Restricted accessResearch articleFirst published online 2015-10
GDF-15 Secreted from Human Umbilical Cord Blood Mesenchymal Stem Cells Delivered Through the Cerebrospinal Fluid Promotes Hippocampal Neurogenesis and Synaptic Activity in an Alzheimer's Disease Model
Our previous studies demonstrated that transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the hippocampus of a transgenic mouse model of Alzheimer's disease (AD) reduced amyloid-β (Aβ) plaques and enhanced cognitive function through paracrine action. Due to the limited life span of hUCB-MSCs after their transplantation, the extension of hUCB-MSC efficacy was essential for AD treatment. In this study, we show that repeated cisterna magna injections of hUCB-MSCs activated endogenous hippocampal neurogenesis and significantly reduced Aβ42 levels. To identify the paracrine factors released from the hUCB-MSCs that stimulated endogenous hippocampal neurogenesis in the dentate gyrus, we cocultured adult mouse neural stem cells (NSCs) with hUCB-MSCs and analyzed the cocultured media with cytokine arrays. Growth differentiation factor-15 (GDF-15) levels were significantly increased in the media. GDF-15 suppression in hUCB-MSCs with GDF-15 small interfering RNA reduced the proliferation of NSCs in cocultures. Conversely, recombinant GDF-15 treatment in both in vitro and in vivo enhanced hippocampal NSC proliferation and neuronal differentiation. Repeated administration of hUBC-MSCs markedly promoted the expression of synaptic vesicle markers, including synaptophysin, which are downregulated in patients with AD. In addition, in vitro synaptic activity through GDF-15 was promoted. Taken together, these results indicated that repeated cisterna magna administration of hUCB-MSCs enhanced endogenous adult hippocampal neurogenesis and synaptic activity through a paracrine factor of GDF-15, suggesting a possible role of hUCB-MSCs in future treatment strategies for AD.
Get full access to this article
View all access options for this article.
References
1.
MillerG. (2010). Pharmacology. The puzzling rise and fall of a dark-horse Alzheimer's drug. Science. 327:1309.
2.
HirtzD, ThurmanDJ, Gwinn-HardyK, MohamedM, ChaudhuriAR and ZalutskyR. (2007). How common are the “common” neurologic disorders?. Neurology, 68:326–337.
3.
QuerfurthHW and LaFerlaFM. (2010). Alzheimer's disease. N Engl J Med, 362:329–344.
4.
LeeRH, PulinAA, SeoMJ, KotaDJ, YlostaloJ, LarsonBL, Semprun-PrietoL, DelafontaineP and ProckopDJ. (2009). Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell, 5:54–63.
5.
BlockGJ, OhkouchiS, FungF, FrenkelJ, GregoryC, PochampallyR, DiMattiaG, SullivanDE and ProckopDJ. (2009). Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1. Stem Cells, 27:670–681.
6.
KaraozE, GencZS, DemircanPC, AksoyA and DuruksuG. (2010). Protection of rat pancreatic islet function and viability by coculture with rat bone marrow-derived mesenchymal stem cells. Cell Death Dis, 1:e36.
7.
CaplanAI and CorreaD. (2011). The MSC: an injury drugstore. Cell Stem Cell, 9:11–15.
8.
OhkouchiS, BlockGJ, KatshaAM, KanehiraM, EbinaM, KikuchiT, SaijoY, NukiwaT and ProckopDJ. (2012). Mesenchymal stromal cells protect cancer cells from ROS-induced apoptosis and enhance the Warburg effect by secreting STC1. Mol Ther, 20:417–423.
9.
KimJY, JeonHB, YangYS, OhW and ChangJW. (2010). Application of human umbilical cord blood-derived mesenchymal stem cells in disease models. World J Stem Cells, 2:34–38.
10.
HsiehJY, WangHW, ChangSJ, LiaoKH, LeeIH, LinWS, WuCH, LinWY and ChengSM. (2013). Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis. PLoS One, 8:e72604.
11.
KimJY, KimDH, KimJH, LeeD, JeonHB, KwonSJ, KimSM, YooYJ, LeeEH, et al. (2012). Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-beta plaques. Cell Death Differ, 19:680–691.
12.
KimJY, KimDH, KimDS, KimJH, JeongSY, JeonHB, LeeEH, YangYS, OhW and ChangJW. (2010). Galectin-3 secreted by human umbilical cord blood-derived mesenchymal stem cells reduces amyloid-beta42 neurotoxicity in vitro. FEBS Lett, 584:3601–3608.
13.
KimJY, KimDH, KimJH, YangYS, OhW, LeeEH and ChangJW. (2012). Umbilical cord blood mesenchymal stem cells protect amyloid-beta42 neurotoxicity via paracrine. World J Stem Cells, 4:110–116.
14.
LeeHJ, LeeJK, LeeH, ShinJW, CarterJE, SakamotoT, JinHK and BaeJS. (2010). The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer's disease. Neurosci Lett, 481:30–35.
15.
LeeHJ, LeeJK, LeeH, CarterJE, ChangJW, OhW, YangYS, SuhJG, LeeBH, JinHK and BaeJS. (2012). Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation. Neurobiol Aging, 33:588–602.
16.
OhW, KimDS, YangYS and LeeJK. (2008). Immunological properties of umbilical cord blood-derived mesenchymal stromal cells. Cell Immunol, 251:116–123.
17.
SeoSW, LeeJII, KimCH, ChangJW, RohJH, OhW, YangYS, LeeK, KimST and NaDL. (2013). A phase I trial of parenchymal injection of umbilical cord stem cells in Alzheimer's disease. J Alzheimer's Assoc, 9:291.
18.
YangSE, HaCW, JungM, JinHJ, LeeM, SongH, ChoiS, OhW and YangYS. (2004). Mesenchymal stem/progenitor cells developed in cultures from UC blood. Cytotherapy, 6:476–486.
19.
WalkerTL and KempermannG. (2014). One mouse, two cultures: isolation and culture of adult neural stem cells from the two neurogenic zones of individual mice. J Vis Exp. e51225. DOI: 10.3791/51225.
20.
KimH, KimHY, ChoiMR, HwangS, NamKH, KimHC, HanJS, KimKS, YoonHS and KimSH. (2010). Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice. Neurosci Lett, 468:190–194.
21.
KimSH and RyanTA. (2009). Synaptic vesicle recycling at CNS snapses without AP-2. J Neurosci, 29:3865–3874.
22.
KimHS, ShinTH, LeeBC, YuKR, SeoY, LeeS, SeoMS, HongIS, ChoiSW, et al. (2013). Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology, 145:1392–1403.e1–e8.
23.
EliopoulosN, StaggJ, LejeuneL, PommeyS and GalipeauJ. (2005). Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood, 106:4057–4065.
24.
GriffinMD, RyanAE, AlagesanS, LohanP, TreacyO and RitterT. (2013). Anti-donor immune responses elicited by allogeneic mesenchymal stem cells: what have we learned so far?. Immunol Cell Biol, 91:40–51.
25.
CampDM, LoefflerDA, FarrahDM, BornemanJN and LeWittPA. (2009). Cellular immune response to intrastriatally implanted allogeneic bone marrow stromal cells in a rat model of Parkinson's disease. J Neuroinflammation, 6:17.
26.
BraakH, BraakE and BohlJ. (1993). Staging of Alzheimer-related cortical destruction. Eur Neurol, 33:403–408.
27.
FerriAL, CavallaroM, BraidaD, Di CristofanoA, CantaA, VezzaniA, OttolenghiS, PandolfiPP, SalaM, DeBiasiS and NicolisSK. (2004). Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development, 131:3805–3819.
28.
KurkiP, VanderlaanM, DolbeareF, GrayJ and TanEM. (1986). Expression of proliferating cell nuclear antigen (PCNA)/cyclin during the cell cycle. Exp Cell Res, 166:209–219.
29.
FrancisF, KoulakoffA, BoucherD, ChafeyP, SchaarB, VinetMC, FriocourtG, McDonnellN, ReinerO, et al. (1999). Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron, 23:247–256.
30.
MunozJR, StoutengerBR, RobinsonAP, SpeesJL and ProckopDJ. (2005). Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc Natl Acad Sci U S A, 102:18171–18176.
31.
Gomez-GaviroMV, ScottCE, SesayAK, MatheuA, BoothS, GalichetC and Lovell-BadgeR. (2012). Betacellulin promotes cell proliferation in the neural stem cell niche and stimulates neurogenesis. Proc Natl Acad Sci U S A, 109:1317–1322.
32.
MignoneJL, KukekovV, ChiangAS, SteindlerD and EnikolopovG. (2004). Neural stem and progenitor cells in nestin-GFP transgenic mice. J Comp Neurol, 469:311–324.
33.
SubramaniamS, StrelauJ and UnsickerK. (2003). Growth differentiation factor-15 prevents low potassium-induced cell death of cerebellar granule neurons by differential regulation of Akt and ERK pathways. J Biol Chem, 278:8904–8912.
34.
StrelauJ, BottnerM, LingorP, Suter-CrazzolaraC, GalterD, JaszaiJ, SullivanA, SchoberA, KrieglsteinK and UnsickerK. (2000). GDF-15/MIC-1 a novel member of the TGF-beta superfamily. J Neural Transm Suppl. 273–276.
35.
StrelauJ, SullivanA, BottnerM, LingorP, FalkensteinE, Suter-CrazzolaraC, GalterD, JaszaiJ, KrieglsteinK and UnsickerK. (2000). Growth/differentiation factor-15/macrophage inhibitory cytokine-1 is a novel trophic factor for midbrain dopaminergic neurons in vivo. J Neurosci, 20:8597–8603.
36.
Carrillo-GarciaC, ProchnowS, SimeonovaIK, StrelauJ, Holzl-WenigG, MandlC, UnsickerK, von Bohlen Und HalbachO and CiccoliniF. (2014). Growth/differentiation factor 15 promotes EGFR signalling, and regulates proliferation and migration in the hippocampus of neonatal and young adult mice. Development, 141:773–783.
37.
LassmannH, WeilerR, FischerP, BancherC, JellingerK, FloorE, DanielczykW, SeitelbergerF and WinklerH. (1992). Synaptic pathology in Alzheimer's disease: immunological data for markers of synaptic and large dense-core vesicles. Neuroscience, 46:1–8.
38.
SzeCI, TroncosoJC, KawasC, MoutonP, PriceDL and MartinLJ. (1997). Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol, 56:933–944.
39.
MartinTF. (2000). Racing lipid rafts for synaptic-vesicle formation. Nat Cell Biol, 2:E9–E11.
40.
OttoH, HansonPI and JahnR. (1997). Assembly and disassembly of a ternary complex of synaptobrevin, syntaxin, and SNAP-25 in the membrane of synaptic vesicles. Proc Natl Acad Sci U S A, 94:6197–6201.
41.
BennettMK, CalakosN and SchellerRH. (1992). Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science, 257:255–259.
42.
BalajiJ and RyanTA. (2007). Single-vesicle imaging reveals that synaptic vesicle exocytosis and endocytosis are coupled by a single stochastic mode. Proc Natl Acad Sci U S A, 104:20576–20581.
43.
DonegaV, van VelthovenCT, NijboerCH, KavelaarsA and HeijnenCJ. (2013). The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment. J Cereb Blood Flow Metab, 33:625–634.
44.
CoqueryN, BleschA, StrohA, Fernandez-KlettF, KleinJ, WinterC and PrillerJ. (2012). Intrahippocampal transplantation of mesenchymal stromal cells promotes neuroplasticity. Cytotherapy, 14:1041–1053.
45.
BottnerM, LaaffM, SchechingerB, RappoldG, UnsickerK and Suter-CrazzolaraC. (1999). Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1). Gene, 237:105–111.
46.
BottnerM, Suter-CrazzolaraC, SchoberA and UnsickerK. (1999). Expression of a novel member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues. Cell Tissue Res, 297:103–110.
47.
StrelauJ, StrzelczykA, RusuP, BendnerG, WieseS, DiellaF, AltickAL, von BartheldCS, KleinR, SendtnerM and UnsickerK. (2009). Progressive postnatal motoneuron loss in mice lacking GDF-15. J Neurosci, 29:13640–13648.
48.
EmsleyJG, MitchellBD, KempermannG and MacklisJD. (2005). Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog Neurobiol, 75:321–341.
49.
KimS, ChangKA, KimJ, ParkHG, RaJC, KimHS and SuhYH. (2012). The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer's disease mice. PLoS One, 7:e45757.
50.
LimJY, JeongCH, JunJA, KimSM, RyuCH, HouY, OhW, ChangJW and JeunSS. (2011). Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia. Stem Cell Res Ther, 2:38.
51.
JiaoH, GuanF, YangB, LiJ, ShanH, SongL, HuX and DuY. (2011). Human umbilical cord blood-derived mesenchymal stem cells inhibit C6 glioma via downregulation of cyclin D1. Neurol India, 59:241–247.
52.
GuanYM, ZhuY, LiuXC, HuangHL, WangZW, LiuB, ZhuYZ and WangQS. (2014). Effect of human umbilical cord blood mesenchymal stem cell transplantation on neuronal metabolites in ischemic rabbits. BMC Neurosci, 15:41.
53.
LeeM, JeongSY, HaJ, KimM, JinHJ, KwonSJ, ChangJW, ChoiSJ, OhW, et al. (2014). Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo. Biochem Biophys Res Commun, 446:983–989.
54.
JangYK, KimM, LeeYH, OhW, YangYS and ChoiSJ. (2014). Optimization of the therapeutic efficacy of human umbilical cord blood-mesenchymal stromal cells in an NSG mouse xenograft model of graft-versus-host disease. Cytotherapy, 16:298–308.
55.
KimDS, KimJH, LeeJK, ChoiSJ, KimJS, JeunSS, OhW, YangYS and ChangJW. (2009). Overexpression of CXC chemokine receptors is required for the superior glioma-tracking property of umbilical cord blood-derived mesenchymal stem cells. Stem Cells Dev, 18:511–519.
56.
KimSM, OhJH, ParkSA, RyuCH, LimJY, KimDS, ChangJW, OhW and JeunSS. (2010). Irradiation enhances the tumor tropism and therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand-secreting human umbilical cord blood-derived mesenchymal stem cells in glioma therapy. Stem Cells, 28:2217–2228.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
