Mesenchymal stem cells (MSCs) have gained considerable interest due to their potential use in cell therapies and tissue engineering. They have been reported to differentiate into various anchorage-dependent cell types, including bone, cartilage, and tendon. Our focus is on the differentiation of MSCs into neuron-like cells through the use of soluble chemical stimuli or specific growth factor supplements. The resulting cells appear to adopt neural phenotypes and express some typical neuronal markers, however, their electrophysiological properties and synaptic function remains unclear.
Results:
This mini-review illustrates how particular characteristics, electrophysiological properties, and synaptic functions of MSCs change during their neuronal differentiation. In particular we focus on changes in ion currents, ion channels, synaptic communication, and neurotransmitter release. We also highlight conflicting results, caused by inconsistencies in the experimental conditions used and in the methodologies adopted.
Conclusions:
We conclude that there is insufficient data and that further, carefully controlled investigations are required in order to ascertain whether MSC-derived neuron-like cells can exhibit the necessary neuronal functions to become clinically relevant for use in neural repairs.
Wislet-GendebienS., WautierF., LeprinceP., RogisterB.. Astrocytic and neuronal fate of mesenchymal stem cells expressing nestin.Brain Res Bull.2005; 68(1-2): 95–102. Medline. doi: 10.1016/j.brainresbull.2005.08.016
2.
YuJ.M., JunE.S., BaeY.C., JungJ.S.. Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo.Stem Cells Dev.2008; 17: 463–473. Medline. doi: 10.1089/scd.2007.0181
3.
BaeJ.S., HanH.S., YounD.H.Bone marrow-derived mesenchymal stem cells promote neuronal networks with functional synaptic transmission after transplantation into mice with neurodegeneration.Stem Cells.2007; 25: 1307–1316. Medline. doi: 10.1634/stemcells.2006-0561
4.
ChoT., BaeJ.H., ChoiH.B.. Human neural stem cells: electrophysiological properties of voltage-gated ion channels.Neuroreport.2002; 13(11): 1447–1452. Medline. doi: 10.1097/00001756-200208070-00020
5.
ParkK.S., JungK.H., KimS.H.Functional expression of ion channels in mesenchymal stem cells derived from umbilical cord vein.Stem Cells.2007; 25(8): 2044–2052. Medline. doi: 10.1634/stemcells.2006-0735
6.
BiancoP., RiminucciM., GronthosS., RobeyP.G.. Bone marrow stromal stem cells: nature, biology, and potential applications.Stem Cells.2001; 19(3): 180–192. Medline. doi: 10.1634/stemcells.19-3-180
7.
KopenG.C., ProckopD.J., PhinneyD.G.. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains.Proc Natl Acad Sci USA.1999; 96(19): 10711–10716. Medline. doi: 10.1073/pnas.96.19.10711
8.
LiY., ChenJ., ChoppM.. Adult bone marrow transplantation after stroke in adultrats.Cell Transplant.2001; 10(1): 31–40.
9.
BrazeltonT.R., RossiF.M., KeshetG.I.From marrow to brain: expression of neuronal phenotypes in adult mice.Science.2000; 290(5497): 1775–1779. Medline. doi: 10.1126/science.290.5497.1775
10.
ChoK.J., TrzaskaK.A., GrecoS.J.Neurons derived from human mesenchymal stem cells show synaptic transmission and can be induced to produce the neurotransmitter substance P by interleukin-1 alpha.Stem Cells.2005; 23(3): 383–391. Medline. doi: 10.1634/stemcells.2004-0251
11.
WoodburyD., SchwarzE.J., ProckopD.J., BlackI.B.. Adult rat and human bone marrow stromal cells differentiate into neurons.J Neurosci Res.2000; 61(4): 364–370. Medline. doi: 10.1002/1097-4547(20000815)61: 4<364:: AID-JNR2>3.0.CO;2-C
12.
Sanchez-RamosJ., SongS., Cardozo-PelaezF.Adult bone marrow stromal cells differentiate into neural cells in vitro.Exp Neurol.2000; 164(2): 247–256. Medline. doi: 10.1006/exnr.2000.7389
13.
DengW., ObrockaM., FischerI., ProckopD.J.. In vitro differentiation of human marrow stromal cells into early progenitors of neural cells by conditions that increase intracellular cyclic AMP.Biochem Biophys Res Commun.2001; 282(1): 148–152. Medline. doi: 10.1006/bbrc.2001.4570
14.
MareschiK., NovaraM., RustichelliD.Neural differentiation of human mesenchymal stem cells: Evidence for expression of neural markers and eag K+ channel types.Exp Hematol.2006; 34(11): 1563–1572. Medline. doi: 10.1016/j.exphem.2006.06.020
15.
EglitisM.A., MezeyE.. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice.Proc Natl Acad Sci USA.1997; 94(8): 4080–4085. Medline. doi: 10.1073/pnas.94.8.4080
16.
LiY., ChenJ., WangL., LuM., ChoppM.. Treatment of stroke in rat with intracarotid administration of marrow stromal cells.Neurology.2001; 56(12): 1666–1672.
17.
MahmoodA., LuD., LiY., ChenJ.L., ChoppM.. Intracranial bone marrow transplantation after traumatic brain injury improving functional outcome in adult rats.J Neurosurg.2001; 94(4): 589–595. Medline. doi: 10.3171/jns.2001.94.4.0589
18.
NakanoK., MigitaM., MochizukiH., ShimadaT.. Differentiation of transplanted bone marrow cells in the adult mouse brain.Transplantation.2001; 71(12): 1735–1740. Medline. doi: 10.1097/00007890-200106270-00006
19.
ZhaoL.R., DuanW.M., ReyesM., KeeneC.D., VerfaillieC.M., LowW.C.. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats.Exp Neurol.2002; 174(1): 11–20. Medline. doi: 10.1006/exnr.2001.7853
20.
HofstetterC.P., SchwarzE.J., HessD.Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery.Proc Natl Acad Sci USA.2002; 99(4): 2199–2204. Medline. doi: 10.1073/pnas.042678299
21.
CampagnoliC., RobertsI.A., KumarS., BennettP.R., BellantuonoI., FiskN.M.. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow.Blood.2001; 98(8): 2396–2402. Medline. doi: 10.1182/blood.V98.8.2396
22.
ZukP.A., ZhuM., AshjianP.Human adipose tissue is a source of multipotent stem cells.Mol Biol Cell.2002; 13(12): 4279–4295. Medline. doi: 10.1091/mbc.E02-02-0105
23.
EricesA., CongetP., MinguellJ.J.. Mesenchymal progenitor cells in human umbilical cord blood.Br J Haematol.2000; 109(1): 234–242. doi: 10.1046/j.1365-2141.2000.01986.x
24.
TondreauT., MeulemanN., DelforgeA.Mesenchymal stem cells derived from CD133-positive cells in mobilized peripheral blood and cord blood: proliferation, Oct4 expression, and plasticity.Stem Cells.2005; 23(8): 1105–1112. Medline. doi: 10.1634/stemcells.2004-0330
PittengerM.F., MackayA.M., BeckS.C.Multilineage potential of adult human mesenchymal stem cells.Science.1999; 284(5411): 143–147. Medline. doi: 10.1126/science.284.5411.143
27.
SimmonsP.J., Torok-StorbB.. Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1.Blood.1991; 78(1): 55–62.
28.
GronthosS., ZannettinoA.C., HayS.J.Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow.J Cell Sci.2003; 116(Pt 9): 1827–1835. Medline. doi: 10.1242/jcs.00369
29.
MartinezC., HofmannT.J., MarinoR., DominiciM., HorwitzE.M.. Human bone marrow mesenchymal stromal cells express the neural ganglioside GD2: a novel surface marker for the identification of MSCs.Blood.2007; 109(10): 4245–4248.
30.
SacchettiB., FunariA., MichienziS.Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment.Cell.2007; 131(2): 324–326. Medline. doi: 10.1016/j.cell.2007.08.025
31.
ShiS., GronthosS.. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp.J Bone Miner Res.2003; 18(4): 696–704. Medline. doi: 10.1359/jbmr.2003.18.4.696
32.
HaynesworthS.E., BaberM.A., CaplanA.I.. Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies.Bone.1992; 13(1): 69–80. Medline. doi: 10.1016/8756-3282(92)90363-2
33.
SordiV., MalosioM.L., MarchesiF.Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets.Blood.2005; 106(2): 419–427. Medline. doi: 10.1182/blood-2004-09-3507
34.
BruderS.P., KurthA.A., SheaM.Bone regeneration by implantation of purified, culture-expanded human mesenchymal stem cells.J Orthop Res.1998; 16(2): 155–162. Medline. doi: 10.1002/jor.1100160202
35.
HorwitzE.M., ProckopD.J., FitzpatrickL.A.Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta.Nat Med.1999; 5(3): 309–313. Medline. doi: 10.1038/6529
36.
KogaH., ShimayaM., MunetaT.Local adherent technique for transplanting mesenchymal stem cells as a potential treatment of cartilage defect.Arthritis Res Ther.2008; 10(4): R84. Medline. doi: 10.1186/ar2460
37.
LiangJ., ZhangH., HuaB.Allogeneic mesenchymal stem cells transplantation in treatment of multiple sclerosis.Mult Scler.2009; 15(5): 644–646. Medline. doi: 10.1177/1352458509104590
LocatelliF., CortiS., DonadoniC.Neuronal differentiation of murine bone marrow Thy-1 and Sca-1 positive cells.J Hematother Stem Cell Res.2003; 12: 727–734. Medline. doi: 10.1089/15258160360732740
40.
TohillM., MantovaniC., WibergM., TerenghiG.. Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration.Neurosci Lett.2004; 362(3): 200–203. Medline. doi: 10.1016/j.neulet.2004.03.077
41.
Wislet-GendebienS., BruyereF., HansG., LeprinceP., MoonenG., RogisterB.. Nestin-positive mesenchymal stem cells favour the astroglial lineage in neural progenitors and stem cells by releasing active BMP4.BMC Neurosci.2004; 5: 33. Medline. doi: 10.1186/1471-2202-5-33
42.
KohyamaJ., AbeH., ShimazakiT.. Brain from bone: efficient “meta-differentiation” of marrow stroma-derived mature osteoblasts to neurons with Noggin or a demethylating agent.Differentiation.2001; 68(4-5): 235–244. doi: 10.1046/j.1432-0436.2001.680411.x
43.
DezawaM., KannoH., HoshinoM.Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation.J Clin Invest.2004; 113(12): 1701–1710.
44.
ArriolaA., KielM.E., ShiY., McKinnonR.D.. Adjunctive MSCs enhance myelin formation by xenogenic oligodendrocyte precursors transplanted in the retina.Cell Res.2010; 20(6): 728–731. Medline. doi: 10.1038/cr.2010.63
45.
ChoiC.B., ChoY.K., PrakashK.V.Analysis of neuron-like differentiation of human bone marrow mesenchymal stem cells.Biochem Biophys Res Commun.2006; 350(1): 138–146. Medline. doi: 10.1016/j.bbrc.2006.09.010
46.
YamaguchiS., KurodaS., KobayashiH.. The effects of neuronal induction on gene expression profile in bone marrow stromal cells (BMSC)–a preliminary study using microarray analysis.Brain Res.2006, 1087(1): 15–27.
47.
HeubachJ.F., GrafE.M., LeutheuserJ.Electrophysiological properties of human mesenchymal stem cells.J Physiol.2004; 554(Pt 3): 659–672. Medline. doi: 10.1113/jphysiol.2003.055806
48.
KawanoS., ShojiS., IchinoseS., YamagataK., TagamiM., HiraokaM.. Characterization of Ca(2+) signaling pathways in human mesenchymal stem cells.Cell Calcium.2002; 32(4): 165–174. Medline. doi: 10.1016/S0143416002001240
49.
LiG.R., SunH., DengX., LauC.P.. Characterization of ionic currents in human mesenchymal stem cells from bone marrow.Stem Cells.2005; 23(3): 371–382. Medline. doi: 10.1634/stemcells.2004-0213
50.
KawanoS., OtsuK., ShojiS., YamagataK., HiraokaM.. Ca(2+) oscillations regulated by Na(+)-Ca(2+) exchanger and plasma membrane Ca(2+) pump induce fluctuations of membrane currents and potentials in human mesenchymal stem cells.Cell Calcium.2003; 34(2): 145–156. Medline. doi: 10.1016/S0143-4160(03)00069-1
51.
WangS.P., WangJ.A., LuoR.H., CuiW.Y., WangH.. Potassium channel currents in rat mesenchymal stem cells and their possible roles in cell proliferation.Clin Exp Pharmacol Physiol.2008; 35(9): 1077–1084. Medline. doi: 10.1111/j.1440-1681.2008.04964.x
52.
LiG.R., DengX.L., SunH., ChungS.S., TseH.F., LauC.P.. Ion channels in mesenchymal stem cells from rat bone marrow.Stem Cells.2006; 24(6): 1519–1528. Medline. doi: 10.1634/stemcells.2005-0307
HungS.C., ChengH., PanC.Y., TsaiM.J., KaoL.S., MaH.L.. In vitro differentiation of size-sieved stem cells into electrically active neural cells.Stem Cells.2002; 20(6): 522–529. Medline. doi: 10.1634/stemcells.20-6-522
55.
SaganichM.J., Vega-Saenz de MieraE., NadalM.S., BakerH., CoetzeeW.A., RudyB.. Cloning of components of a novel subthreshold-activating K1 channel with a unique pattern of expression in the cerebral cortex.J Neurosci.1999; 19(24): 10789–10802.
56.
LudwigJ., WeselohR., KarschinC.Cloning and functional expression of rat eag2, a new member of the ether-a’-go-go family of potassium channels and comparison of its distribution with that of eag1.Mol Cell Neurosci.2000; 16(1): 59–70. Medline. doi: 10.1006/mcne.2000.0851
57.
SchonherrR., GessnerG., LoberK., HeinemannS.H.. Functional distinction of human EAG1 and EAG2 potassium channels.FEBS Lett.2002; 514(2-3): 204–208. Medline. doi: 10.1016/S0014-5793(02)02365-7
58.
JuM., WrayD.. Molecular identification and characterisation of the human eag2 potassium channel.FEBS Lett.2002; 524(1-3): 204–210. Medline. doi: 10.1016/S0014-5793(02)03055-7
59.
BorowiecA.S., HagueF., HarirN.IGF-1 activates hEAG K(+) channels through an Akt-dependent signaling pathway in breast cancer cells: role in cell proliferation.J Cell Physiol.2007; 212(3): 690–701. Medline. doi: 10.1002/jcp.21065
60.
AshcroftF.M.. Ion Channels and Disease.San Diego, CA: Academic Press; 2000.
61.
HilleB.. Ion Channels of Excitable Membranes.3rd ed.Sunderland, MA: Sinauer Associates Inc.; 2001.
62.
Wislet-GendebienS., LeprinceP., MoonenG., RogisterB.. Regulation of neural markers nestin and GFAP expression by cultivated bone marrow stromal cells.J Cell Sci.2003; 116(Pt 16): 3295–3302. Medline. doi: 10.1242/jcs.00639
DezawaM., KannoH., HoshinoM.Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation.J Clin Invest.2004; 113(12): 1701–1710.
65.
UchidaK., MomiyamaT., OkanoH.Potential functional neural repair with grafted neural stem cells of early embryonic neuroepithelial origin.Neurosci Res.2005; 52(3): 276–286. Medline. doi: 10.1016/j.neures.2005.03.015
66.
HermannA., MaiselM., WegnerF.Multipotent neural stem cells from the adult tegmentum with dopaminergic potential develop essential properties of functional neurons.Stem Cells.2006; 24(4): 949–964. Medline. doi: 10.1634/stemcells.2005-0192
67.
Wislet-GendebienS., HansG., LeprinceP., RigoJ.M., MoonenG., RogisterB.. Plasticity of cultured mesenchymal stem cells: switch from nestin-positive to excitable neuron-like phenotype.Stem Cells.2005; 23(3): 392–402. Medline. doi: 10.1634/stemcells.2004-0149
68.
GrosseG., DraguhnA., HohneL., TappR., VehR.W., Ahnert-HilgerG.. Expression of Kv1 potassium channels in mouse hippocampal primary cultures: development and activity-dependent regulation.J Neurosci.2000; 20(5): 1869–1882.
69.
BibelM., RichterJ., SchrenkK.Differentiation of mouse embryonic stem cells into a defined neuronal lineage.Nat Neurosci.2004; 7(9): 1003–1009. Medline. doi: 10.1038/nn1301
70.
MoeM.C., VargheseM., DanilovA.I.Multipotent progenitor cells from the adult human brain: neurophysiological differentiation to mature neurons.Brain.2005; 128(Pt 9): 2189–2199. Medline. doi: 10.1093/brain/awh574
71.
BertaniN., MalatestaP., VolpiG., SonegoP., PerrisR.. Neurogenic potential of human mesenchymal stem cells revisited: analysis by immunostaining, time-lapse video and microarray.J Cell Sci.2005; 118(Pt 17): 3925–3936. Medline. doi: 10.1242/jcs.02511
72.
NeuhuberB., GalloG., HowardL., KosturaL., MackayA., FischerI.. Reevaluation of in vitro differentiation protocols for bone marrow stromal cells: disruption of actin cytoskeleton induces rapid morphological changes and mimics neuronal phenotype.J Neurosci Res.2004; 77(2): 192–204. Medline. doi: 10.1002/jnr.20147
73.
LuP., BleschA., TuszynskiM.H.. Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact?J Neurosci Res.2004; 77(2): 174–191. Medline. doi: 10.1002/jnr.20148
74.
TaoH., RaoR., MaD.D.. Cytokine-induced stable neuronal differentiation of human bone marrow mesenchymal stem cells in a serum/feeder cell-free condition.Dev Growth Differ.2005; 47(6): 423–433. Medline. doi: 10.1111/j.1440-169X.2005.00810.x
75.
EscandonE., SoppetD., RosenthalA.Regulation of neurotrophin receptor expression during embryonic and postnatal development.J Neurosci.1994; 14(4): 2054–2068.
76.
CriglerL., RobeyR.C., AsawachaicharnA., GauppD., PhinneyD.G.. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis.Exp Neurol.2006; 198(1): 54–64. Medline. doi: 10.1016/j.expneurol.2005.10.029
77.
LiY., ChenJ., ChenX.G.Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery.Neurology.2002; 59(4): 514–523.
78.
Grisoli'aJ.S.. CNS stem cell transplantation: clinical and ethical perspectives.Brain Res Bull.2002; 57(6): 823–826. Medline. doi: 10.1016/S0361-9230(01)00766-3
79.
OkanoH.. Neural stem cells: progression of basic research and perspective for clinical application.Keio J Med.2002; 51(3): 115–128. Medline. doi: 10.2302/kjm.51.115
80.
SnyderE.Y., DaleyG.Q., GoodellM.. Taking stock and planning for the next decade: realistic prospects for stem cell therapies for the nervous system.J Neurosci Res.2004; 76(2): 157–168. Medline. doi: 10.1002/jnr.20033
81.
BaizabalJ.M., Furlan-MagarilM., Santa-OlallaJ., CovarrubiasL.. Neural stem cells in development and regenerative medicine.Arch Med Res.2003; 34(6): 572–588. Medline. doi: 10.1016/j.arcmed.2003.09.002
82.
HermannA., GastlR., LiebauS.Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells.J Cell Sci.2004; 117(Pt 19): 4411–4422. Medline. doi: 10.1242/jcs.01307
83.
FuL., FuL., HuangY., LeeT.D., FormanS.J., ShihC.C.. Derivation of neural stem cells from mesenchymal stem cells: evidence for a bipotential stem cell population.Stem Cells Dev.2008; 17(6): 1109–1121.
84.
DonatoR., MiljanE.A., HinesS.J.Differential development of neuronal physiological responsiveness in two human neural stem cell lines.BMC Neurosci.2007; 8: 36. Medline. doi: 10.1186/1471-2202-8-36
85.
LiuJ., HeQ.J., ZouW.Catalpol increases hippocampal neuroplasticity and up-regulates PKC and BDNF in the aged rats.Brain Res.2006; 1123(1): 68–79. Medline. doi: 10.1016/j. brainres.2006.09.058
86.
GrecoS.. J. Zhou, C. Ye, J. H. Rameshwar, P. An interdisciplinary approach and characterization of neuronal cells transdifferentiated from human mesenchymal stem cells.Stem Cells Dev.2007; 16(5): 811–826.
87.
PacaryE., LegrosH., ValableS.Synergistic effects of CoCl(2) and ROCK inhibition on mesenchymal stem cell differentiation into neuron-like cells.J Cell Sci.2006, 119(Pt 13): 2667–2678.
88.
Wislet-GendebienS., WautierF., LeprinceP., RogisterB.. Astrocytic and neuronal fate of mesenchymal stem cells expressing nestin.Brain Res Bull.2005; 68(1-2): 95–102.
89.
LiJ.M., ZhuH., LuS.Migration and differentiation of human mesenchymal stem cells in the normal rat brain.Neurol Res.2011; 33(1): 84–92.
90.
PisatiF., BossolascoP., MeregalliM.Induction of neurotrophin expression via human adult mesenchymal stem cells: implication for cell therapy in neurodegenerative diseases.Cell Transplant.2007; 16(1): 41–55.
91.
ParkH.J., LeeP.H., BangO.Y., LeeG., AhnY.H.. Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson's disease.J Neurochem.2008; 107(1): 141–151.
92.
BlandiniF, CovaL, ArmenteroM. T.Transplantation of undifferentiated human mesenchymal stem cells protects against 6-hydroxydopamine neurotoxicity in the rat.Cell Transplant.2011; 19(2): 203–217.
93.
XiongN., ZhangZ., HuangJ.VEGF-expressing human umbilical cord mesenchymal stem cells, an improved therapy strategy for Parkinson's disease.Gene Ther.2011; 18(4): 394–402.
94.
KempK., GordonD., WraithD.C.Fusion between human mesenchymal stem cells and rodent cerebellar Purkinje cells.Neuropathol Appl Neurobiol.2011; 37(2): 166–178.
95.
MaW., FitzgeraldW., LiuQ.Y.CNS stem and progenitor cell differentiation into functional neuronal circuits in three-dimensional collagen gels.Exp Neurol.2004; 190(2): 276–288. Medline. doi: 10.1016/j.expneurol.2003.10.016
96.
SongH.J., StevensC.F., GageF.H.. Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons.Nat Neurosci.2002; 5(5): 438–445.
97.
CuiZ.F., XuX., TrainorN., TriffittJ.T., UrbanJ.P.G., TirlapurU.K.. Application of multiple parallel perfused microbioreactors and three-dimensional stem cell culture for toxicity testing.Toxicol In Vitro.2007; 21(7): 1318–1324. Medline. doi: 10.1016/j.tiv.2007.05.015
