [16]. These processessuggest that increases in APP in the AD brain mayinduce formation of glial cells, resulting in a lackof stem cells for neural replacement [14].

Sourcing neural stem cells can be a difficult task,but the recent development of inducedpluripotent stem (iPS) cell technology hasprovided a new resource of patient-derived stemcells which can be used to produce cells of neurallineages. This process uses a combination ofinducible genes to transform somatic cells (eg

fibroblasts) into stem cells, with the capacity todifferentiate into a different type of cell (egneuron). This method has already been tested onseveral disease cell lines, such as DS, Parkinsons

disease (PD), Huntington disease (HD) andmuscular dystrophy [17], importantly showingthat the genetic defects present in the somaticcells are passed into the iPS cells. Further workconcentrating on a patient with Amyotrophiclateral sclerosis (ALS), has shown that the relevantdefective cell type, ie motor neurons, can beproduced [18]; a crucial step in producing relevant

cells for analysis of genetic effects and targetingof new drugs. This method is particularly useful asit allows a range of cell lines to be generated frompatients with several different geneticabnormalities, it is not necessary that theunderlying genetic cause is known and it allowsfor the analysis of interactions between severaldifferent genotypes affecting disease risk.

iPS cells are an important development for theexamination of sporadic forms of disease, whichmay involve several different risk altering

polymorphisms, for example APOE in Alzheimersdisease [17]. Another advantage of this method isthat the starting somatic material, eg fibroblasts,are highly available when compared to thedifficulties involved in obtaining NSC post mortemsamples. For example, to treat one patient withPD, tissue from several human embryos is requiredto replace the loss of dopaminergic neurons. If thecorrect type of cells can be grown in adequatequantities in a laboratory, several practical andethical issues will be resolved. This may beparticularly important for developing drugs for

sporadic disease, as high-throughput screening ofthe impact of drugs upon specific patientpathologies can be compared between differentsporadic forms.

A hybrid cell line to analyse Huntingtons disease(HD) has recently been established, which hasboth neural and stem cell characteristics [18]. HDpatholog progressed alongside in vitro neuraldevelopment. This model will prove a useful toolfor pathological analysis and drug development.This provides an advantage over other cell lines

which develop pathology over a similar timecourse to that seen in HD patients. Thedevelopment of lines like this is important forneurodegenerative diseases, where peripheral celltypes do not show the same pathologies, and theproteins and aggregates present in the affectedneurons may not be processed in the samemanner in non-neuronal cells. The HD cell linedeveloped here does have the disadvantage ofbeing tetraploid and potentially unstable, and sowork must still continue on iPS cell linedevelopment which has the advantage of being

produced from readily accessible somatic cells.

Hybrid cell models of PD have also beendeveloped by fusing patient platelets with


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mitochondrial-DNA-free neuroblastoma lines. Thesehave provided a platform for therapeutic analyses,such as gene therapy, but the use of suchneuroblastoma lines influences the cell cycle, and soultimately this technology needs to be progressedto use NPCs, and patient brain mitochondrial DNA.Potentially, there could be differences between non-mitotic neuronal mitochondrial DNA and that in

cells which have been frequently replaced. This workis currently under development [19].

Research using NSCs has progressed at a fast rate,but there is still much further work needed beforethis field reaches its full potential, both in terms ofbasic research and therapeutic use. These two areasgo hand in hand, in that we need to use basicresearch to analyse how NSCs respond to differentgenetic, environmental and pathological factorsbefore we can optimise their efficiency as atreatment. The examples discussed in this article

show the broad range of directions that stem cellwork is following, and this field will be an excitingone to follow in the years to come.

References

[1] Palmer TD, Takahashi J, Gage FH. The adult rathippocampus contains primordial neural stemcells. Mol Cell Neurosci 1997;8:389-404.[2] Felling RJ, Levison SW. Enhanced neurogenesisfollowing stroke. J Neurosci Res 2003;73:277-83.[3] Jin K, Peel AL, Mao XO, Xie L, Cottrell BA,

Henshall DC, Greenberg DA. Increasedhippocampal neurogenesis in Alzheimer's disease.Proc Natl Acad Sci U S A 2004;101:343-7.[4] Ziabreva I, Ballard C, Johnson M, Larsen JP,McKeith I, Perry R, Aarsland D, Perry E. Loss ofMusashi1 in Lewy body dementia associated withcholinergic deficit. Neuropathol Appl Neurobiol2007;33:586-90.[5] Ekonomou A, Ballard CG, Pathmanaban ON,Perry RH, Perry EK, Kalaria RN, Minger SL.Increased neural progenitors in vasculardementia. Neurobiol Aging. 2010 Feb 4. Epub

ahead of print.[6] Svendsen CN, ter Borg MG, Armstrong RJ,Rosser AE, Chandran S, Ostenfeld T, Caldwell MA.Anew method for the rapid and long term growthof human neural precursor cells. J NeurosciMethods 1998;85:141-52.[7] Vescovi AL, Parati EA, Gritti A, Poulin P, FerrarioM, Wanke E, Frlichsthal-Schoeller P, Cova L,Arcellana-Panlilio M, Colombo A, Galli R. Isolationand cloning of multipotential stem cells from theembryonic human CNS and establishment oftransplantable human neural stem cell lines by

epigenetic stimulation. Exp Neurol 1999;156:71-83.[8] Molofsky AV, Slutsky SG, Joseph NM, He S,Pardal R, Krishnamurthy J, Sharpless NE, MorrisonSJ. Increasing p16INK4a expression decreasesforebrain progenitors and neurogenesis duringageing. Nature 2006;443:448-52.[9] Cairney CJ, Sanguinetti G, Ranghini E, ChantryAD, Nostro MC, Bhattacharyya A, Svendsen CN,Keith WN, Bellantuono I. A systems biologyapproach to Down syndrome: identification ofNotch/Wnt dysregulation in a model of stem cells

aging. Biochim Biophys Acta 2009;1792:353-63.[10] Porayette P, Gallego MJ, Kaltcheva MM,Bowen RL, Vadakkadath Meethal S, Atwood CS.Differential processing of amyloid-beta precursorprotein directs human embryonic stem cellproliferation and differentiation into neuronalprecursor cells. J Neurochem. J Biol Chem. 2009Aug 28;284(35):23806-17. Epub 2009 Jun 19.[11] Heo C, Chang KA, Choi HS, Kim HS, Kim S,Liew H, Kim JA, Yu E, Ma J, Suh YH. Effects of themonomeric, oligomeric, and fibrillar Abeta42peptides on the proliferation and differentiation

of adult neural stem cells from subventricularzone. 2007 Jul;102(2):493-500. Epub 2007 Apr 30.[12] Santilli G, Lamorte G, Carlessi L, Ferrari D,Rota Nodari L, Binda E, Delia D, Vescovi AL, DeFilippis L. Mild hypoxia enhances proliferation and

Quick-read summary

Stem cells can be used to develop realisticmodels of neurodegenarative diseases in thelab

Recreating conditions in the brain canimprove understanding of what is goingwrong in conditions like Parkinsons andAlzheimers disease.

Putting stem cells in different conditions inthe lab can help to reveal whether they willbenefit the brain if used directly as atreatment to repair damage.

A new technique, called iPS technology, hasenabled researchers to create a plentiful

supply of stem cells that contain valuablegenetic information about diseases.


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multipotency of human neural stem cells. PLoSOne. 2010 Jan 5;5(1):e8575.[13] Awaya A, Kobayashi H, Horikomi K, Tanaka S,Kabir AM, Yokoyama K, Ohno H, Kato K, Kitahara T,Tomino I, Isayama S, Nakamura S. Neurotropicpyrimidine heterocyclic compounds. I. The newlysynthesized pyrimidine compounds promoteneurite outgrowth of GOTO and neuro 2aneuroblastoma cell lines, and potentiate nervegrowth factor (NGF)-induced neurite sprouting ofPC 12 cells. Biol Pharm Bull 1993;16:248-53.[14] Sugaya K, Merchant S. How to approachAlzheimers disease therapy using stem celltechnologies. J Alzheimers Dis 2008;15:241-54.[15] Qu T, Brannen CL, Kim HM, Sugaya K. Humanneural stem cells improve cognitive function ofaged brain. Neuroreport 2001;12:1127-32.[16] Bahn S, Mimmack M, Ryan M, Caldwell MA,Jauniaux E, Starkey M, Svendsen CN, Emson P.Neuronal target genes of the neuron-restrictivesilencer factor in neurospheres derived from fetuseswith Down's syndrome: a gene expression study.Lancet 2002;359:310-5.[17] Park IH, Arora N, Huo H, Maherali N, Ahfeldt T,Shimamura A, Lensch MW, Cowan C, Hochedlinger

K, Daley GQ. Disease-specific induced pluripotentstem cells. Cell. 2008 Sep 5;134(5):877-86. Epub2008 Aug 7.[18] Dimos JT, Rodolfa KT, Niakan KK, WeisenthalLM, Mitsumoto H, Chung W, Croft GF, Saphier G,Leibel R, Goland R, Wichterle H, Henderson CE,Eggan K. Induced pluripotent stem cells generatedfrom patients with ALS can be differentiated intomotor neurons. Science 2008;321:1218-21.[19] Corder EH, Saunders AM, Strittmatter WJ,Schmechel DE, Gaskell PC, Small GW, Roses AD,Haines JL, Pericak-Vance MA.Gene dose ofapolipoprotein E type 4 allele and the risk ofAlzheimer's disease in late onset families. Science1993 13;261(:921-3.[20] Laowtammathron C, Cheng ECh, Cheng PH,Snyder BR, Yang SH, Johnson Z, Lorthongpanich C,Kuo HC, Parnpai R, Chan AW. Monkey hybrid stemcells develop cellular features of Huntington'sdisease. BMC Cell Biol 2010;11:12.[21] Trimmer PA, Bennett JP Jr. The cybrid model ofsporadic Parkinson's disease. Exp Neurol2009;218:320-5.

Alzheimers Society: Involving people inresearch

We work with the scientific community inpartnership with people affected by dementia, andcurrently invest over 6 million in dementiaresearch.

People with dementia and their carers make aunique and valuable contribution to our work. Theirknowledge and passion ensures our researchfunding is allocated to projects that address thereal needs and concerns of people with dementia

and their carers.

The Quality Research in Dementia (QRD) networkThis team of 180 carers, former carers and peoplewith dementia play an integral role in the researchprogramme. Their duties include:

setting our research priorities prioritising and commenting on grant

applications sitting on grant selection panels monitoring on-going projects funded by

Alzheimer's Society telling others about the results of research.

We are currently recruiting volunteers for the QRDNetwork. Anyone who is interested should contactus at [email protected]

Alzheimer's Society is dedicated to defeatingdementia through research into the cause,cure, care and prevention of dementia.


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Lay summary

Stem cells as a research tool

Most cells have specific roles, but stem cells aredifferent. They are basic cells with the capacity todevelop into more specialised cells as needed. Manyresearchers are investigating whether stem cells can be

used to repair the damage caused byneurodegenerative conditions such as Parkinsonsdisease and Alzheimers disease. However, stem cellscan also be helpful as a research tool. Using them tocreate laboratory models of the cells and conditions inour brains, particularly the processes involved in thegrowth and decline of nerve cells, can improveunderstanding of neurodegenerative conditions.

Exploring Downs syndrome

Developing a model of Downs syndrome from stem

cells has enabled researchers to investigate themechanisms underlying three characteristics of thiscondition: altered development of nerve cells, anincreased risk of developing Alzheimers disease andaccelerated ageing.

Researchers have created copies of neurons withDowns syndrome by stimulating stem cells taken fromsomeone with the condition. This model of thesyndrome has advantages over ones developed usingmice because it incorporates human rather than mousegenes. Also, because the developing cells are accessible

(rather than inside a mouse) they can provideinformation about processes at any point, rather thanonly at specific points of development.

We know that stem cells become fewer and less activeas we get older. Studying Downs syndrome neuralstem cells, which experience accelerated ageing, hasrevealed changes in how they repair their DNA,maintain themselves and deal with inflammation asthey age. Analysing them has provided generalconclusions about neural stem cell ageing, such aswhich changes are typical as they become older.

The right conditions

Sticky deposits or plaques of beta amyloid protein inthe brain are a defining characteristic of Alzheimersdisease. Research in the lab has shown that thepresence of beta amyloid reduces the ability of humanembryonic stem cells to develop into new brain cells.This is clearly a problem if stem cells are to offer hopeas a source of repair and treatment as there is littlepoint in putting new stem cells into a toxicenvironment. Researchers are now investigating the

effects that different forms of beta amyloid have onneural stem cells. They are also seeking to understandwhat happens to stem cells once they enter a brain

that has a neurodegenerative disease. Will theydevelop into the type of cell that is needed to helpcombat the condition? If so, will they end up at thecorrect place in the brain?

How and where stem cells develop and replicate can betracked using a chemical known as BrdU (short forBromodeoxyuridine). Researchers have also used thismethod to assess the success of drugs that stimulatestem cells.

Other research has revealed that introducing new stemcells into the brain could lead to an over production ofthe wrong type of brain cells. There is evidence thatintroducing neural stem cells could lead to theproduction of glial cells, a type of brain cell that acts as

a supportive structure for neurons, rather than the newneurons that a diseased brain needs.

A significant step

In the last few years researchers have developed atechnique that avoids some of the ethical issues (andscarce supply) associated with using stem cells derivedfrom embryos. Inducible pluripotent stem cells (iPS)technology involves inserting four specific genes intoan already specialised cell, such as a skin cell, andreprogramming it into an embryonic-like stem cell with

the capacity to become any type of cell in the body.

iPS technology can create a plentiful supply of stemcells that have the same genetic make-up as a patientwith a particular disease. It has been used to createmuch needed cell lines (cells that can be cultured in thelaboratory and used for research) containing thisvaluable genetic material from people with Downssyndrome, Parkinsons disease, Huntingtons diseaseand muscular dystrophy. US researchers have taken iPStechnology a step further and created actual copies ofdefective neurons from a person with ALS (a type of

motor neuron disease).

Work in progress

Researchers are working hard to develop accuratemodels of neurodegenerative diseases that can beproduced easily at a reasonable cost. As well asimproving understanding of the diseases, these modelswill bring down the cost and speed up the testing ofpotential new drug treatments for these conditions.Researchers use and understanding of neural stemcells is progressing at a good pace, but there is more

work to be done before this field reaches its fullpotential.


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Adult stem cells: a resource for therapy

Stem cell therapies aim to replace cells lost dueto injury or disease in order to restore sometissue function. This may be achieved bytransplanting cells into the injured site or bysystemic delivery through the vascular system.Another possible approach to replace lost cells

would be through the activation of endogenousprogenitor populations, which could migrate tothe site of injury, proliferate and integrate intothe existing tissue [1].

Both strategies are currently under investigationfor neurodegenerative diseases such asAlzheimers, Huntingtons and Parkinsonsdiseases, and for patients suffering from stroke.The prime candidates for such tissue repairapproaches are stem cells, which are defined bytheir ability to self-renew and their ability to give

rise to more than one differentiated cell type.Adult stem cells (ASC) can be found in manytissues of the postnatal organism such as thebrain, the liver, the skin and the bone marrow,where they contribute new cells to theirsurrounding tissue [2]. Brain-derived neural stemcells, are able to form neurons, astrocytes andoligodendrocytes in the brain [2]. Contrary tofully differentiated cells, stem cells areparticularly attractive for cell replacementstrategies as they retain the ability toproliferate, migrate, and replace lost cell types.

At present, two different types of adult stemcells, neural stem cells and mesenchymal stemcells, have been tested for transplantation intodifferent models of neurodegenerative disease.Both cell types are considered to have beneficialeffects after transplantation, and could exertneuroprotective and immunomodulatory effects.

Stem cells present in the brain: neural stemcells

The adult brain contains neural stem cells

(NSCs), which have been identified in thesubgranular zone of the hippocampus and thelining of the lateral ventricles [3]. Other regionsof the brain such as the cortex [4] or thecerebellum [5] have also been suggested to

harbour neural stem cells, but this is still underinvestigation. Neural progenitor cells from theventricular area have been shown to migrate alongthe rostral migratory stream towards the olfactorybulb, where they develop into mature neuronswhich integrate into the existing neural network[6]. Neural stem cells from the subgranular zone,on the other hand, show limited migratory

behaviour as they only migrate within thehippocampus from the subgranular zone into thedentate gyrus [6]. The functional significance ofadult neurogenesis in the olfactory bulb and thehippocampus is still the topic of ongoing research[7], but it is thought to be involved in learningprocesses [7, 8]. However, in both locations, mostof the newly developed neurons seem to die withinthe first four weeks [8]. This is also apparent afterbrain injury: the examination of human post-strokebrain has shown activation of endogenous NSCsup to 90 days after stroke, but this activation

doesnt seem to have any impact on thedevelopment of new neurons [9], suggesting thebrain is unable to fully repair itself after an injury.

Nevertheless, the activation of endogenousneuroprogenitor populations seems crucial forbrain function, as the inhibition of NSCproliferation in a model of cerebral corticalischemia worsens neurological deficits [10].Therefore, the role of endogenous stem cellactivation within the brain might be mainly toprotect the remaining tissue and prevent

secondary neuron loss through the production ofneurotrophic and neuroprotective factors, such asbrain derived neuronal factor (BDNF) and vascularendothelial growth factor (VEGF) [10].

To support endogenous stem cells and enhancerecovery after brain injury, NSC transplants havebeen performed in several animal models ofneurodegeneration. The administration of NSCsinto a primate model of Parkinson disease hasprovided behavioural improvements [11], probablythrough the production of neurotrophic factors

such as GDNF (glial cell derived neurotrophicfactor) since the number of cells which developedinto neurons was limited. In one model ofAlzheimers disease, the intra-hippocampaltransplantation of neural progenitors resulted inthe attenuation of inflammatory responses and

Adult stem cells for stem cell therapies: progressand perspectivesStephanie Strohbuecker, Dr Cristina Tufarelli and Dr Virginie Sottile *Wolfson Centre for Stem Cells, Tissue Engineering and Modelling, School of Clinical Sciences, Divisionof Human Development, University of Nottingham, CBS Building University Park, Nottingham NG7

2RD* Corresponding author email: [email protected]


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neuroprotection [12], while in another mousemodel of Alzheimers disease thetransplantation of NSCs was reported toimprove cognition mediated by the neurotrophicfactor BDNF [13]. Furthermore, the intravenousadministration of neural precursor cells threedays after the induction of a stroke lesionimproved the recovery through anti-

inflammatory effects, which led to decreasedglia-scar-formation and protection fromsecondary neuron loss [14]. The neurotrophicand immunomodulatory properties of NSCsmight play an important role in addition to thereplacement of lost cells for the beneficialeffects observed [1].

Stem cells in the bone marrow: mesenchymalstem cells

Another type of adult stem cells considered forcell therapy is the mesenchymal stem cell (MSC)population. MSCs, also called bone marrowstromal stem cells, reside in the stromal fractionof the bone marrow, where they contribute toskeletal homeostasis and provide support forhaematopoiesis [2, 15]. MSCs typically give riseto bone cells (osteoblasts), cartilage cells

(chondrocytes) and fat cells (adipocytes) [15],and they are already involved in tissueengineering approaches for bone and cartilagerepair [15]. MSCs represent a promising resourcefor future medical applications, since they arereadily accessible by aspiration and could beused for autologous transplants. In addition,they display low levels of majorhistocompatibility complex (MHC) moleculesand seem to suppress immune reactions [15].They are therefore considered to be immune-privileged.

Another recently described attracting feature ofMSCs is the occurrence of transdifferentiationevents, when MSCs form cells beyond their ownlineage such as cardiomyocytes, hepatocytes or

neuron-like cells [2, 15]. The possible potential ofMSCs to form neuron-like cells in vivo and in vitrohas recently raised the hope that MSCs may serveas a cell resource for neurodegenerative diseases[15]. However, this transdifferentiation ability isstill the subject of research, as some of theobservations reported were attributed to cellfusion [16] or the disruption of the cytoskeleton

[17]. Nevertheless, the injection of MSCs into sitesof neuronal loss appears overall beneficial [18, 19],and experiments carried out in animal modelssuggest that MSCs provide positive effects for therecovery of, for example, spinal cord lesions [15].When injected into the striatum of a Huntingtonsdisease mouse model, MSCs contributed to animprovement over the time course of 30 days afterinjection, even though the injected cells were notdetectable after 15 days post-injection [18]. Inanother example, naive MSCs applied to thestriatum of a rat Parkinson model enhanced the

proliferation and survival of endogenous cells,although their differentiation into neurogenic celltypes was not detectable [19].

These studies hint to the capacity of MSCs tocreate an improved microenvironment for theendogenous progenitor cells through theproduction of neurotrophic or growth factors [18,19]. In vitro experiments have furtherdemonstrated that MSCs can increase neuron andastrocyte formation, promote neurite outgrowth,and support long-term survival of neurons in

culture [20]. Irrespective of whether positiveeffects of MSCs are due to the secretion ofneuroprotective factors, the recruitment ofendogenous progenitor cells [2, 15] or bona fidetransdifferentiation events, this phenomenon isworth exploring further.

Stem cell-based therapies: future perspectives

Although stem cell transplantations carried out inanimal models have shown promising results, thereare still many hurdles to overcome before these

approaches can be translated into the clinic. Onemajor challenge is the development of a safemethod for the delivery of stem cells to the site ofinjury. In addition, the stage of differentiation ofthese cells needs careful consideration: grafts offully differentiated cells are associated with asmaller efficiency due to poor viability [1],however, undifferentiated cell types may present ahigher risk of undirected differentiation anduncontrolled proliferation. It is therefore likely thatdifferent types of neurodegenerative diseases maybenefit from using stem cells at diverse stages of

differentiation. In Parkinsons disease for instance,where a specific type of neuron is lost, pre-differentiated cells might be suitable. For diseasessuch as stroke or Alzheimers disease, where

Neural stem cells in culture(Image courtesy of Dr Virginie Sottile)


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different cell types are affected, immaturetransplants with the capacity to produce morethan one cell type may be needed to replace thelost tissue.

The microenvironment in which stem cells areplaced also needs consideration, as local soluble

factors are likely to affect differentiation eventsin the tissue [21]. Environmental factors need tobe included: accumulating evidence suggeststhat pro-inflammatory cytokines are associatedwith a negative effect on neural differentiation,while anti-inflammatory cytokines may have theopposite effect. The inflammatory status of thebrain and the possible activation ofinflammatory responses therefore need to beconsidered with cell replacement strategies [22].Developing our understanding of the processescontrolling the activation, migration and

differentiation of stem cells will therefore be acritical step towards harnessing the benefits ofstem cells for new regenerative therapies.

References[1] Burns, TC, Verfaillie, CM and Low, WC, Stem cells

for ischemic brain injury: a critical review. J CompNeurol, 2009. 515(1):125-44.

[2] Jackson, L, et al., Adult mesenchymal stem cells:differentiation potential and therapeuticapplications. J Postgrad Med, 2007. 53(2):121-7.

[3] Liu, YP, et al., The potential of neural stem cells torepair stroke-induced brain damage. ActaNeuropathol, 2009. 117(5):469-80.

[4] Gould, E, How widespread is adult neurogenesis in

mammals? Nat Rev Neurosci, 2007. 8(6):481-8.[5] Alcock, J, et al., Expression of Sox1, Sox2 and Sox9

is maintained in adult human cerebellar cortex.Neurosci Lett, 2009. 450(2):114-6.

[6] Cayre, M, Canoll, P and Goldman, JE, Cell

migration in the normal and pathological postnatalmammalian brain. Prog Neurobiol, 2009. 88(1):41-63.

[7] Whitman, MC and Greer, CA, Adult neurogenesisand the olfactory system. Prog Neurobiol, 2009. 89(2):162-75.

[8] Zhao, C, Deng, W, and Gage, FH, Mechanisms andfunctional implications of adult neurogenesis. Cell,2008. 132(4):645-60.

[9] Nakayama, D, et al., Injury-induced neural stem/progenitor cells in post-stroke human cerebralcortex. Eur J Neurosci, 2010. 31(1):90-8.

[10] Li, B, et al., Brain self-protection: The role ofendogenous neural progenitor cells in adult brainafter cerebral cortical ischemia. Brain Res. 1327:91-102.

[11] Redmond, DE Jr., et al., Behavioral improvement ina primate Parkinson's model is associated withmultiple homeostatic effects of human neural stemcells. Proc Natl Acad Sci U S A, 2007. 104(29):12175-80.

[12] Ryu, JK, et al., Neural progenitor cells attenuateinflammatory reactivity and neuronal loss in ananimal model of inflamed AD brain. JNeuroinflammation, 2009. 6:39.

[13] Blurton-Jones, M, et al., Neural stem cells improvecognition via BDNF in a transgenic model ofAlzheimer disease. Proc Natl Acad Sci U S A, 2009.106(32):13594-9.

[14] Bacigaluppi, M, et al., Delayed post-ischaemicneuroprotection following systemic neural stem celltransplantation involves multiple mechanisms.Brain, 2009. 132(Pt 8):2239-51.

[15] Kitada, M and Dezawa, M, Induction system of

neural and muscle lineage cells from bone marrowstromal cells; a new strategy for tissuereconstruction in degenerative diseases. HistolHistopathol, 2009. 24(5):631-42.

[16] Rodic, N, Rutenberg, MS, and Terada, N, Cell fusionand reprogramming: resolving our transdifferences.Trends Mol Med, 2004. 10(3):93-6.

[17] Croft, AP and Przyborski, SA, Formation of neuronsby non-neural adult stem cells: potentialmechanism implicates an artifact of growth inculture. Stem Cells, 2006. 24(8):1841-51.

[18] Snyder, BR, et al., Human multipotent stromal cells(MSCs) increase neurogenesis and decrease atrophy

of the striatum in a transgenic mouse model forHuntington's disease. PLoS One, 2010. 5(2):e9347.[19] Cova, L, et al., Multiple neurogenic and

neurorescue effects of human mesenchymal stemcell after transplantation in an experimental modelof Parkinson's disease. Brain Res, 2009. 1311:12-27.

[20] Croft, AP and Przyborski, SA, Mesenchymal stemcells expressing neural antigens instruct aneurogenic cell fate on neural stem cells. ExpNeurol, 2009. 216(2):329-41.

[21] Taupin, P, Adult neural stem cells, neurogenicniches, and cellular therapy. Stem Cell Rev, 2006. 2(3):213-9.

[22] Mathieu, P, et al., The more you have, the less youget: the functional role of inflammation onneuronal differentiation of endogenous andtransplanted neural stem cells in the adult brain. JNeurochem, 2010. 112:136885.

Quick-read summary Adult stem cells are versatile cells that

could be used to repair the damage in thebrain caused by neurodegenerativeconditions such as Parkinsons andAlzheimers disease.

We know that stem cells are active in thebrain and can help to protect cells,however they do not seem able togenerate large numbers of new cells.

Research into the possibility oftransplanting adult stem cells into thebrain is at an early stage.

More research is needed to identify thebest type of cell to transplant, how they

can be delivered to the point of damage


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Adult stem cells offer the tantalising possibility of anautomatic, self-repairing treatment for diseases causedby the damage and loss of neurons in the brain.

What do stem cells do?

Stem cells have the job of maintaining and repairingtissue. They are basic cells that can develop into morethan one type of specialised cell as needed. Forexample, the neural stem cells found in the brain areable to develop into any of the brains three major celltypes (astrocytes, oligodendrocytes and neurons). Stemcells can travel to replace lost cells and can also renewthemselves. Adults have stem cells in a number ofdifferent locations, including the brain, liver, skin andbone marrow. So, the question is, how close are we to

harnessing the abilities of these industrious cells?

Stem cells in the brain

We know that two areas of the adult brain containneural stem cells. Other sites within the brain are stillbeing investigated.

Neural stem cells that are based in the lateral ventriclesnear the centre of the brain migrate towards thebrains olfactory bulb (responsible for processinginformation about odours). Once there they mature

into neurons, which can become integrated into theexisting networks of the brain. The neural stem cellsbased in the hippocampus have more limited travelplans. They do move, but only from one zone of thehippocampus to another.

Both sets of stem cells are from areas of the braininvolved in learning processes, but the purpose ofeither of these cellular journeys remains unclear.Intriguingly, at both destinations, most of the newlydeveloped neurons seem to die within four weeks.

After a stroke, we know that stem cells can be activefor up to 90 days, but they dont develop into newneurons. Research shows that preventing stem cellsfrom being active, even if they dont become neurons,increases damage to the brain. Scientists believe thatactive stem cells protect the remaining tissue byproducing proteins called growth factors and othernurturing chemicals.

Transplanting adult stem cells

As the stem cells in the brain appear unable to repair

serious damage, one answer is to use transplants todirectly boost their numbers. Researchers have usedanimal models to explore the effects of transplantingneural stem cells into brains with a neurodegenerative

disease. Such transplants have reduced the symptomsof Parkinsons and Alzheimers disease as well asstroke. The evidence suggests that such transplants canbenefit damaged brains by reducing inflammation and

producing chemicals that nurture other cells, as well asby replacing lost cells.

Mesenchymal stem cells are found in our bone marrow.They usually produce bone, cartilage and fat cells,however recent research has shown that they can alsoproduce neuron-like cells. Bone marrow could prove tobe a useful source of cells suitable for transplantationinto the brain as the cells are easy to get at and haveparticular qualities that make them unlikely to provokea reaction from the immune system. Research hasfound that mesenchymal stem cells can help to repair

damage and boost the growth and survival of neurons.The exact mechanisms behind this are not yetunderstood, but it seems wise to continue exploring thepossibilities that these cells offer.

Stem cell therapies: the future

Research into transplanting stem cells is at a basicstage. Some progress has been made, however thereare many hurdles to overcome such as:

identifying the best way to safely deliver new

cells to the site of injury establishing at which point in their

development it is best to transplant cells

understanding the conditions in the braininto which the cells are being transplanted.

We know that transplanting fully developed stem cellstends to be less successful, but the risk withundeveloped cells is that there is no guarantee of themturning into the amount or type of cells needed. Thesolution is likely to be dictated by the type of damage

being addressed. For example, developed cells wouldwork best for Parkinsons disease, which is caused bythe loss of a specific neuron. On the other hand,conditions caused by more general damage, such asstroke or Alzheimers disease, might be better servedby transplants of more immature cells.

Researchers need to gain a clearer understanding ofthe brain chemicals that will affect newly transplantedstem cells. We know inflammation tends to reduce thedevelopment of neural cells, while suppression ofinflammation has the opposite effect. In summary, the

task for research is to establish clarity about theprocesses that control or influence the activation,movement and development of stem cells.

Lay summary

Stem cells as a therapeutic tool


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Stem cell research update: Report from a StemCell Research Forum, Kings College LondonDr Anne CorbettAlzheimers Society Research, Devon House, 58 St Katharines Way, London E1W 1JXCorrespondence: [email protected]

Stem cells are one of the most cutting-edgefields in medical research today. The potentialfor medical and research applications based onstem cell technology has fuelled significantinterest and investment. The past two decadeshave brought great advances in ourunderstanding of stem cell function and in thedevelopment of new tools for working withthem. Dementia and other neurodegenerativediseases are just one area of medicine thatcould benefit from stem cell research in the

future. The Biomedical Research Centre atKings College London houses a leading stemcell research facility. The Centre recently hosteda Stem Cell Research Forum to present theresearch that is currently underway.

Promising developments with neural stemcells

Most directly relevant to dementia research isthe centres work into neural stem cells (NSC).NSC found in the hippocampus and

subventricular zone lining the lateral ventriclesof the brain can differentiate into neurons andglia, presenting the possibility of a treatmentbased on stimulating these cells to replacedamaged nerve cells. Tools for producingimmortalised NSC are now available, allowingresearchers to control the expansion of the cellpopulation. This advance has enabled in vitroresearch, which was previously problematic as itis difficult to gather stem cells in large enoughnumbers for analysis. NSC lines are nowavailable for various regions of the brain

including the cerebellum, cortex and spinal cord,and could form the basis of a therapy in thefuture. Introduction of a human cortical line intoanimal models of stroke has been shown tostimulate endogenous neurogenesis, leading toimprovements in behavioural symptoms. Aclinical trial of the use of human cortical gradestem cells as a potential therapy for stroke hasbeen approved by the Medicines and Healthcareproducts Regulations Agency (MHRA), withpreliminary findings expected within the nexttwo years. This approach appears promising and

early stage research is now investigatingwhether NSC could also be stimulated toactually rebuild damaged brain tissue.

The various human NSC lines have taken longerthan anticipated to develop because ofunforeseen challenges in working with them. NSCusually lose their positional specification when putinto culture, thus losing their fate determinationfunction. This has been a focus of recentsuccessful research which has developed a spinalcord line that differentiates into all types ofneurones. The cells show a normal karyotype andhave retained the ability to form neurospheres, arecognised key activity of NSC. In vitro analysis of

these cells reveals that they are responsive tomorphogens that dictate the fate of NSC in thespinal cord. This is determined by position in thespinal cord that translates to a gradient inmorphogens such as Sonic hedgehog (SHH).Activation of genetic domains equivalent to thisresponse can be used to track the fate of theprogenitor cells in vitro, revealing distinctpopulations of progenitor cells. This technique isnow being applied to animal models of spinal cordinjury. The research is still in the very early stagesbut has already shown that the NSC survive and

propagate within the models, and migrate to thelocation of injury. Initial analysis indicates thatthe cells differentiate and result in improvementsin behaviour of the animals. It is too early to sayhow treatment with NSC results in this outcomebut this research is a proof of concept that couldbe applied to treatment of spinal cord, or evenbrain, injury in the future.

There are many other applications for NSC lines inresearch. They are particularly valuable for thediscovery and development of drugs which could

direct stem cells to differentiate into neurons. DrSandrine Thuret is working with one of these celllines to model depression, whilst other groups areinvestigating the action of neuroleptics andemploying genetic manipulation to mimic mentaldisorders. Research into the epigenetics of stemcells is also ongoing.

Screening and stem cell lines

The Assisted Conception Unit at Kings Collegespecialises in the derivation of therapeutic grade

human embryonic stem cells (hESC). The unitprovides preimplantation diagnosis of geneticdiseases, a process that involves the removal ofinner cell mass from embryos at the eight cell


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stage for extraction and analysis of geneticmaterial. The unit is currently able to detectgenetic mutations linked to forty diseasesincluding cystic fibrosis, Huntingtons diseaseand breast cancer, and can also develop stemcell lines for research into these conditions. Anumber of research groups are now using thesecell lines, for example to investigate derivation

of keratinocytes for dermatological research andfunctional insulin secreting beta-cells as apotential treatment for diabetes. Research isalso focused on improving hESC culturetechniques and the unit has updated their cellculture processes, replacing all animal-derivedsupplements, such as complement and serum,with alternatives.

There is potential relevance to dementiaresearch in this work since a number of geneticmutations are linked to Alzheimers disease.

Recognised mutations in the genes encodingamyloid precursor protein (APP) and presenilins(PSEN-1 and PSEN-2) carry a high risk of early-onset Alzheimers and could in theory bedetected in an embryo. The most highlycharacterised genetic risk factor for late-onsetAlzheimers disease is the ApoE4 allele. ApoE4 isextremely unlikely to be a suitable candidate forpre-implantation screening since it carries onlyan increased risk of Alzheimers disease ratherthan an absolute one. However, a cell linecarrying this mutation would greatly facilitate

research into the biology of Alzheimers disease.Cell lines carrying the APP and P-SEN mutationswould be similarly valuable to research intoearly-onset Alzheimers. As yet no such cell linesare available at Kings but the technology existsand the research group intend to continueextending their library of detectable conditions.

Patching up the vascular system

Differentiation of stem cells into the vascularlineage has great potential for medical

applications that could translate to dementia.Vascular dementia is caused by damage as aresult of interruptions in the blood supply to thebrain, which in turn is frequently linked tovascular disease. Treatment for vascular diseasefrequently involves angioplasty procedures thatstrip the endothelium from blood vessels, whicheventually become atherosclerotic over time.Research is therefore ongoing to develop a stemcell therapy that would replace the lost smoothmuscle cells and endothelial cells. Findings haveshown that stem cells subjected to flow shear

differentiate into the vascular lineage, and thesignalling pathways responsible are now beingdissected. This process has been attempted in

animal models where damaged vessels becomepositive for endothelial and smooth muscle cellmarkers following introduction of stem cells. Thistechnology is employing the inducible pluripotentstem cell (iPS) technique to produce cell lines thatcould be the basis for therapeutic vascular tissueengineering technology in the future.

Stem cells for new teeth and bones

Mesenchymal stem cells (MSC) are found in bothbone marrow and the pulp inside mammalianteeth. They differentiate into odontoblasts andameloblasts that create enamel and dentinerespectively, and osteoblasts which produce bone.Osteoclasts, the agonist of osteroblasts, areproduced from heamatopoetic stem cells (HSC).iPS technology has been exploited to produce cellsthat differentiate into these important cells andresearch is underway to fully understand how they

function and to develop treatments for bonedisorders and to repair damage to teeth. Althoughthis research is not immediately relevant todementia, it has contributed important advancesin technologies for cell culture and manipulationthat can be used across the entire range of stemcell research.

The sociology of stem cells

The majority of researchers in the stem cell fieldhave a background of biology and medicine.

However, there is a group of researchers based atthe Centre for Biomedicine and Society that takea very different angle on stem cells. The SocialScience Stem Cell Initiative investigates the ethicsand social implications of stem cell research,including the processes, practice and implicationsof the research. Their work involves collaboratingwith specialist units, interviewing staff, scientistsand stakeholders, attending steering meetingsand visiting laboratories. They focus ontranslational research and ask questions of thesocial responsibility of stem cell research. For

example, do research institutes raise expectationsof stem cell research too high? Do scientistspresent realistic time frames for their research tothe public? How has this influenced investment instem cell research and the resultinginfrastructure? Is the supposed linear route oftranslational research unrealistic ormisrepresentative? These are questions thatbiomedical researchers are unlikely to haveencountered, and reveal the significant gapbetween medical research and social sciences.Bridging the gap between these two worlds is no

easy task but this appears to be an importantissue to raise in a world where science isincreasingly becoming a public and policy issue.


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We heard a series of great presentations of

exciting, cutting-edge research, right at theforefront of new development. After severalpresentations however, once Id overcome thewonderment of the science, a nagging doubtcame into my mind Are we pursuing sciencefor its own sake and ignoring the pragmatismwhich may lead us more swiftly to newtherapies?

This question emerged in my mind after severalpresentations highlighting that clear benefitswere evident in post-stroke rodents and in

rodents with spinal cord injury after treatmentwith neural stem cells. This occurred despiteseveral fascinating observations in the strokeanimals the stem cells didnt actually survivevery well and in the animals with spinal injurythere was no evidence that the neural stem cellshad integrated with other neurons or innervatedmuscle cells. Whilst the focus of thepresentations addressed how we can betterenable stem cells to develop into the right typeof neurons, survive better and integrate betterwith existing neuronal networks, I couldnt help

feeling that this missed the point. The keyquestion in my mind Why was the therapyworking? And, if it is effective, does the whyreally matter?

Many therapies in medicine, especially inpsychiatry, have been discovered by accident.

Antidepressants, for example, were discovered

when it was observed that people being treatedfor tuberculosis were less depressed than wouldhave been expected! Does it really matter if atherapy works for a reason other than thatwhich we initially hypothesised? It may be thattreatment with stem cells promotes the activityof the stem cells already in the brain, promotesother growth factors that enhance regenerationor may even reduce inflammation. If this typeof therapeutic approach works for one of thesereasons, it may be possible to offer effectivetherapies that are far less invasive, as it may not

even be necessary to introduce stem cells intothe brain.

Neural stem cells of sufficient quality to use fortreating people in clinical trials are nowavailable, and one or two very small preliminaryclinical trials are underway. Given the promisingresults of the animal work I would like to seemore focus on clinical trials of these treatmentsin man, with a pragmatic approach to resolvingkey scientific dilemmas such as why the therapyis effective.

In the final session we heard a social scienceperspective, which explained the differences inculture and views between basic scientists andclinicians. My views are clearly very typical ofthose held by clinicians and so I am leftreflecting on whether Im right or whether I am

Quick-read summary Researchers at KCL have overcome technical of growing neural stem cells for different regions of

the brain.

After positive results from animal models, results from using human cortical neural stem cells torepair the brains of people who have had a stroke are expected in the next two years.

Research into using stem cells to improve the health of arteries and thus improve blood flow tothe brain and prevent vascular dementia is positive, although at an early stage.

Researchers are investigating the ethical and social impact of stem cell research as well as the

biological possibilities.

Am I right or am I a stereotype?Professor Clive BallardDirector of Research, Alzheimers Society


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Stem cell research is a fast-moving area. Researchgenerally focuses on improving understanding of how

stem cells function and how we can use them torepair damage or prevent disease. Because stem cellscan grow into nerve cells they offer the potential torepair brain damage caused by neurologicalconditions, such as dementia

Neural stem cellsTwo areas of the adult brain contain neural stem cells.Cells from both of these sites can develop intoneurons and glial cells (a type of brain cell that acts asa supportive structure for neurons).

Investigations into whether neural stem cells can bestimulated to replace damaged nerve cells have beenhampered by the difficulty of producing the amountof stem cells in the lab needed to enable properanalysis. A process called immortalisation, whichenables cells to grow and divide indefinitely, hasresolved this problem.

Researchers have been able to continuously growneural stem cells in the lab for various regions of thebrain, including the cerebellum, cortex and spinalcord. These established cell lines could form the basis

of a therapy in the future.

Research has shown that inserting human corticalneural stem cells into the brains of animals that havehad a stroke can stimulate the development of newneurons and improve the symptoms of stroke. Thismethod is now being tested on people who have hada stroke and results are expected within two years.

In general, getting lab-grown human neural stem cellsto retain their characteristics has proved a difficulttask. However, the team at KCL have developed a line

of human spinal cord neural stem cells that candevelop into all types of neurons, have normalchromosomes and behave normally when introducedinto animal models.

Research is still at a very early stage, but results fromintroducing these cells into animals with spinal cordinjury have been good with signs of new cells beinggenerated and improvements in symptoms.

Researchers at KCL are working with human neuralstem cell lines in a number of different ways including

researching depression, the effects of tranquillisers onthe nervous system and manipulating genes withincells to mimic mental disorders to improveunderstanding of them.

Screening and stem cell linesResearchers at KCL have access to stem cell lines derived

from embryos with genetic conditions such as cysticfibrosis and Huntingdons disease. This is enablingvaluable research into potential treatments for a widerange of conditions.

There are a number of genetic mutations linked toAlzheimers disease. Mutations in three genes carry ahigh risk of early-onset Alzheimers disease and theApoE4 variation of the Apolipoprotein gene is anestablished genetic risk factor for late onset Alzheimersdisease. As yet there are no cell lines that contain thesemutations available at KCL, but the technology exists to

create them. Developing such cell lines would offersignificant opportunities to improve understanding of thebiology of Alzheimers disease.

Patching up the vascular systemVascular dementia is caused by problems in the supply ofblood to the brain. It is often linked to vascular diseasesuch as the hardening and narrowing of blood vessels(arteries).

Current treatments include widening the arteries(angioplasty) and stripping away the thickened lining,

however this is only ever a temporary fix. Stem cellresearch offers the prospect of being able to engineertissue on the spot as a treatment for vascular problems.

We know that stem cells can develop into vascular cells.Research using animal models has shown positive signsthat damaged blood vessels may be able to develop newlinings and elasticity after stem cells have beenintroduced. Researchers are currently developing stem celllines that could be used for re-engineering vascular tissuein this way.

Teeth and bones side benefitsSpecific stem cells found inside bone marrow and teethhave the job of producing cells to repair bones and teeth.Researchers are investigating how these processes can becontrolled to develop treatments for bone and teethdiseases. Improving understanding of how to manipulatestem cells in this way could identify techniques that couldprove useful in dementia research.

The sociology of stem cellsMost stem cell research is biological or medical, howeverat Kings College London the Social Science Stem Cell

Initiative investigates the ethical and social impact ofstem cell research, including how the research is carriedout, whether it is being done in a socially responsiblemanner and what impact the results will have on our lives.

Lay summary

An overview of the stem cell research currentlyunderway at Kings College London (KCL)


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Contacts

Academic Editor / Director of ResearchProfessor Clive Ballard

Head of ResearchDr Susanne SorensenT 020 7423 3600

Commissioning Editor / ResearchCommunications OfficerDr Anne CorbettT 020 7423 3609E [email protected]

Scientific Liaison OfficerDr James PickettT 020 7423 3607E [email protected]

Executive Administrative OfficerMatt MurrayT 020 7423 3603E [email protected]

General [email protected]

Research funding [email protected]

Websitealzheimers.org.uk/research

[email protected] alzheimers.org.uk/research

Registered charity no. 296645. A company limited by guarantee and registered in England no. 2115499.

Call for Proposals

Scientists, clinicians and healthcareprofessionals can now apply for our researchgrants into the cause, cure, care andprevention of all types of dementia.

Research fellowshipsClosing date: 29 October 2010

Dissemination grants

Closing date: 26 November 2010

Full details available at alzheimers.org.uk/research

Or contact us [email protected]

alzheimers research e-journal issue 10 2012

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