Current NeuropharmacologyCurrent NeuropharmacologyCurrent Neuropharmacology1570-159X1875-6190Bentham Science64455610.2174/1570159X22666240603084558NeurologyResearch ArticleThe Role of Induced Pluripotent Stem Cells in the Treatment of StrokeDarbanYasamaninfo@benthamscience.netAskariHamidinfo@benthamscience.netGhasemi-KasmanMaryaminfo@benthamscience.netYavarpour-BaliHanieinfo@benthamscience.netDehpanahAmirabbasinfo@benthamscience.netGholizadeParniainfo@benthamscience.netNosratiyanNasrininfo@benthamscience.netStudent Research Committee, Babol University of Medical SciencesCellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences1507202422142368238307012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1570-159X/article/view/644556

:Stroke is a neurological disorder with high disability and mortality rates. Almost 80% of stroke cases are ischemic stroke, and the remaining are hemorrhagic stroke. The only approved treatment for ischemic stroke is thrombolysis and/or thrombectomy. However, these treatments cannot sufficiently relieve the disease outcome, and many patients remain disabled even after effective thrombolysis. Therefore, rehabilitative therapies are necessary to induce remodeling in the brain. Currently, stem cell transplantation, especially via the use of induced pluripotent stem cells (iPSCs), is considered a promising alternative therapy for stimulating neurogenesis and brain remodeling. iPSCs are generated from somatic cells by specific transcription factors. The biological functions of iPSCs are similar to those of embryonic stem cells (ESCs), including immunomodulation, reduced cerebral blood flow, cerebral edema, and autophagy. Although iPSC therapy plays a promising role in both hemorrhagic and ischemic stroke, its application is associated with certain limitations. Tumor formation, immune rejection, stem cell survival, and migration are some concerns associated with stem cell therapy. Therefore, cell-free therapy as an alternative method can overcome these limitations. This study reviews the therapeutic application of iPSCs in stroke models and the underlying mechanisms and constraints of these cells. Moreover, cell-free therapy using exosomes, apoptotic bodies, and microvesicles as alternative treatments is discussed.

Strokestem cellsinduced pluripotent stem celltransplantationtumorgenicityexosomes.Roger, V.L.; Go, A.S.; Lloyd-Jones, D.M.; Benjamin, E.J.; Berry, J.D.; Borden, W.B.; Bravata, D.M.; Dai, S.; Ford, E.S.; Fox, C.S.; Fullerton, H.J.; Gillespie, C.; Hailpern, S.M.; Heit, J.A.; Howard, V.J.; Kissela, B.M.; Kittner, S.J.; Lackland, D.T.; Lichtman, J.H.; Lisabeth, L.D.; Makuc, D.M.; Marcus, G.M.; Marelli, A.; Matchar, D.B.; Moy, C.S.; Mozaffarian, D.; Mussolino, M.E.; Nichol, G.; Paynter, N.P.; Soliman, E.Z.; Sorlie, P.D.; Sotoodehnia, N.; Turan, T.N.; Virani, S.S.; Wong, N.D.; Woo, D.; Turner, M.B. Heart disease and stroke statistics-2012 update: A report from the American Heart Association. Circulation, 2012, 125(1), e2-e220. PMID: 22179539Hinkle, J.L.; Guanci, M.M. Acute ischemic stroke review. J. Neurosci. Nurs., 2007, 39(5), 285-310. doi: 10.1097/01376517-200710000-00005 PMID: 17966295World Health OrganizationNeurological disorders: Public health challenges 2006. Available from: https://www.who.int/publications/i/item/9789241563369Amarenco, P.; Bogousslavsky, J.; Caplan, L.R.; Donnan, G.A.; Hennerici, M.G. New approach to stroke subtyping: The A-S-C-O (phenotypic) classification of stroke. Cerebrovasc. Dis., 2009, 27(5), 502-508. doi: 10.1159/000210433 PMID: 19342826Abbott, N.J. Röِnnbäck, L.; Hansson, E. Astrocyte–endothelial interactions at the blood–brain barrier. Nat. Rev. Neurosci., 2006, 7(1), 41-53. doi: 10.1038/nrn1824 PMID: 16371949del Zoppo, G.J.; Saver, J.L.; Jauch, E.C.; Adams, H.P., Jr Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: A science advisory from the American Heart Association/American Stroke Association. Stroke, 2009, 40(8), 2945-2948. doi: 10.1161/STROKEAHA.109.192535 PMID: 19478221Saver, J.L.; Goyal, M.; van der Lugt, A.; Menon, B.K.; Majoie, C.B.L.M.; Dippel, D.W.; Campbell, B.C.; Nogueira, R.G.; Demchuk, A.M.; Tomasello, A.; Cardona, P.; Devlin, T.G.; Frei, D.F.; du Mesnil de Rochemont, R.; Berkhemer, O.A.; Jovin, T.G.; Siddiqui, A.H.; van Zwam, W.H.; Davis, S.M. Castañٌo, C.; Sapkota, B.L.; Fransen, P.S.; Molina, C.; van Oostenbrugge, R.J.; Chamorro, Á; Lingsma, H.; Silver, F.L.; Donnan, G.A.; Shuaib, A.; Brown, S.; Stouch, B.; Mitchell, P.J.; Davalos, A.; Roos, Y.B.W.E.M.; Hill, M.D. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: A meta-analysis. JAMA, 2016, 316(12), 1279-1288. doi: 10.1001/jama.2016.13647 PMID: 27673305Gervois, P.; Wolfs, E.; Ratajczak, J.; Dillen, Y.; Vangansewinkel, T.; Hilkens, P.; Bronckaers, A.; Lambrichts, I.; Struys, T. Stem cell-based therapies for ischemic stroke: Preclinical results and the potential of imaging-assisted evaluation of donor cell fate and mechanisms of brain regeneration. Med. Res. Rev., 2016, 36(6), 1080-1126. doi: 10.1002/med.21400 PMID: 27439773Li, Y.; Yu, S.P.; Mohamad, O.; Genetta, T.; Wei, L. Sublethal transient global ischemia stimulates migration of neuroblasts and neurogenesis in mice. Transl. Stroke Res., 2010, 1(3), 184-196. doi: 10.1007/s12975-010-0016-6 PMID: 21792374Li, W.L.; Yu, S.P.; Ogle, M.E.; Ding, X.S.; Wei, L. Enhanced neurogenesis and cell migration following focal ischemia and peripheral stimulation in mice. Dev. Neurobiol., 2008, 68(13), 1474-1486. doi: 10.1002/dneu.20674 PMID: 18777565Kornack, D.R.; Rakic, P. The generation, migration, and differentiation of olfactory neurons in the adult primate brain. Proc. Natl. Acad. Sci. USA, 2001, 98(8), 4752-4757. doi: 10.1073/pnas.081074998 PMID: 11296302Menezes, J.R.L.; Smith, C.M.; Nelson, K.C.; Luskin, M.B. The division of neuronal progenitor cells during migration in the neonatal mammalian forebrain. Mol. Cell. Neurosci., 1995, 6(6), 496-508. doi: 10.1006/mcne.1995.0002 PMID: 8742267Smith, C.M.; Luskin, M.B. Cell cycle length of olfactory bulb neuronal progenitors in the rostral migratory stream. Dev. Dyn., 1998, 213(2), 220-227. doi: 10.1002/(SICI)1097-0177(199810)213:23.0.CO;2-I PMID: 9786422Kokaia, Z.; Thored, P.; Arvidsson, A.; Lindvall, O. Regulation of stroke-induced neurogenesis in adult brain--recent scientific progress. Cereb. Cortex, 2006, 16(Suppl. 1), i162-i167. doi: 10.1093/cercor/bhj174 PMID: 16766702Wu, Q.; Yang, B.; Hu, K.; Cao, C.; Man, Y.; Wang, P. Deriving osteogenic cells from induced pluripotent stem cells for bone tissue engineering. Tissue Eng. Part B Rev., 2017, 23(1), 1-8. doi: 10.1089/ten.teb.2015.0559 PMID: 27392674Mohamad, O.; Drury-Stewart, D.; Song, M.; Faulkner, B.; Chen, D.; Yu, S.P.; Wei, L. Vector-free and transgene-free human iPS cells differentiate into functional neurons and enhance functional recovery after ischemic stroke in mice. PLoS One, 2013, 8(5), e64160. doi: 10.1371/journal.pone.0064160 PMID: 23717557Yuan, T.; Liao, W.; Feng, N.H.; Lou, Y.L.; Niu, X.; Zhang, A.J.; Wang, Y.; Deng, Z.F. Human induced pluripotent stem cell-derived neural stem cells survive, migrate, differentiate, and improve neurologic function in a rat model of middle cerebral artery occlusion. Stem Cell Res. Ther., 2013, 4(3), 73. doi: 10.1186/scrt224 PMID: 23769173Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006, 126(4), 663-676. doi: 10.1016/j.cell.2006.07.024 PMID: 16904174Yu, F.; Li, Y.; Morshead, C. Induced pluripotent stem cells for the treatment of stroke: The potential and the pitfalls. Curr. Stem Cell Res. Ther., 2013, 8(5), 407-414. doi: 10.2174/1574888X113089990052 PMID: 23895059Gurdon, J.B. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol., 1962, 10(5), 622-640. doi: 10.1242/dev.10.4.622Wilmut, I.; Schnieke, AE.; McWhir, J.; Kind, AJ.; Campbell, KHS. Viable offspring derived from fetal and adult mammalian cells. Nature, 1997, 385(6619), 810.Abe, K.; Yamashita, T.; Takizawa, S.; Kuroda, S.; Kinouchi, H.; Kawahara, N. Stem cell therapy for cerebral ischemia: From basic science to clinical applications. J. Cereb. Blood Flow Metab., 2012, 32(7), 1317-1331. doi: 10.1038/jcbfm.2011.187 PMID: 22252239Mandai, M.; Watanabe, A.; Kurimoto, Y.; Hirami, Y.; Morinaga, C.; Daimon, T.; Fujihara, M.; Akimaru, H.; Sakai, N.; Shibata, Y.; Terada, M.; Nomiya, Y.; Tanishima, S.; Nakamura, M.; Kamao, H.; Sugita, S.; Onishi, A.; Ito, T.; Fujita, K.; Kawamata, S.; Go, M.J.; Shinohara, C.; Hata, K.; Sawada, M.; Yamamoto, M.; Ohta, S.; Ohara, Y.; Yoshida, K.; Kuwahara, J.; Kitano, Y.; Amano, N.; Umekage, M.; Kitaoka, F.; Tanaka, A.; Okada, C.; Takasu, N.; Ogawa, S.; Yamanaka, S.; Takahashi, M. Autologous induced stem-cell–derived retinal cells for macular degeneration. N. Engl. J. Med., 2017, 376(11), 1038-1046. doi: 10.1056/NEJMoa1608368 PMID: 28296613Okita, K.; Yamanaka, S. Induced pluripotent stem cells: Opportunities and challenges. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2011, 366(1575), 2198-2207. doi: 10.1098/rstb.2011.0016 PMID: 21727125Kajikawa, K.; Imaizumi, K.; Shinozaki, M.; Shibata, S.; Shindo, T.; Kitagawa, T.; Shibata, R.; Kamata, Y.; Kojima, K.; Nagoshi, N.; Matsumoto, M.; Nakamura, M.; Okano, H. Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells. Mol. Brain, 2020, 13(1), 120. doi: 10.1186/s13041-020-00662-w PMID: 32883317Mathur, A.; Loskill, P.; Shao, K.; Huebsch, N.; Hong, S.; Marcus, S.G.; Marks, N.; Mandegar, M.; Conklin, B.R.; Lee, L.P.; Healy, K.E. Human iPSC-based cardiac microphysiological system for drug screening applications. Sci. Rep., 2015, 5(1), 8883. doi: 10.1038/srep08883 PMID: 25748532Gutbier, S.; Wanke, F.; Dahm, N.; Rümmelin, A.; Zimmermann, S.; Christensen, K. Köِchl, F.; Rautanen, A.; Hatje, K.; Geering, B.; Zhang, J.D.; Britschgi, M.; Cowley, S.A.; Patsch, C. Large-scale production of human iPSC-derived macrophages for drug screening. Int. J. Mol. Sci., 2020, 21(13), 4808. doi: 10.3390/ijms21134808 PMID: 32645954Feng, L.; Chao, J.; Tian, E.; Li, L.; Ye, P.; Zhang, M.; Chen, X.; Cui, Q.; Sun, G.; Zhou, T.; Felix, G.; Qin, Y.; Li, W.; Meza, E.D.; Klein, J.; Ghoda, L.; Hu, W.; Luo, Y.; Dang, W.; Hsu, D.; Gold, J.; Goldman, S.A.; Matalon, R.; Shi, Y. Cell-based therapy for canavan disease using human iPSC-derived NPCs and OPCs. Adv. Sci. (Weinh.), 2020, 7(23), 2002155. doi: 10.1002/advs.202002155 PMID: 33304759Sugai, K.; Sumida, M.; Shofuda, T.; Yamaguchi, R.; Tamura, T.; Kohzuki, T.; Abe, T.; Shibata, R.; Kamata, Y.; Ito, S.; Okubo, T.; Tsuji, O.; Nori, S.; Nagoshi, N.; Yamanaka, S.; Kawamata, S.; Kanemura, Y.; Nakamura, M.; Okano, H. First-in-human clinical trial of transplantation of iPSC-derived NS/PCs in subacute complete spinal cord injury: Study protocol. Regen. Ther., 2021, 18, 321-333. doi: 10.1016/j.reth.2021.08.005 PMID: 34522725Choi, D.W.; Rothman, S.M. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu. Rev. Neurosci., 1990, 13(1), 171-182. doi: 10.1146/annurev.ne.13.030190.001131 PMID: 1970230Deleglise, B.; Lassus, B.; Soubeyre, V.; Doulazmi, M.; Brugg, B.; Vanhoutte, P.; Peyrin, J.M. Dysregulated neurotransmission induces trans-synaptic degeneration in reconstructed neuronal networks. Sci. Rep., 2018, 8(1), 11596. doi: 10.1038/s41598-018-29918-1 PMID: 30072750Qin, J.; Ma, X.; Qi, H.; Song, B.; Wang, Y.; Wen, X.; Wang, Q.M.; Sun, S.; Li, Y.; Zhang, R.; Liu, X.; Hou, H.; Gong, G.; Xu, Y. Transplantation of induced pluripotent stem cells alleviates cerebral inflammation and neural damage in hemorrhagic stroke. PLoS One, 2015, 10(6), e0129881. doi: 10.1371/journal.pone.0129881 PMID: 26086994Lee, I.H.; Huang, S.S.; Chuang, C.Y.; Liao, K.H.; Chang, L.H.; Chuang, C.C.; Su, Y.S.; Lin, H.J.; Hsieh, J.Y.; Su, S.H.; Lee, O.K.S.; Kuo, H.C. Delayed epidural transplantation of human induced pluripotent stem cell-derived neural progenitors enhances functional recovery after stroke. Sci. Rep., 2017, 7(1), 1943. doi: 10.1038/s41598-017-02137-w PMID: 28512358Huang, J.Y.; Hong, Y.T.; Chuang, J.I. Fibroblast growth factor 9 prevents MPP+-induced death of dopaminergic neurons and is involved in melatonin neuroprotection in vivo and in vitro. J. Neurochem., 2009, 109(5), 1400-1412. doi: 10.1111/j.1471-4159.2009.06061.x PMID: 19476551Shurin, G.V.; Ferris, R.; Tourkova, I.L.; Perez, L.; Lokshin, A.; Balkir, L.; Collins, B.; Chatta, G.S.; Shurin, M.R. Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo. J. Immunol., 2005, 174(9), 5490-5498. doi: 10.4049/jimmunol.174.9.5490 PMID: 15843547Banisadr, G.; Bhattacharyya, B.J.; Belmadani, A.; Izen, S.C.; Ren, D.; Tran, P.B.; Miller, R.J. The chemokine BRAK/CXCL14 regulates synaptic transmission in the adult mouse dentate gyrus stem cell niche. J. Neurochem., 2011, 119(6), 1173-1182. doi: 10.1111/j.1471-4159.2011.07509.x PMID: 21955359Zhang, J.; Moats-Staats, B.M.; Ye, P.; D’Ercole, A.J. Expression of insulin-like growth factor system genes during the early postnatal neurogenesis in the mouse hippocampus. J. Neurosci. Res., 2007, 85(8), 1618-1627. doi: 10.1002/jnr.21289 PMID: 17455296Jin, K.; Mao, X.O.; Eshoo, M.W.; Nagayama, T.; Minami, M.; Simon, R.P.; Greenberg, D.A. Microarray analysis of hippocampal gene expression in global cerebral ischemia. Ann. Neurol., 2001, 50(1), 93-103. doi: 10.1002/ana.1073 PMID: 11456315Mehrian-Shai, R.; Chen, C.D.; Shi, T.; Horvath, S.; Nelson, S.F.; Reichardt, J.K.V.; Sawyers, C.L. Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc. Natl. Acad. Sci. USA, 2007, 104(13), 5563-5568. doi: 10.1073/pnas.0609139104 PMID: 17372210Tatarishvili, J.; Oki, K.; Monni, E.; Koch, P.; Memanishvili, T.; Buga, A.M.; Verma, V.; Popa-Wagner, A.; Brüstle, O.; Lindvall, O.; Kokaia, Z. Human induced pluripotent stem cells improve recovery in stroke-injured aged rats. Restor. Neurol. Neurosci., 2014, 32(4), 547-558. doi: 10.3233/RNN-140404 PMID: 24916776Lau, V.W.; Platt, S.R.; Stice, S.L.; West, F.D. Induced pluripotent stem-cell-derived neural cell types in treatment of stroke. Cell Therapy For Brain Injury; Springer: Berlin, Heidelberg, 2015, pp. 147-172.Chen, S.J.; Chang, C.M.; Tsai, S.K.; Chang, Y.L.; Chou, S.J.; Huang, S.S.; Tai, L.K.; Chen, Y.C.; Ku, H.H.; Li, H.Y.; Chiou, S.H. Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue. Stem Cells Dev., 2010, 19(11), 1757-1767. doi: 10.1089/scd.2009.0452 PMID: 20192839Grøّnning Hansen, M.; Laterza, C.; Palma-Tortosa, S.; Kvist, G.; Monni, E.; Tsupykov, O.; Tornero, D.; Uoshima, N.; Soriano, J.; Bengzon, J.; Martino, G.; Skibo, G.; Lindvall, O.; Kokaia, Z. Grafted human pluripotent stem cell-derived cortical neurons integrate into adult human cortical neural circuitry. Stem Cells Transl. Med., 2020, 9(11), 1365-1377. doi: 10.1002/sctm.20-0134 PMID: 32602201Baker, E.W.; Platt, S.R.; Lau, V.W.; Grace, H.E.; Holmes, S.P.; Wang, L.; Duberstein, K.J.; Howerth, E.W.; Kinder, H.A.; Stice, S.L.; Hess, D.C.; Mao, H.; West, F.D. Induced pluripotent stem cell-derived neural stem cell therapy enhances recovery in an ischemic stroke pig model. Sci. Rep., 2017, 7(1), 10075. doi: 10.1038/s41598-017-10406-x PMID: 28855627Arai, K.; Jin, G.; Navaratna, D.; Lo, E.H. Brain angiogenesis in developmental and pathological processes: Neurovascular injury and angiogenic recovery after stroke. FEBS J., 2009, 276(17), 4644-4652. doi: 10.1111/j.1742-4658.2009.07176.x PMID: 19664070Brumm, A.J.; Carmichael, S.T. Not just a rush of blood to the head. Nat. Med., 2012, 18(11), 1609-1610. doi: 10.1038/nm.2990 PMID: 23135507Cai, M.; Zhang, W.; Weng, Z.; Stetler, R.A.; Jiang, X.; Shi, Y.; Gao, Y.; Chen, J. Promoting neurovascular recovery in aged mice after ischemic stroke - prophylactic effect of omega-3 polyunsaturated fatty acids. Aging Dis., 2017, 8(5), 531-545. doi: 10.14336/AD.2017.0520 PMID: 28966799Jiang, X.; Suenaga, J.; Pu, H.; Wei, Z.; Smith, A.D.; Hu, X.; Shi, Y.; Chen, J. Post-stroke administration of omega-3 polyunsaturated fatty acids promotes neurovascular restoration after ischemic stroke in mice: Efficacy declines with aging. Neurobiol. Dis., 2019, 126, 62-75. doi: 10.1016/j.nbd.2018.09.012 PMID: 30218758Oki, K.; Tatarishvili, J.; Wood, J.; Koch, P.; Wattananit, S.; Mine, Y.; Monni, E.; Tornero, D.; Ahlenius, H.; Ladewig, J.; Brüstle, O.; Lindvall, O.; Kokaia, Z. Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem Cells, 2012, 30(6), 1120-1133. doi: 10.1002/stem.1104 PMID: 22495829Chan, S.J.; Esposito, E.; Hayakawa, K.; Mandaville, E.; Smith, R.A.A.; Guo, S.; Niu, W.; Wong, P.T.H.; Cool, S.M.; Lo, E.H.; Nurcombe, V. Vascular endothelial growth factor 165-binding heparan sulfate promotes functional recovery from cerebral ischemia. Stroke, 2020, 51(9), 2844-2853. doi: 10.1161/STROKEAHA.119.025304 PMID: 32772683Kelleher, J.; Dickinson, A.; Cain, S.; Hu, Y.; Bates, N.; Harvey, A.; Ren, J.; Zhang, W.; Moreton, F.C.; Muir, K.W.; Ward, C.; Touyz, R.M.; Sharma, P.; Xu, Q.; Kimber, S.J.; Wang, T. Patient-specific iPSC Model of a genetic vascular dementia syndrome reveals failure of mural cells to stabilize capillary structures. Stem Cell Rep, 2019, 13(5), 817-831. doi: 10.1016/j.stemcr.2019.10.004 PMID: 31680059Xia, Y.; Ling, X.; Hu, G.; Zhu, Q.; Zhang, J.; Li, Q.; Zhao, B.; Wang, Y.; Deng, Z. Small extracellular vesicles secreted by human iPSC-derived MSC enhance angiogenesis through inhibiting STAT3-dependent autophagy in ischemic stroke. Stem Cell Res. Ther., 2020, 11(1), 313. doi: 10.1186/s13287-020-01834-0 PMID: 32698909Ceradini, D.J.; Kulkarni, A.R.; Callaghan, M.J.; Tepper, O.M.; Bastidas, N.; Kleinman, M.E.; Capla, J.M.; Galiano, R.D.; Levine, J.P.; Gurtner, G.C. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat. Med., 2004, 10(8), 858-864. doi: 10.1038/nm1075 PMID: 15235597Suzuki, Y.; Rahman, M.; Mitsuya, H. Diverse transcriptional response of CD4+ T cells to stromal cell-derived factor SDF-1: Cell survival promotion and priming effects of SDF-1 on CD4+ T cells. J. Immunol., 2001, 167(6), 3064-3073. doi: 10.4049/jimmunol.167.6.3064 PMID: 11544290Shyu, W.C.; Lin, S.Z.; Yen, P.S.; Su, C.Y.; Chen, D.C.; Wang, H.J.; Li, H. Stromal cell-derived factor-1 alpha promotes neuroprotection, angiogenesis, and mobilization/homing of bone marrow-derived cells in stroke rats. J. Pharmacol. Exp. Ther., 2008, 324(2), 834-849. doi: 10.1124/jpet.107.127746 PMID: 18029549Ziai, W.C. Hematology and inflammatory signaling of intracerebral hemorrhage. Stroke, 2013, 44(6)(1), S74, S78. doi: 10.1161/STROKEAHA.111.000662 PMID: 23709738Eckert, A.; Huang, L.; Gonzalez, R.; Kim, H.S.; Hamblin, M.H.; Lee, J.P. Bystander effect fuels human induced pluripotent stem cell-derived neural stem cells to quickly attenuate early stage neurological deficits after stroke. Stem Cells Transl. Med., 2015, 4(7), 841-851. doi: 10.5966/sctm.2014-0184 PMID: 26025980Li, H.; Wu, J.; Shen, H.; Yao, X.; Liu, C.; Pianta, S.; Han, J.; Borlongan, C.V.; Chen, G. Autophagy in hemorrhagic stroke: Mechanisms and clinical implications. Prog. Neurobiol., 2018, 163-164, 79-97. doi: 10.1016/j.pneurobio.2017.04.002 PMID: 28414101Thiebaut, A.M.; Hedou, E.; Marciniak, S.J.; Vivien, D.; Roussel, B.D. Proteostasis during cerebral ischemia. Front. Neurosci., 2019, 13, 637. doi: 10.3389/fnins.2019.00637 PMID: 31275110Buckley, K.M.; Hess, D.L.; Sazonova, I.Y.; Periyasamy-Thandavan, S.; Barrett, J.R.; Kirks, R.; Grace, H.; Kondrikova, G.; Johnson, M.H.; Hess, D.C.; Schoenlein, P.V.; Hoda, M.N.; Hill, W.D. Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. Exp. Transl. Stroke Med., 2014, 6(1), 8. doi: 10.1186/2040-7378-6-8 PMID: 24991402Shi, R.; Weng, J.; Zhao, L.; Li, X.M.; Gao, T.M.; Kong, J. Excessive autophagy contributes to neuron death in cerebral ischemia. CNS Neurosci. Ther., 2012, 18(3), 250-260. doi: 10.1111/j.1755-5949.2012.00295.x PMID: 22449108Ryan, F.; Khodagholi, F.; Dargahi, L.; Minai-Tehrani, D.; Ahmadiani, A. Temporal pattern and crosstalk of necroptosis markers with autophagy and apoptosis associated proteins in ischemic hippocampus. Neurotox. Res., 2018, 34(1), 79-92. doi: 10.1007/s12640-017-9861-3 PMID: 29313217Cui, D.R.; Wang, L.; Jiang, W.; Qi, A.H.; Zhou, Q.H.; Zhang, X.L. Propofol prevents cerebral ischemia-triggered autophagy activation and cell death in the rat hippocampus through the NF-κB/p53 signaling pathway. Neuroscience, 2013, 246, 117-132. doi: 10.1016/j.neuroscience.2013.04.054 PMID: 23644056Al-Ahmad, A.J.; Pervaiz, I.; Karamyan, V.T. Neurolysin substrates bradykinin, neurotensin and substance P enhance brain microvascular permeability in a human in vitro model. J. Neuroendocrinol., 2021, 33(2), e12931. doi: 10.1111/jne.12931 PMID: 33506602Wu, Y.; Wu, J.; Ju, R.; Chen, Z.; Xu, Q. Comparison of intracerebral transplantation effects of different stem cells on rodent stroke models. Cell Biochem. Funct., 2015, 33(4), 174-182. doi: 10.1002/cbf.3083 PMID: 25914321Tornero, D.; Tsupykov, O.; Granmo, M.; Rodriguez, C. Grøّnning-Hansen, M.; Thelin, J.; Smozhanik, E.; Laterza, C.; Wattananit, S.; Ge, R.; Tatarishvili, J.; Grealish, S.; Brüstle, O.; Skibo, G.; Parmar, M.; Schouenborg, J.; Lindvall, O.; Kokaia, Z. Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli. Brain, 2017, 140(3), aww347. doi: 10.1093/brain/aww347 PMID: 28115364Jensen, M.B.; Yan, H.; Krishnaney-Davison, R.; Al Sawaf, A.; Zhang, S.C. Survival and differentiation of transplanted neural stem cells derived from human induced pluripotent stem cells in a rat stroke model. J. Stroke Cerebrovasc. Dis., 2013, 22(4), 304-308. doi: 10.1016/j.jstrokecerebrovasdis.2011.09.008 PMID: 22078778Chang, D.J.; Lee, N.; Park, I.H.; Choi, C.; Jeon, I.; Kwon, J.; Oh, S.H.; Shin, D.A.; Do, J.T.; Lee, D.R.; Lee, H.; Hong, K.S.; Daley, G.Q.; Song, J.; Moon, H. Therapeutic potential of human induced pluripotent stem cells in experimental stroke. Cell Transplant., 2013, 22(8), 1427-1440. doi: 10.3727/096368912X657314 PMID: 23044029Oh, S.H.; Jeong, Y.W.; Choi, W.; Noh, J.E.; Lee, S.; Kim, H.S. Multimodal therapeutic effects of neural precursor cells derived from human-induced pluripotent stem cells through episomal plasmid-based reprogramming in a rodent model of ischemic stroke. Stem Cells Int., 2020, 2020, 4061516. doi: 10.1155/2020/4061516Liu, S.P.; Fu, R.H.; Wu, D.C.; Hsu, C.Y.; Chang, C.H.; Lee, W.; Lee, Y.D.; Liu, C.H.; Chien, Y.J.; Lin, S.Z.; Shyu, W.C. Mouse-induced pluripotent stem cells generated under hypoxic conditions in the absence of viral infection and oncogenic factors and used for ischemic stroke therapy. Stem Cells Dev., 2014, 23(4), 421-433. doi: 10.1089/scd.2013.0182 PMID: 24266622Kawai, H.; Yamashita, T.; Ohta, Y.; Deguchi, K.; Nagotani, S.; Zhang, X.; Ikeda, Y.; Matsuura, T.; Abe, K. Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J. Cereb. Blood Flow Metab., 2010, 30(8), 1487-1493. doi: 10.1038/jcbfm.2010.32 PMID: 20216552Zong, Y.; Xin, L.; Goldstein, A.S.; Lawson, D.A.; Teitell, M.A.; Witte, O.N. ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells. Proc. Natl. Acad. Sci. USA, 2009, 106(30), 12465-12470. doi: 10.1073/pnas.0905931106 PMID: 19592505Huang, C.Y.; Fujimura, M.; Noshita, N.; Chang, Y.Y.; Chan, P.H. SOD1 down-regulates NF-kappaB and c-Myc expression in mice after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab., 2001, 21(2), 163-173. doi: 10.1097/00004647-200102000-00008 PMID: 11176282Baudino, T.A.; McKay, C.; Pendeville-Samain, H.; Nilsson, J.A.; Maclean, K.H.; White, E.L.; Davis, A.C.; Ihle, J.N.; Cleveland, J.L. c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. Genes Dev., 2002, 16(19), 2530-2543. doi: 10.1101/gad.1024602 PMID: 12368264Miljan, E.A.; Sinden, J.D. Stem cell treatment of ischemic brain injury. Curr. Opin. Mol. Ther., 2009, 11(4), 394-403. PMID: 19649984Albekairi, T.H.; Vaidya, B.; Patel, R.; Nozohouri, S.; Villalba, H.; Zhang, Y.; Lee, Y.S.; Al-Ahmad, A.; Abbruscato, T.J. Brain delivery of a potent opioid receptor agonist, biphalin during ischemic stroke: Role of organic anion transporting polypeptide (OATP). Pharmaceutics, 2019, 11(9), 467. doi: 10.3390/pharmaceutics11090467 PMID: 31509975Payne, S.L.; Anandakumaran, P.N.; Varga, B.V.; Morshead, C.M.; Nagy, A.; Shoichet, M.S. In vitro maturation of human iPSC-derived neuroepithelial cells influences transplant survival in the stroke-injured rat brain. Tissue Eng. Part A, 2018, 24(3-4), 351-360. doi: 10.1089/ten.tea.2016.0515 PMID: 28594288Benoit, J.P.; Faisant, N.; Venier-Julienne, M.C.; Menei, P. Development of microspheres for neurological disorders: From basics to clinical applications. J. Control. Release, 2000, 65(1-2), 285-296. doi: 10.1016/S0168-3659(99)00250-3 PMID: 10699288Nicholas, A.P.; McInnis, C.; Gupta, K.B.; Snow, W.W.; Love, D.F.; Mason, D.W.; Ferrell, T.M.; Staas, J.K.; Tice, T.R. The fate of biodegradable microspheres injected into rat brain. Neurosci. Lett., 2002, 323(2), 85-88. doi: 10.1016/S0304-3940(01)02534-4 PMID: 11950499Bible, E.; Chau, D.Y.S.; Alexander, M.R.; Price, J.; Shakesheff, K.M.; Modo, M. Attachment of stem cells to scaffold particles for intra-cerebral transplantation. Nat. Protoc., 2009, 4(10), 1440-1453. doi: 10.1038/nprot.2009.156 PMID: 19798079Tornero, D.; Wattananit, S. Grøّnning Madsen, M.; Koch, P.; Wood, J.; Tatarishvili, J.; Mine, Y.; Ge, R.; Monni, E.; Devaraju, K.; Hevner, R.F.; Brüstle, O.; Lindvall, O.; Kokaia, Z. Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery. Brain, 2013, 136(12), 3561-3577. doi: 10.1093/brain/awt278 PMID: 24148272Knight, D.K.; Gillies, E.R.; Mequanint, K. Strategies in functional poly(ester amide) syntheses to study human coronary artery smooth muscle cell interactions. Biomacromolecules, 2011, 12(7), 2475-2487. doi: 10.1021/bm200149k PMID: 21619072Huang, Y.; Wang, L.; Li, S.; Liu, X.; Lee, K.; Verbeken, E.; van de Werf, F.; de Scheerder, I. Stent-based tempamine delivery on neointimal formation in a porcine coronary model. Acute Card. Care, 2006, 8(4), 210-216. doi: 10.1080/17482940600949661 PMID: 17162547Kropp, M.; Morawa, K.M.; Mihov, G.; Salz, A.; Harmening, N.; Franken, A.; Kemp, A.; Dias, A.; Thies, J.; Johnen, S.; Thumann, G. Biocompatibility of poly(ester amide) (PEA) microfibrils in ocular tissues. Polymers (Basel), 2014, 6(1), 243-260. doi: 10.3390/polym6010243Darsalia, V.; Allison, S.J.; Cusulin, C.; Monni, E.; Kuzdas, D.; Kallur, T.; Lindvall, O.; Kokaia, Z. Cell number and timing of transplantation determine survival of human neural stem cell grafts in stroke-damaged rat brain. J. Cereb. Blood Flow Metab., 2011, 31(1), 235-242. doi: 10.1038/jcbfm.2010.81 PMID: 20531461Memanishvili, T.; Kupatadze, N.; Tugushi, D.; Katsarava, R.; Wattananit, S.; Hara, N.; Tornero, D.; Kokaia, Z. Generation of cortical neurons from human induced-pluripotent stem cells by biodegradable polymeric microspheres loaded with priming factors. Biomed. Mater., 2016, 11(2), 025011. doi: 10.1088/1748-6041/11/2/025011 PMID: 27007569Wu, R.; Luo, S.; Yang, H.; Hu, X.; Lin, A.; Pan, G.; Zhong, X.; Li, Z. Transplantation of neural progenitor cells generated from human urine epithelial cell-derived induced pluripotent stem cells improves neurological functions in rats with stroke. Discov. Med., 2020, 29(156), 53-64. PMID: 32598863Ould-Brahim, F.; Sarma, S.N.; Syal, C.; Lu, K.J.; Seegobin, M.; Carter, A.; Jeffers, M.S.; Doré, C.; Stanford, W.L.; Corbett, D.; Wang, J. Metformin preconditioning of human induced pluripotent stem cell-derived neural stem cells promotes their engraftment and improves post-stroke regeneration and recovery. Stem Cells Dev., 2018, 27(16), 1085-1096. doi: 10.1089/scd.2018.0055 PMID: 29893190Chau, M.J.; Deveau, T.C.; Song, M.; Gu, X.; Chen, D.; Wei, L. iPSC transplantation increases regeneration and functional recovery after ischemic stroke in neonatal rats. Stem Cells, 2014, 32(12), 3075-3087. doi: 10.1002/stem.1802 PMID: 25132189McCrary, M.R.; Jesson, K.; Wei, Z.Z.; Logun, M.; Lenear, C.; Tan, S.; Gu, X.; Jiang, M.Q.; Karumbaiah, L.; Yu, S.P.; Wei, L. Cortical transplantation of brain-mimetic glycosaminoglycan scaffolds and neural progenitor cells promotes vascular regeneration and functional recovery after ischemic stroke in mice. Adv. Healthc. Mater., 2020, 9(5), 1900285. doi: 10.1002/adhm.201900285 PMID: 31977165Wang, Z.; Zheng, D.; Tan, Y.S.; Yuan, Q.; Yuan, F.; Zhang, S.C. Enabling survival of transplanted neural precursor cells in the ischemic brain. Adv. Sci. (Weinh.), 2023, 10(33), 2302527. doi: 10.1002/advs.202302527 PMID: 37867250Yu, S.P.; Tung, J.K.; Wei, Z.Z.; Chen, D.; Berglund, K.; Zhong, W.; Zhang, J.Y.; Gu, X.; Song, M.; Gross, R.E.; Lin, S.Z.; Wei, L. Optochemogenetic stimulation of transplanted iPS-NPCs enhances neuronal repair and functional recovery after ischemic stroke. J. Neurosci., 2019, 39(33), 6571-6594. doi: 10.1523/JNEUROSCI.2010-18.2019 PMID: 31263065Nih, L.R.; Moshayedi, P.; Llorente, I.L.; Berg, A.R.; Cinkornpumin, J.; Lowry, W.E.; Segura, T.; Carmichael, S.T. Engineered HA hydrogel for stem cell transplantation in the brain: Biocompatibility data using a design of experiment approach. Data Brief, 2017, 10, 202-209. doi: 10.1016/j.dib.2016.11.069 PMID: 27995155Chau, M.; Deveau, T.C.; Song, M.; Wei, Z.Z.; Gu, X.; Yu, S.P.; Wei, L. Transplantation of iPS cell-derived neural progenitors overexpressing SDF-1α increases regeneration and functional recovery after ischemic stroke. Oncotarget, 2017, 8(57), 97537-97553. doi: 10.18632/oncotarget.22180 PMID: 29228630Zhao, T.; Zhang, Z.N.; Rong, Z.; Xu, Y. Immunogenicity of induced pluripotent stem cells. Nature, 2011, 474(7350), 212-215. doi: 10.1038/nature10135 PMID: 21572395Bang, O.Y.; Kim, E.H.; Cha, J.M.; Moon, G.J. Adult stem cell therapy for stroke: Challenges and progress. J. Stroke, 2016, 18(3), 256-266. doi: 10.5853/jos.2016.01263 PMID: 27733032Schenke-Layland, K.; Rhodes, K.E.; Angelis, E.; Butylkova, Y.; Heydarkhan-Hagvall, S.; Gekas, C.; Zhang, R.; Goldhaber, J.I.; Mikkola, H.K.; Plath, K.; MacLellan, W.R. Reprogrammed mouse fibroblasts differentiate into cells of the cardiovascular and hematopoietic lineages. Stem Cells, 2008, 26(6), 1537-1546. doi: 10.1634/stemcells.2008-0033 PMID: 18450826Hanna, J.; Markoulaki, S.; Schorderet, P.; Carey, B.W.; Beard, C.; Wernig, M.; Creyghton, M.P.; Steine, E.J.; Cassady, J.P.; Foreman, R.; Lengner, C.J.; Dausman, J.A.; Jaenisch, R. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell, 2008, 133(2), 250-264. doi: 10.1016/j.cell.2008.03.028 PMID: 18423197Lee, M.O.; Moon, S.H.; Jeong, H.C.; Yi, J.Y.; Lee, T.H.; Shim, S.H.; Rhee, Y.H.; Lee, S.H.; Oh, S.J.; Lee, M.Y.; Han, M.J.; Cho, Y.S.; Chung, H.M.; Kim, K.S.; Cha, H.J. Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proc. Natl. Acad. Sci. USA, 2013, 110(35), E3281-E3290. doi: 10.1073/pnas.1303669110 PMID: 23918355Zhu, Y.; Wan, S.; Zhan, R. Inducible pluripotent stem cells for the treatment of ischemic stroke: Current status and problems. Rev. Neurosci., 2012, 23(4), 393-402. doi: 10.1515/revneuro-2012-0042 PMID: 23089605Amabile, G.; Meissner, A. Induced pluripotent stem cells: Current progress and potential for regenerative medicine. Trends Mol. Med., 2009, 15(2), 59-68. doi: 10.1016/j.molmed.2008.12.003 PMID: 19162546Cai, J.; Li, W.; Su, H.; Qin, D.; Yang, J.; Zhu, F.; Xu, J.; He, W.; Guo, X.; Labuda, K.; Peterbauer, A.; Wolbank, S.; Zhong, M.; Li, Z.; Wu, W.; So, K.F.; Redl, H.; Zeng, L.; Esteban, M.A.; Pei, D. Generation of human induced pluripotent stem cells from umbilical cord matrix and amniotic membrane mesenchymal cells. J. Biol. Chem., 2010, 285(15), 11227-11234. doi: 10.1074/jbc.M109.086389 PMID: 20139068Lister, R.; Pelizzola, M.; Kida, Y.S.; Hawkins, R.D.; Nery, J.R.; Hon, G.; Antosiewicz-Bourget, J.; O’Malley, R.; Castanon, R.; Klugman, S.; Downes, M.; Yu, R.; Stewart, R.; Ren, B.; Thomson, J.A.; Evans, R.M.; Ecker, J.R. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature, 2011, 471(7336), 68-73. doi: 10.1038/nature09798 PMID: 21289626Wakabayashi, K.; Nagai, A.; Sheikh, A.M.; Shiota, Y.; Narantuya, D.; Watanabe, T.; Masuda, J.; Kobayashi, S.; Kim, S.U.; Yamaguchi, S. Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model. J. Neurosci. Res., 2010, 88(5), 1017-1025. doi: 10.1002/jnr.22279 PMID: 19885863Chen, J.; Li, Y.; Katakowski, M.; Chen, X.; Wang, L.; Lu, D.; Lu, M.; Gautam, S.C.; Chopp, M. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J. Neurosci. Res., 2003, 73(6), 778-786. doi: 10.1002/jnr.10691 PMID: 12949903Cui, J.; Cui, C.; Cui, Y.; Li, R.; Sheng, H.; Jiang, X.; Tian, Y.; Wang, K.; Gao, J. Bone marrow mesenchymal stem cell transplantation increases GAP-43 expression via ERK1/2 and PI3K/Akt pathways in intracerebral hemorrhage. Cell. Physiol. Biochem., 2017, 42(1), 137-144. doi: 10.1159/000477122 PMID: 28505619Azevedo-Pereira, RL.; Daadi, MM. Isolation and purification of self-renewable human neural stem cells for cell therapy in experimental model of ischemic stroke. Methods Mol. Biol., 2013, 1059, 157-167. doi: 10.1007/978-1-62703-574-3_14Gao, L.; Xu, W.; Li, T.; Chen, J.; Shao, A.; Yan, F.; Chen, G. Stem cell therapy: A promising therapeutic method for intracerebral hemorrhage. Cell Transplant., 2018, 27(12), 1809-1824. doi: 10.1177/0963689718773363 PMID: 29871521Hu, C.; Zhao, L.; Zhang, L.; Bao, Q.; Li, L. Mesenchymal stem cell-based cell-free strategies: Safe and effective treatments for liver injury. Stem Cell Res. Ther., 2020, 11(1), 377. doi: 10.1186/s13287-020-01895-1 PMID: 32883343Villarreal, C.F.; Evangelista, A.F.; Soares, M.B.P. Cell-free therapy: A neuroregenerative approach to sensory neuropathy? Neural Regen. Res., 2019, 14(8), 1383-1384. doi: 10.4103/1673-5374.253522 PMID: 30964062Singh, A.B.; Harris, R.C. Autocrine, paracrine and juxtacrine signaling by EGFR ligands. Cell. Signal., 2005, 17(10), 1183-1193. doi: 10.1016/j.cellsig.2005.03.026 PMID: 15982853Budnik, V. Ruiz-Cañٌada, C.; Wendler, F. Extracellular vesicles round off communication in the nervous system. Nat. Rev. Neurosci., 2016, 17(3), 160-172. doi: 10.1038/nrn.2015.29 PMID: 26891626Castellana, D.; Toti, F.; Freyssinet, J.M. Membrane microvesicles: Macromessengers in cancer disease and progression. Thromb. Res., 2010, 125(Suppl. 2), S84-S88. doi: 10.1016/S0049-3848(10)70021-9 PMID: 20434014Castellana, D.; Zobairi, F.; Martinez, M.C.; Panaro, M.A.; Mitolo, V.; Freyssinet, J.M.; Kunzelmann, C. Membrane microvesicles as actors in the establishment of a favorable prostatic tumoral niche: A role for activated fibroblasts and CX3CL1-CX3CR1 axis. Cancer Res., 2009, 69(3), 785-793. doi: 10.1158/0008-5472.CAN-08-1946 PMID: 19155311Maas, S.L.N.; Breakefield, X.O.; Weaver, A.M. Extracellular vesicles: Unique intercellular delivery vehicles. Trends Cell Biol., 2017, 27(3), 172-188. doi: 10.1016/j.tcb.2016.11.003 PMID: 27979573Hur, Y.H.; Cerione, R.A.; Antonyak, M.A. Extracellular vesicles and their roles in stem cell biology. Stem Cells, 2020, 38(4), 469-476. doi: 10.1002/stem.3140 PMID: 31828924Reclusa, P.; Taverna, S.; Pucci, M.; Durendez, E.; Calabuig, S.; Manca, P.; Serrano, M.J.; Sober, L.; Pauwels, P.; Russo, A.; Rolfo, C. Exosomes as diagnostic and predictive biomarkers in lung cancer. J. Thorac. Dis., 2017, 9(S13), S1373-S1382. doi: 10.21037/jtd.2017.10.67 PMID: 29184676Peng, G.; Yuan, Y.; Wu, S.; He, F.; Hu, Y.; Luo, B. MicroRNA let-7e is a potential circulating biomarker of acute stage ischemic stroke. Transl. Stroke Res., 2015, 6(6), 437-445. doi: 10.1007/s12975-015-0422-x PMID: 26415639Frühbeis, C. Fröِhlich, D.; Krämer-Albers, E.M. Emerging roles of exosomes in neuron-glia communication. Front. Physiol., 2012, 3, 119. doi: 10.3389/fphys.2012.00119 PMID: 22557979Aryani, A.; Denecke, B. Exosomes as a nanodelivery system: A key to the future of neuromedicine? Mol. Neurobiol., 2016, 53(2), 818-834. doi: 10.1007/s12035-014-9054-5 PMID: 25502465Fröِhlich, D.; Kuo, W.P.; Frühbeis, C.; Sun, J.J.; Zehendner, C.M.; Luhmann, H.J.; Pinto, S.; Toedling, J.; Trotter, J.; Krämer-Albers, E.M. Multifaceted effects of oligodendroglial exosomes on neurons: Impact on neuronal firing rate, signal transduction and gene regulation. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2014, 369(1652), 20130510. doi: 10.1098/rstb.2013.0510 PMID: 25135971Krämer-Albers, E.M.; Bretz, N.; Tenzer, S.; Winterstein, C.; Möِbius, W.; Berger, H.; Nave, K.A.; Schild, H.; Trotter, J. Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: Trophic support for axons? Proteomics Clin. Appl., 2007, 1(11), 1446-1461. doi: 10.1002/prca.200700522 PMID: 21136642You, L.; Wang, Z.; Li, H.; Shou, J.; Jing, Z.; Xie, J.; Sui, X.; Pan, H.; Han, W. The role of STAT3 in autophagy. Autophagy, 2015, 11(5), 729-739. doi: 10.1080/15548627.2015.1017192 PMID: 25951043Oh, M.; Lee, J.; Kim, Y.; Rhee, W.; Park, J. Exosomes derived from human induced pluripotent stem cells ameliorate the aging of skin fibroblasts. Int. J. Mol. Sci., 2018, 19(6), 1715. doi: 10.3390/ijms19061715 PMID: 29890746Ye, M.; Ni, Q.; Qi, H.; Qian, X.; Chen, J.; Guo, X.; Li, M.; Zhao, Y.; Xue, G.; Deng, H.; Zhang, L. Exosomes derived from human induced pluripotent stem cells-endothelia cells promotes postnatal angiogenesis in mice bearing ischemic limbs. Int. J. Biol. Sci., 2019, 15(1), 158-168. doi: 10.7150/ijbs.28392 PMID: 30662356Tian, T.; Zhang, H.X.; He, C.P.; Fan, S.; Zhu, Y.L.; Qi, C.; Huang, N.P.; Xiao, Z.D.; Lu, Z.H.; Tannous, B.A.; Gao, J. Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials, 2018, 150, 137-149. doi: 10.1016/j.biomaterials.2017.10.012 PMID: 29040874Joladarashi, D.; Garikipati, V.N.S.; Thandavarayan, R.A.; Verma, S.K.; Mackie, A.R.; Khan, M.; Gumpert, A.M.; Bhimaraj, A.; Youker, K.A.; Uribe, C.; Suresh Babu, S.; Jeyabal, P.; Kishore, R.; Krishnamurthy, P. Enhanced cardiac regenerative ability of stem cells after ischemia-reperfusion injury. J. Am. Coll. Cardiol., 2015, 66(20), 2214-2226. doi: 10.1016/j.jacc.2015.09.009 PMID: 26564600Santoso, M.R.; Ikeda, G.; Tada, Y.; Jung, J.H.; Vaskova, E.; Sierra, R.G.; Gati, C.; Goldstone, A.B.; von Bornstaedt, D.; Shukla, P.; Wu, J.C.; Wakatsuki, S.; Woo, Y.J.; Yang, P.C. Exosomes from induced pluripotent stem cell-derived cardiomyocytes promote autophagy for myocardial repair. J. Am. Heart Assoc., 2020, 9(6), e014345. doi: 10.1161/JAHA.119.014345 PMID: 32131688Nong, K.; Wang, W.; Niu, X.; Hu, B.; Ma, C.; Bai, Y.; Wu, B.; Wang, Y.; Ai, K. Hepatoprotective effect of exosomes from human-induced pluripotent stem cell-derived mesenchymal stromal cells against hepatic ischemia-reperfusion injury in rats. Cytotherapy, 2016, 18(12), 1548-1559. doi: 10.1016/j.jcyt.2016.08.002 PMID: 27592404Hettiarachchi, NT.; Boyle, JP.; Dallas, ML.; Al-Owais, MM.; Scragg, JL. Peers, C Heme oxygenase-1 derived carbon monoxide suppresses Aβ1-42 toxicity in astrocytes. Cell Death Dis., 2017, 8(6), e2884. doi: 10.1038/cddis.2017.276Carmichael, S.T. Rodent models of focal stroke: Size, mechanism, and purpose. NeuroRx, 2005, 2(3), 396-409. doi: 10.1602/neurorx.2.3.396 PMID: 16389304Krencik, R.; Weick, J.P.; Liu, Y.; Zhang, Z.J.; Zhang, S.C. Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat. Biotechnol., 2011, 29(6), 528-534. doi: 10.1038/nbt.1877 PMID: 21602806Li, X.; Tao, Y.; Bradley, R.; Du, Z.; Tao, Y.; Kong, L.; Dong, Y.; Jones, J.; Yan, Y.; Harder, C.R.K.; Friedman, L.M.; Bilal, M.; Hoffmann, B.; Zhang, S.C. Fast generation of functional subtype astrocytes from human pluripotent stem cells. Stem Cell Rep, 2018, 11(4), 998-1008. doi: 10.1016/j.stemcr.2018.08.019 PMID: 30269954Llorente, I.L.; Xie, Y.; Mazzitelli, J.A.; Hatanaka, E.A.; Cinkornpumin, J.; Miller, D.R.; Lin, Y.; Lowry, W.E.; Carmichael, S.T. Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents. Sci. Transl. Med., 2021, 13(590), eaaz6747. doi: 10.1126/scitranslmed.aaz6747 PMID: 33883275Ma, D.K.; Ming, G.; Song, H. Glial influences on neural stem cell development: Cellular niches for adult neurogenesis. Curr. Opin. Neurobiol., 2005, 15(5), 514-520. doi: 10.1016/j.conb.2005.08.003 PMID: 16144763Curtis, MA.; Kam, M.; Nannmark, U.; Anderson, MF.; Axell, MZ.; Wikkelso, C. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science, 2007, 315(5816), 1243-1249.Gage, F.H. Mammalian neural stem cells. Science, 2000, 287(5457), 1433-1438. doi: 10.1126/science.287.5457.1433 PMID: 10688783Chen, K-H.; Lin, K-C.; Wallace, C.G.; Li, Y-C.; Shao, P-L.; Chiang, J.Y.; Sung, P.H.; Yip, H.K. Human induced pluripotent stem cell-derived mesenchymal stem cell therapy effectively reduced brain infarct volume and preserved neurological function in rat after acute intracranial hemorrhage. Am. J. Transl. Res., 2019, 11(9), 6232-6248. PMID: 31632590Chen, L.; Zhang, G.; Khan, A.A.; Guo, X.; Gu, Y. Clinical efficacy and meta-analysis of stem cell therapies for patients with brain ischemia. Stem Cells Int., 2016, 2016, 1-8. doi: 10.1155/2016/6129579 PMID: 27656217Detante, O.; Moisan, A.; Hommel, M.; Jaillard, A. Controlled clinical trials of cell therapy in stroke: Meta-analysis at six months after treatment. Int. J. Stroke, 2017, 12(7), 748-751. doi: 10.1177/1747493017696098 PMID: 28884654Díez-Tejedor, E.; Gutiérrez-Fernández, M.; Martínez-Sánchez, P.; Rodríguez-Frutos, B. Ruiz-Ares, G.; Lara, M.L.; Gimeno, B.F. Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: A safety assessment: A phase II randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. J. Stroke Cerebrovasc. Dis., 2014, 23(10), 2694-2700. doi: 10.1016/j.jstrokecerebrovasdis.2014.06.011 PMID: 25304723Liu, X; Jia, X. RNeuroprotection of stem cells against ischemic brain injury: From bench to clinic. Transl. Stroke Res 2027, 10, 01163.