Resveratrol promotes the survival and neuronal differentiation of hypoxia-conditioned neuronal progenitor cells in rats with cerebral ischemia
Yao Yao1, Rui Zhou1, Rui Bai2, Jing Wang1, Mengjiao Tu1, Jingjing Shi1, Xiao He1, Jinyun Zhou1, Liu Feng1, Yuanxue Gao1, Fahuan Song1, Feng Lan2, Xingguo Liu4, Mei Tian1(), Hong Zhang1,3,5,6()
1. Department of Nuclear Medicine and PET-CT Center, The Second Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China 2. Beijing Laboratory for Cardiovascular Precision Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China 3. Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou 310027, China 4. Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China 5. Shanxi Medical University, Taiyuan 030001, China 6. The College of Biomedical Engineering and Instrument Science of Zhejiang University, Hangzhou 310027, China
Hypoxia conditioning could increase the survival of transplanted neuronal progenitor cells (NPCs) in rats with cerebral ischemia but could also hinder neuronal differentiation partly by suppressing mitochondrial metabolism. In this work, the mitochondrial metabolism of hypoxia-conditioned NPCs (hcNPCs) was upregulated via the additional administration of resveratrol, an herbal compound, to resolve the limitation of hypoxia conditioning on neuronal differentiation. Resveratrol was first applied during the in vitro neuronal differentiation of hcNPCs and concurrently promoted the differentiation, synaptogenesis, and functional development of neurons derived from hcNPCs and restored the mitochondrial metabolism. Furthermore, this herbal compound was used as an adjuvant during hcNPC transplantation in a photothrombotic stroke rat model. Resveratrol promoted neuronal differentiation and increased the long-term survival of transplanted hcNPCs. 18-fluorine fluorodeoxyglucose positron emission tomography and rotarod test showed that resveratrol and hcNPC transplantation synergistically improved the neurological and metabolic recovery of stroke rats. In conclusion, resveratrol promoted the neuronal differentiation and therapeutic efficiency of hcNPCs in stroke rats via restoring mitochondrial metabolism. This work suggested a novel approach to promote the clinical translation of NPC transplantation therapy.
M George Paul, K Steinberg Gary. Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments. Neuron 2015; 87(2): 297–309 https://doi.org/10.1016/j.neuron.2015.05.041
3
H Kim, MJ Cooke, MS Shoichet. Creating permissive microenvironments for stem cell transplantation into the central nervous system. Trends Biotechnol 2012; 30(1): 55–63 https://doi.org/10.1016/j.tibtech.2011.07.002
JD Bernstock, L Peruzzotti-Jametti, D Ye, FA Gessler, D Maric, N Vicario, YJ Lee, S Pluchino, JM Hallenbeck. Neural stem cell transplantation in ischemic stroke: a role for preconditioning and cellular engineering. J Cereb Blood Flow Metab 2017; 37(7): 2314–2319 https://doi.org/10.1177/0271678X17700432
8
L Tian, W Zhu, Y Liu, Y Gong, A Lv, Z Wang, X Ding, S Li, Y Fu, Y Lin, Y Yan. Neural stem cells transfected with leukemia inhibitory factor promote neuroprotection in a rat model of cerebral ischemia. Neurosci Bull 2019; 35(5): 901–908 https://doi.org/10.1007/s12264-019-00405-5
9
JW Kim, I Tchernyshyov, GL Semenza, CV Dang. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3(3): 177–185 https://doi.org/10.1016/j.cmet.2006.02.002
10
ZZ Wei, JH Lee, Y Zhang, YB Zhu, TC Deveau, X Gu, MM Winter, J Li, L Wei, SP Yu. Intracranial transplantation of hypoxia-preconditioned iPSC-derived neural progenitor cells alleviates neuropsychiatric defects after traumatic brain injury in juvenile rats. Cell Transplant 2016; 25(5): 797–809 https://doi.org/10.3727/096368916X690403
11
SRL Stacpoole, DJ Webber, B Bilican, A Compston, S Chandran, RJM Franklin. Neural precursor cells cultured at physiologically relevant oxygen tensions have a survival advantage following transplantation. Stem Cells Transl Med 2013; 2(6): 464–472 https://doi.org/10.5966/sctm.2012-0144
12
MH Theus, L Wei, L Cui, K Francis, X Hu, C Keogh, SP Yu. In vitrohypoxic preconditioning of embryonic stem cells as a strategy of promoting cell survival and functional benefits after transplantation into the ischemic rat brain. Exp Neurol 2008; 210(2): 656–670 https://doi.org/10.1016/j.expneurol.2007.12.020
13
C Lange, M Turrero Garcia, I Decimo, F Bifari, G Eelen, A Quaegebeur, R Boon, H Zhao, B Boeckx, J Chang, C Wu, F Le Noble, D Lambrechts, M Dewerchin, CJ Kuo, WB Huttner, P Carmeliet. Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis. EMBO J 2016; 35(9): 924–941 https://doi.org/10.15252/embj.201592372
14
A Mohyeldin, T Garzon Muvdi, A Quinones Hinojosa. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 2010; 7(2): 150–161 https://doi.org/10.1016/j.stem.2010.07.007
15
X Zheng, L Boyer, M Jin, J Mertens, Y Kim, L Ma, M Hamm, FH Gage, T Hunter. Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation. eLife 2016; 5: e13374 https://doi.org/10.7554/eLife.13374
16
M Agostini, F Romeo, S Inoue, MV Niklison-Chirou, AJ Elia, D Dinsdale, N Morone, RA Knight, TW Mak, G Melino. Metabolic reprogramming during neuronal differentiation. Cell Death Differ 2016; 23(9): 1502–1514 https://doi.org/10.1038/cdd.2016.36
17
AK Chouhan, MV Ivannikov, Z Lu, M Sugimori, RR Llinas, GT Macleod. Cytosolic calcium coordinates mitochondrial energy metabolism with presynaptic activity. J Neurosci 2012; 32(4): 1233–1243 https://doi.org/10.1523/JNEUROSCI.1301-11.2012
Z Li, KI Okamoto, Y Hayashi, M Sheng. The Importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 2004; 119(6): 873–887 https://doi.org/10.1016/j.cell.2004.11.003
20
M Uittenbogaard, A Chiaramello. Mitochondrial biogenesis: a therapeutic target for neurodevelopmental disorders and neurodegenerative diseases. Curr Pharm Des 2014; 20(35): 5574–5593 https://doi.org/10.2174/1381612820666140305224906
21
JA Baur, DA Sinclair. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 2006; 5(6): 493–506 https://doi.org/10.1038/nrd2060
22
N Singh, M Agrawal, S Doré. Neuroprotective properties and mechanisms of resveratrol in in vitro and in vivo experimental cerebral stroke models. ACS Chem Neurosci 2013; 4(8): 1151–1162 https://doi.org/10.1021/cn400094w
23
Q Wang, J Xu, GE Rottinghaus, A Simonyi, D Lubahn, GY Sun, AY Sun. Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res 2002; 958(2): 439–447 https://doi.org/10.1016/S0006-8993(02)03543-6
24
M Lagouge, C Argmann, Z Gerhart Hines, H Meziane, C Lerin, F Daussin, N Messadeq, J Milne, P Lambert, P Elliott, B Geny, M Laakso, P Puigserver, J Auwerx. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006; 127(6): 1109–1122 https://doi.org/10.1016/j.cell.2006.11.013
25
J Milosevic, I Adler, A Manaenko, SC Schwarz, G Walkinshaw, M Arend, LA Flippin, A Storch, J Schwarz. Non-hypoxic stabilization of hypoxia-inducible factor a (HIF-a): relevance in neural progenitor/stem cells. Neurotox Res 2009; 15(4): 367–380 https://doi.org/10.1007/s12640-009-9043-z
C Shen, W Cheng, P Yu, L Wang, L Zhou, L Zeng, Q Yang. Resveratrol pretreatment attenuates injury and promotes proliferation of neural stem cells following oxygen-glucose deprivation/reoxygenation by upregulating the expression of Nrf2, HO-1 and NQO1 in vitro. Mol Med Rep 2016; 14(4): 3646–3654 https://doi.org/10.3892/mmr.2016.5670
28
N Zhao, CC Liu, AJ Van Ingelgom, YA Martens, C Linares, JA Knight, MM Painter, PM Sullivan, G Bu. Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes. Neuron 2017; 96(1): 115–129.e5 https://doi.org/10.1016/j.neuron.2017.09.003
29
AY Shih, P Blinder, PS Tsai, B Friedman, G Stanley, PD Lyden, D Kleinfeld. The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit. Nat Neurosci 2013; 16(1): 55–63 https://doi.org/10.1038/nn.3278
30
J Wang, F Chao, F Han, G Zhang, Q Xi, J Li, H Jiang, J Wang, G Yu, M Tian, H Zhang. PET demonstrates functional recovery after transplantation of induced pluripotent stem cells in a rat model of cerebral ischemic injury. J Nucl Med 2013; 54(5): 785–792 https://doi.org/10.2967/jnumed.112.111112
31
TA Gorr. Hypometabolism as the ultimate defence in stress response: how the comparative approach helps understanding of medically relevant questions. Acta Physiol (Oxf) 2017; 219(2): 409–440 https://doi.org/10.1111/apha.12747
32
MV Gustafsson, X Zheng, T Pereira, K Gradin, S Jin, J Lundkvist, JL Ruas, L Poellinger, U Lendahl, M Bondesson. Hypoxia requires Notch signaling to maintain the undifferentiated cell state. Dev Cell 2005; 9(5): 617–628 https://doi.org/10.1016/j.devcel.2005.09.010
33
JR Sims, SW Lee, K Topalkara, J Qiu, J Xu, Z Zhou, MA Moskowitz. Sonic hedgehog regulates ischemia/hypoxia-induced neural progenitor proliferation. Stroke 2009; 40(11): 3618–3626 https://doi.org/10.1161/STROKEAHA.109.561951
F Yin, A Boveris, E Cadenas. Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration. Antioxid Redox Signal 2014; 20(2): 353–371 https://doi.org/10.1089/ars.2012.4774
36
LC O’Brien, PM Keeney, JP Bennett Jr. Differentiation of human neural stem cells into motor neurons stimulates mitochondrial biogenesis and decreases glycolytic flux. Stem Cells Dev 2015; 24(17): 1984–1994 https://doi.org/10.1089/scd.2015.0076
37
L Cordeau-Lossouarn, JL Vayssière, JC Larcher, F Gros, B Croizat. Mitochondrial maturation during neuronal differentiation in vivo and in vitro. Biol Cell 1991; 71(1): 57–65 https://doi.org/10.1016/0248-4900(91)90051-N
38
H Zhang, P Gao, R Fukuda, G Kumar, B Krishnamachary, KI Zeller, V Dang Chi, GL Semenza. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 2007; 11(5): 407–420 https://doi.org/10.1016/j.ccr.2007.04.001
39
RC Scarpulla. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 2011; 1813(7): 1269–1278 https://doi.org/10.1016/j.bbamcr.2010.09.019
40
Z Safaeinejad, F Kazeminasab, A Kiani Esfahani, K Ghaedi, MH Nasr Esfahani. Multi-effects of resveratrol on stem cell characteristics: effective dose, time, cell culture conditions and cell type-specific responses of stem cells to resveratrol. Eur J Med Chem 2018; 155: 651–657 https://doi.org/10.1016/j.ejmech.2018.06.037
41
V Kumar, A Pandey, S Jahan, RK Shukla, D Kumar, A Srivastava, S Singh, CS Rajpurohit, S Yadav, VK Khanna, AB Pant. Differential responses of trans-resveratrol on proliferation of neural progenitor cells and aged rat hippocampal neurogenesis. Sci Rep 2016; 6(1): 28142 https://doi.org/10.1038/srep28142
42
C Buhnemann, A Scholz, C Bernreuther, CY Malik, H Braun, M Schachner, KG Reymann, M Dihne. Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain 2006; 129(12): 3238–3248 https://doi.org/10.1093/brain/awl261
43
K Oki, J Tatarishvili, J Wood, P Koch, S Wattananit, Y Mine, E Monni, D Tornero, H Ahlenius, J Ladewig, O Brustle, O Lindvall, Z Kokaia. Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem Cells 2012; 30(6): 1120–1133 https://doi.org/10.1002/stem.1104
44
MA Micci, PJ Pasricha. Neural stem cells for the treatment of disorders of the enteric nervous system: strategies and challenges. Dev Dyn 2007; 236(1): 33–43 https://doi.org/10.1002/dvdy.20975
45
AP Raval, KR Dave, MA Pérez Pinzon. Resveratrol mimics ischemic preconditioning in the brain. J Cereb Blood Flow Metab 2006; 26(9): 1141–1147 https://doi.org/10.1038/sj.jcbfm.9600262
46
YH Hsieh, SS Huang, FC Wei, LM Hung. Resveratrol attenuates ischemia-reperfusion-induced leukocyte-endothelial cell adhesive interactions and prolongs allograft survival across the MHC barrier. Circ J 2007; 71(3): 423–428 https://doi.org/10.1253/circj.71.423
47
H Zhang, F Song, C Xu, H Liu, Z Wang, J Li, S Wu, Y Shen, Y Chen, Y Zhu, R Du, M Tian. Spatiotemporal PET imaging of dynamic metabolic changes after therapeutic approaches of induced pluripotent stem cells, neuronal stem cells, and a Chinese patent medicine in stroke. J Nucl Med 2015; 56(11): 1774–1779
48
K Fodor, DM Tit, B Pasca, C Bustea, D Uivarosan, L Endres, C Iovan, MM Abdel-Daim, S Bungau. Long-term resveratrol supplementation as a secondary prophylaxis for stroke. Oxid Med Cell Longev 2018; 2018: 1–10 https://doi.org/10.1155/2018/4147320
49
D Clark, UI Tuor, R Thompson, A Institoris, A Kulynych, X Zhang, DW Kinniburgh, F Bari, DW Busija, PA Barber. Protection against recurrent stroke with resveratrol: endothelial protection. PLoS One 2012; 7(10): e47792 https://doi.org/10.1371/journal.pone.0047792
