Stroke can cause permanent neurological damage, complications, and even death. However, there is no treatment exists to restore its lost function. Human embryonic stems transplantation therapy was a novel and potential therapeutic approach for stroke. However, as we have seen, the ethical controversy pertains to embryonic stem cell research. Human induced pluripotent stem cells (iPSCs) are the latest generation of stem cells that may be a solution to the controversy of using embryonic cells. In our study, we generated iPSCs from adult human fibroblasts by introduction of four defined transcription factors (Oct4, Sox2, Nanog, and Lin-28). And then, we investigated the efficacy of iPSCs transplantation therapy for stroke on the animal models of middle cerebral artery occlusion. Surprisingly, we found that transplanted iPSCs migrated to injured brain areas, and differentiated into neuron-like cells successfully. After 4–16 days iPSCs grafting, sensorimotor function of rats has been improved significantly. In one word, we may prove that iPSCs therapy in stroke to be an effective form of treatment.
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Central nervous system
Percentage hemisphere lesion volume
Human embryonic stem cells
Induced pluripotent stem cells
Middle cerebral artery occlusion
Somatic cells nuclear transfer
Adams H, Adams R, Del Zoppo G, Goldstein LB (2005) Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke 36:916–923
Flax JD, Aurora S, Yang C, Simonin C, Wills AM, Billinghurst LL, Jendoubi M, Sidman RL, Wolfe JH, Kim SU, Snyder EY (1998) Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat Biotechnol 16:1033–1039
Caldwell MA, He X, Wilkie N, Pollack S, Marshall G, Wafford KA, Svendsen CN (2001) Growth factors regulate the survival and fate of cells derived from human neurospheres. Nat Biotechnol 19:475–479
Kelly S, Bliss TM, Shah AK, Sun GH, Ma M, Foo WC, Masel J, Yenari MA, Weissman IL, Uchida N, Palmer T, Steinberg GK (2004) Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proc Natl Acad Sci USA 101:11839–11844
Ourednik J, Ourednik V, Lynch WP, Schachner M, Snyder EY (2002) Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol 20:1103–1110
Kim JH, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N, Lee SH, Nguyen J, Sanchez-Pernaute R, Bankiewicz K, McKay R (2002) Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 418:50–56
Takagi Y, Takahashi J, Saiki H, Morizane A, Hayashi T, Kishi Y, Fukuda H, Okamoto Y, Koyanagi M, Ideguchi M, Hayashi H, Imazato T, Kawasaki H, Suemori H, Omachi S, Iida H, Itoh N, Nakatsuji N, Sasai Y, Hashimoto N (2005) Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J Clin Invest 115:102–109
Yamanaka S (2008) Induction of pluripotent stem cells from mouse fibroblasts by four transcription factors. Cell Prolif 41:51–56
Zhao LR, Duan WM, Reyes M, Keene CD, Verfaillie CM, Low WC (2002) Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol 174:11–20
Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, Chiba T, Yamanaka S (2008) Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 321:699–702
Byrne JA, Pedersen DA, Clepper LL, Nelson M, Sanger WG, Gokhale S, Wolf DP, Mitalipov SM (2007) Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature 450:497–502
Yamanaka S (2007) Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 1:39–49
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676
Lowry WE, Richter L, Yachechko R, Pyle AD, Tchieu J, Sridharan R, Clark AT, Plath K (2008) Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci USA 105:2883–2888
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872
Touboul T, Hannan NR, Corbineau S, Martinez A, Martinet C, Branchereau S, Mainot S, Strick-Marchand H, Pedersen R, Di Santo J, Weber A, Vallier L (2010) Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development. Hepatology 51:1754–1765
Allahtavakoli M, Moloudi R, Arababadi MK, Shamsizadeh A, Javanmardi K (2009) Delayed post ischemic treatment with Rosiglitazone attenuates infarct volume, neurological deficits and neutrophilia after embolic stroke in rat. Brain Res 1271:121–127
Li JS, Zhang W, Kang ZM, Ding SJ, Liu WW, Zhang JH, Guan YT, Sun XJ (2009) Hyperbaric oxygen preconditioning reduces ischemia-reperfusion injury by inhibition of apoptosis via mitochondrial pathway in rat brain. Neuroscience 159:1309–1315
Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91
Veizovic T, Beech JS, Stroemer RP, Watson WP, Hodges H (2001) Resolution of stroke deficits following contralateral grafts of conditionally immortal neuroepithelial stem cells. Stroke 32:1012–1019
Li J, Henman MC, Tatlisumak T, Shaw GG, Doyle KM (2005) The pre-ischaemic neuroprotective effects of N1-dansyl-spermine in a transient focal cerebral ischaemia model in mice. Brain Res 1055:180–185
Kwakkel G, Kollen BJ, van der Grond J, Prevo AJ (2003) Probability of regaining dexterity in the flaccid upper limb: impact of severity of paresis and time since onset in acute stroke. Stroke 34:2181–2186
Borlongan CV, Tajima Y, Trojanowski JQ, Lee VM, Sanberg PR (1998) Transplantation of cryopreserved human embryonal carcinoma-derived neurons (NT2N cells) promotes functional recovery in ischemic rats. Exp Neurol 149:310–321
Saporta S, Borlongan CV, Sanberg PR (1999) Neural transplantation of human neuroteratocarcinoma (hNT) neurons into ischemic rats. A quantitative dose-response analysis of cell survival and behavioral recovery. Neuroscience 91:519–525
Chu K, Kim M, Park KI, Jeong SW, Park HK, Jung KH, Lee ST, Kang L, Lee K, Park DK, Kim SU, Roh JK (2004) Human neural stem cells improve sensorimotor deficits in the adult rat brain with experimental focal ischemia. Brain Res 1016:145–153
Willing AE, Vendrame M, Mallery J, Cassady CJ, Davis CD, Sanchez-Ramos J, Sanberg PR (2003) Mobilized peripheral blood cells administered intravenously produce functional recovery in stroke. Cell Transplant 12:449–454
Modo M, Stroemer RP, Tang E, Veizovic T, Sowniski P, Hodges H (2000) Neurological sequelae and long-term behavioural assessment of rats with transient middle cerebral artery occlusion. J Neurosci Methods 104:99–109
The authors would like to thank members of Professor Wu Xinzhong’s laboratory for their helpful discussion. This work was partially supported by Natural Science Foundation of China, grant number, 30570632. Pudong New Area, the leading health systems, medical personnel training programs, grant number, PWRq2007-03.
Conflict of interest
All authors have no competing interest to declare.
Mei Jiang and Lei Lv have contributed equally to this work.
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Jiang, M., Lv, L., Ji, H. et al. Induction of pluripotent stem cells transplantation therapy for ischemic stroke. Mol Cell Biochem 354, 67–75 (2011). https://doi.org/10.1007/s11010-011-0806-5
- Brain ischemia
- Induced pluripotent stem cells
- Transcription factors
- Transplantation therapy