Recent Advances in Mono- and Combined Stem Cell Therapies of Stroke in Animal Models and Humans
Abstract
:1. Introduction
2. Stem Cell Monotherapies in Animal Models
2.1. Human Placenta Amniotic Membrane-Derived Mesenchymal Stem Cells
2.2. Human Amnion Epithelial Cells (hAECs)
2.3. Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells (hUCB-MSCs)
2.4. Exogenous Human Neuronal Progenitor Cells
2.5. Human Bone Marrow Endothelial Progenitor Cells to Repair BBB
2.6. Adult Human Pluripotent-Like Olfactory Stem Cells
2.7. Induced Pluripotent Stem Cells (iPSCs) of Human Origin
2.8. Studies Using Genetically Modified Multipotent Mesenchymal Stem Cells in Animal Models
2.9. Adipose Stem Cells
2.10. Bone Marrow Stromal Cells
2.11. Combination Therapies in Animal Models
2.12. The Combined Effect of Bone Marrow Stromal Cells, Exercise, and Thyroid Hormones
2.13. Autologous Stem Cell Monotherapies in Humans
2.14. Mechanisms Underyling the Beneficial Effects of Transplanted MSCs
2.15. Conditioned Medium from Adult Neural Progenitor Cells
2.16. Extracellular Vesicles Hypothesis
2.17. Mitochondria Hypothesis
3. Conclusions
Acknowledgments
Conflicts of Interest
References
- Savitz, S.I.; Fisher, M. Future of neuroprotection for acute stroke: In the aftermath of the SAINT trials. Ann. Neurol. 2007, 61, 396–402. [Google Scholar] [CrossRef] [PubMed]
- Ginsberg, M.D. Neuroprotection for ischemic stroke: Past, present and future. Neuropharmacology 2008, 55, 363–389. [Google Scholar] [CrossRef] [PubMed]
- Lener, T.; Gimona, M.; Aigner, L.; Börger, V.; Buzas, E.; Camussi, G.; Chaput, N.; Chatterjee, D.; Court, F.F.; Del Portillo, H.H.; et al. Applying extracellular vesicles based therapeutics in clinical trials—An ISEV position paper. J. Extracell. Vesicles 2015, 4, 30087. [Google Scholar] [CrossRef]
- Kong, T.; Park, J.M.; Jang, J.H.; Kim, C.Y.; Bae, S.H.; Choi, Y.; Jeong, Y.H.; Kim, C.; Chang, S.W.; Kim, J.; et al. Immunomodulatory effect of CD200-positive human placenta-derived stem cells in the early phase of stroke. Exp. Mol. Med. 2018, 50, e425. [Google Scholar] [CrossRef]
- Hermanto, Y.; Sunohara, T.; Faried, A.; Takagi, Y.; Takahashi, J.; Maki, T.; Miyamoto, S. Transplantation of feeder-free human induced pluripotent stem cell-derived cortical neuron progenitors in adult male Wistar rats with focal brain ischemia. J. Neurosci. Res. 2018, 96, 863–874. [Google Scholar] [CrossRef] [PubMed]
- Evans, M.A.; Lim, R.; Ah Kim, H.; Chu, H.X.; Gardiner-Mann, C.V.; Taylor, K.W.E.; Chan, C.T.; Brait, V.H.; Lee, S.; Nhu Dinh, Q.; et al. Acute or Delayed Systemic Administration of Human Amnion Epithelial Cells Improves Outcomes in Experimental Stroke. Stroke 2018, 49, 700–709. [Google Scholar] [CrossRef]
- Chelluboina, B.; Nalamolu, K.R.; Mendez, G.G.; Klopfenstein, J.D.; Pinson, D.M.; Wang, D.Z.; Veeravalli, K.K. Mesenchymal Stem Cell Treatment Prevents Post-Stroke Dysregulation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases. Cell. Physiol. Biochem. 2017, 44, 1360–1369. [Google Scholar] [CrossRef]
- George, P.M.; Bliss, T.M.; Hua, T.; Lee, A.; Oh, B.; Levinson, A.; Mehta, S.; Sun, G.; Steinberg, G.K. Electrical preconditioning of stem cells with a conductive polymer scaffold enhances stroke recovery. Biomaterials 2017, 142, 31–40. [Google Scholar] [CrossRef]
- Oh, B.; George, P. Conductive polymers to modulate the post-stroke neural environment. Brain Res. Bull. 2019, 148, 10–17. [Google Scholar] [CrossRef]
- Garbuzova-Davis, S.; Haller, E.; Lin, R.; Borlongan, C.V. Intravenously Transplanted Human Bone Marrow Endothelial Progenitor Cells Engraft Within Brain Capillaries, Preserve Mitochondrial Morphology, and Display Pinocytotic Activity Towards BBB Repair in Ischemic Stroke Rats. Stem cells 2017, 35, 1246–1258. [Google Scholar] [CrossRef]
- Fan, J.R.; Lee, H.T.; Lee, W.; Lin, C.H.; Hsu, C.Y.; Hsieh, C.H.; Shyu, W.C. Potential role of CBX7 in regulating pluripotency of adult human pluripotent-like olfactory stem cells in stroke model. Cell Death Dis. 2018, 9, 502. [Google Scholar] [CrossRef] [PubMed]
- Baker, 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.; et al. Induced Pluripotent Stem Cell-Derived Neural Stem Cell Therapy Enhances Recovery in an Ischemic Stroke Pig Model. Sci. Rep. 2017, 7, 10075. [Google Scholar] [CrossRef] [PubMed]
- Lau, V.W.; Platt, S.R.; Grace, H.E.; Baker, E.W.; West, F.D. Human iNPC therapy leads to improvement in functional neurologic outcomes in a pig ischemic stroke model. Brain Behav. 2018, 8, e00972. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.; Li, Y.; Wang, L. Ischemic rat brain extracts induce human marrow stromal cell growth factor production. Neuropathology 2002, 22, 275–279. [Google Scholar] [CrossRef] [PubMed]
- Wei, W.; Huang, Y.; Li, D.; Gou, H.F.; Wang, W. Improved therapeutic potential of MSCs by genetic modification. Gene Ther. 2018, 25, 538–547. [Google Scholar] [CrossRef] [PubMed]
- Wyse, R.D.; Dunbar, G.L.; Rossignol, J. Use of genetically modified mesenchymal stem cells to treat neurodegenerative diseases. Int. J. Mol. Sci. 2014, 15, 1719–1745. [Google Scholar] [CrossRef] [PubMed]
- Tuszynski, M.H.; Thal, L.; Pay, M.; Salmon, D.P.U.H.S.; Bakay, R.; Patel, P.; Blesch, A.; Vahlsing, H.L.; Ho, G.; Tong, G.; et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat. Med. 2005, 11, 551–555. [Google Scholar] [CrossRef]
- Venkataramana, N.K.; Kumar, S.K.; Balaraju, S.; Radhakrishnan, R.C.; Bansal, A.; Dixit, A.; Rao, D.K.; Das, M.; Jan, M.; Gupta, P.K.; et al. Open-labeled study of autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Transl. Res. 2010, 155, 62–70. [Google Scholar] [CrossRef]
- Li, Y.; Chang, S.; Li, W.; Tang, G.; Ma, Y.; Liu, Y.; Yuan, F.; Zhang, Z.; Yang, G.Y.; Wang, Y. cxcl12-engineered endothelial progenitor cells enhance neurogenesis and angiogenesis after ischemic brain injury in mice. Stem Cell Res. Ther. 2018, 9, 139. [Google Scholar] [CrossRef]
- Nagahama, H.; Nakazaki, M.; Sasaki, M.; Kataoka-Sasaki, Y.; Namioka, T.; Namioka, A.; Oka, S.; Onodera, R.; Suzuki, J.; Sasaki, Y.; et al. Preservation of interhemispheric cortical connections through corpus callosum following intravenous infusion of mesenchymal stem cells in a rat model of cerebral infarction. Brain Res. 2018, 1695, 37–44. [Google Scholar] [CrossRef]
- Grudzenski, S.; Baier, S.; Ebert, A.; Pullens, P.; Lemke, A.; Bieback, K.; Dijkhuizen, R.M.; Schad, L.R.; Alonso, A.; Hennerici, M.G.; et al. The effect of adipose tissue-derived stem cells in a middle cerebral artery occlusion stroke model depends on their engraftment rate. Stem Cell Res Ther. 2017, 8, 96. [Google Scholar] [CrossRef] [PubMed]
- Mu, L.; Bakreen, A.; Juntunen, M.; Korhonen, P.; Oinonen, E.; Cui, L.; Myllyniemi, M.; Zhao, S.; Miettinen, S.; Jolkkonen, J. Combined Adipose Tissue-Derived Mesenchymal Stem Cell Therapy and Rehabilitation in Experimental Stroke. Front. Neurol. 2019, 10, 235. [Google Scholar] [CrossRef] [PubMed]
- Cheng, Z.; Wang, L.; Qu, M.; Liang, H.; Li, W.; Li, Y.; Deng, L.; Zhang, Z.; Yang, G.Y. Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice. J. Neuroinflammat. 2018, 15, 135. [Google Scholar] [CrossRef] [PubMed]
- Chen, J.; Yang, Y.; Shen, L.; Ding, W.; Chen, X.; Wu, E.; Cai, K.; Wang, G. Hypoxic Preconditioning Augments the Therapeutic Efficacy of Bone Marrow Stromal Cells in a Rat Ischemic Stroke Model. Cell. Mol. Neurobiol. 2017, 37, 1115–1129. [Google Scholar] [CrossRef] [PubMed]
- Balseanu, A.T.; Buga, A.M.; Catalin, B.; Wagner, D.C.; Boltze, J.; Zagrean, A.M.; Reymann, K.; Schaebitz, W.; Popa-Wagner, A. Multimodal Approaches for Regenerative Stroke Therapies: Combination of Granulocyte Colony-Stimulating Factor with Bone Marrow Mesenchymal Stem Cells is Not Superior to G-CSF Alone. Front. Aging Neurosci. 2014, 6, 130. [Google Scholar] [CrossRef]
- Buga, A.M.; Scheibe, J.; Moller, K.; Ciobanu, O.; Posel, C.; Boltze, J.; Popa-Wagner, A. Granulocyte colony-stimulating factor and bone marrow mononuclear cells for stroke treatment in the aged brain. Curr. Neurovasc. Res. 2015, 12, 155–162. [Google Scholar] [CrossRef]
- Akhoundzadeh, K.; Vakili, A.; Sameni, H.R.; Vafaei, A.A.; Rashidy-Pour, A.; Safari, M.; Mohammadkhani, R. Effects of the combined treatment of bone marrow stromal cells with mild exercise and thyroid hormone on brain damage and apoptosis in a mouse focal cerebral ischemia model. Metab. Brain Dis. 2017, 4, 1267–1277. [Google Scholar] [CrossRef]
- Bhatia, V.; Gupta, V.; Khurana, D.; Sharma, R.R.; Khandelwal, N. Randomized Assessment of the Safety and Efficacy of Intra-Arterial Infusion of Autologous Stem Cells in Subacute Ischemic Stroke. Am. J. Neuroradiol. 2018, 39, 899–904. [Google Scholar] [CrossRef]
- Bhasin, A.; Kumaran, S.S.; Bhatia, R.; Mohanty, S.; Srivastava, M.V.P. Safety and Feasibility of Autologous Mesenchymal Stem Cell Transplantation in Chronic Stroke in Indian patients. A four-year follow up. J. Stem Cells Regen. Med. 2017, 13, 14–19. [Google Scholar]
- Fu, Y.; Karbaat, L.; Wu, L.; Leijten, J.; Both, S.K.; Karperien, M. Trophic Effects of Mesenchymal Stem Cells in Tissue Regeneration. Tissue Eng. Part B Rev. 2017, 23, 515–528. [Google Scholar] [CrossRef]
- Gnecchi, M.; Zhang, Z.; Ni, A.; Dzau, V.J. Paracrine mechanisms in adult stem cell signaling and therapy. Circ. Res. 2008, 103, 1204–1219. [Google Scholar] [CrossRef] [PubMed]
- Cunningham, C.J.; Redondo-Castro, E.; Allan, S.M. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J. Cereb. Blood Flow Metab. 2018, 38, 1276–1292. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gunawardena, T.N.A.; Rahman, M.T.; Abdullah, B.J.J.; Kasim, N.H.A. Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine. J. Tissue Eng. Regen. Med. 2019, 13, 569–586. [Google Scholar] [CrossRef] [PubMed]
- Jiang, R.H.; Wu, C.J.; Xu, X.Q.; Lu, S.S.; Zu, Q.Q.; Zhao, L.B.; Wang, J.; Liu, S.; Shi, H.B. Hypoxic conditioned medium derived from bone marrow mesenchymal stromal cells protects against ischemic stroke in rats. J. Cell. Physiol. 2019, 234, 1354–1368. [Google Scholar] [CrossRef] [PubMed]
- Tsai, M.J.; Tsai, S.K.; Hu, B.R.; Liou, D.Y.; Huang, S.L.; Huang, M.C.; Huang, W.-C.; Cheng, H.; Huang, S.-S. Recovery of neurological function of ischemic stroke by application of conditioned medium of bone marrow mesenchymal stem cells derived from normal and cerebral ischemia rats. J. Biomed. Sci. 2014, 21, 5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bhang, S.H.; Lee, S.; Shin, J.Y.; Lee, T.J.; Jang, H.K.; Kim, B.S. Efficacious and clinically relevant conditioned medium of human adipose-derived stem cells for therapeutic angiogenesis. Mol. Ther. 2014, 22, 862–872. [Google Scholar] [CrossRef] [Green Version]
- Wei, X.; Du, Z.; Zhao, L.; Feng, D.; Wei, G.; He, Y.; Tan, J.; Lee, W.-H.; Hampel, H.; Dodel, R.; et al. IFATS collection: The conditioned media of adipose stromal cells protect against hypoxia-ischemia-induced brain damage in neonatal rats. Stem Cells 2009, 27, 478–488. [Google Scholar] [CrossRef]
- Wei, L.; Fraser, J.L.; Lu, Z.Y.; Hu, X.; Yu, S.P. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol. Dis. 2012, 46, 635–645. [Google Scholar] [CrossRef] [Green Version]
- Doeppner, T.R.; Bähr, M.; Giebel, B.; Hermann, D.M. Immunological and non-immunological effects of stem cell-derived extracellular vesicles on the ischaemic brain. Ther. Adv. Neurol. Disord. 2018, 11, 1756286418789326. [Google Scholar] [CrossRef] [Green Version]
- Hermann, D.M.; Buga, A.M.; Popa-Wagner, A. Neurovascular remodeling in the aged ischemic brain. J. Neural. Transm. 2015, 122, 25–33. [Google Scholar] [CrossRef]
- Doeppner, T.R.; Herz, J.; Görgens, A.; Schlechter, J.; Ludwig, A.K.; Radtke, S.; de Miroschedji, K.; Horn, P.A.; Giebel, B.; Hermann, D.M. Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression. Stem Cells Transl. Med. 2015, 4, 1131–1143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Salami, F.; Tavassoli, A.; Mehrzad, J.; Parham, A. Immunomodulatory effects of mesenchymal stem cells on leukocytes with emphasis on neutrophils. Immunobiology 2018, 223, 786–791. [Google Scholar] [CrossRef] [PubMed]
- Lee, H.Y.; Hong, I.S. Double-edged sword of mesenchymal stem cells: Cancer-promoting versus therapeutic potential. Cancer Sci. 2017, 108, 1939–1946. [Google Scholar] [CrossRef] [PubMed]
- Xin, H.; Li, Y.; Cui, Y.; Yang, J.J.; Zhang, Z.G.; Chopp, M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J. Cereb. Blood Flow Metab. 2013, 33, 1711–1715. [Google Scholar] [CrossRef] [Green Version]
- Zagrean, A.M.; Hermann, D.M.; Opris, I.; Zagrean, L.; Popa-Wagner, A. Multicellular Crosstalk between Exosomes and the Neurovascular Unit after Cerebral Ischemia. Therapeutic Implications. Front. Neurosci. 2018, 12, 811. [Google Scholar] [CrossRef]
- Zhang, Z.G.; Buller, B.; Chopp, M. Exosomes—Beyond stem cells for restorative therapy in stroke and neurological injury. Nat. Rev. Neurol. 2019, 15, 193–203. [Google Scholar] [CrossRef]
- Holm, M.M.; Kaiser, J.; Schwab, M.E. Extracellular Vesicles: Multimodal Envoys in Neural Maintenance and Repair. Trends Neurosci. 2018, 41, 360–372. [Google Scholar] [CrossRef]
- Sandhir, R.; Halder, A.; Sunkaria, A. Mitochondria as a centrally positioned hub in the innate immune response. Biochim. Biophys. Acta 2017, 1863, 1090–1097. [Google Scholar] [CrossRef]
- Paliwal, S.; Chaudhuri, R.; Agrawal, A.; Mohanty, S. Correction to: Human tissue-specific MSCs demonstrate differential mitochondria transfer abilities that may determine their regenerative abilities. Stem Cell Res. Ther. 2019, 10, 215. [Google Scholar] [CrossRef] [Green Version]
- Babenko, V.A.; Silachev, D.N.; Popkov, V.A.; Zorova, L.D.; Pevzner, I.B.; Plotnikov, E.Y.; Sukhikh, G.T.; Zorov, D.B. Miro1 Enhances Mitochondria Transfer from Multipotent Mesenchymal Stem Cells (MMSC) to Neural Cells and Improves the Efficacy of Cell Recovery. Molecules 2018, 23, 687. [Google Scholar] [CrossRef] [Green Version]
- Argibay, B.; Trekker, J.; Himmelreich, U.; Beiras, A.; Topete, A.; Taboada, P.; Pérez-Mato, M.; Vieites-Prado, A.; Iglesias-Rey, R.; Rivas, J.; et al. Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia. Sci. Rep. 2017, 7, 40758. [Google Scholar] [CrossRef] [PubMed]
- Nagpal, A.; Choy, F.C.; Howell, S.; Hillier, S.; Chan, F.; Hamilton-Bruce, M.A.; Koblar, S.A. Safety and effectiveness of stem cell therapies in early-phase clinical trials in stroke: A systematic review and meta-analysis. Stem Cell Res. Ther. 2017, 8, 191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Cell Source | Route | Timing | Subject | Effects | Reference |
---|---|---|---|---|---|
hAMSC | iTCX | 24 h PS | MCAo, rat | Immunomodulatory function; improved behaviour | [4] |
hAECs | iv | 1.5-h; 1–3 days PS | MCAo, mice | Reduced inflammation, infarct volume and functional deficits. | [6] |
hUCB-MSCs | tv | 1-day PS | MCAo, rat | Prevented the induction of matrix metalloproteinases | [7] |
hNPCs | iTCX | 1-week PS | MCAo, rat | Improved functional results | [8,9] |
hBMEPCs | iv | 48-h PS | Improved angiogenesis | [10] | |
hAPOSCs | iTCX | 1-hr PS | MCAo, mice | Decreased infarct volume; improved angiogenesis and functional results | [11] |
hAPOSCs | iTCX | 3–6 h PS | humans | No side effects after 12 mo | [11] |
hiNSC | 5-days PS | MCAo, pig | Good recovery of brain integrity, perfusion and function | [12,13] | |
hADMSCs | ia | 1-h PS | MCAo, rat | Improved infarct volume | [21] |
hEPC-cxcl12 | iTCX | 1-week PS | MCAo, mice | Improved angiogenesis, neurogenesis and functional results | [19] |
rBM-MSCs | iv | 2-h PS | MCAo, rat | Improved interhemispheric connectivity | [20] |
H-rBMSCs | iTCX | 1-h PS | MCAo, mice | Diminished infarct volumes, attenuated blood-brain barrier disruption | [23,24] |
hADMSCs+Eenv | iv | 2-days PS | MCAo, rat | Improved behavioural outcome | [22] |
rBM-MSCs+ G-CSF | iv | 3-h PS | MCAo, rat | Improved behavioural outcome | [25] |
rBM-MNs+ G-CSF | iv | 3-h PS | MCAo, rat | Improved behavioural outcome | [26] |
MSCs+T3 | 24-h PS | Decreased infarct volume, decrease in apoptosis | [27] | ||
MSC+PA | 24-h PS | Decreased infarct volume, decrease in apoptosis | [27] |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Surugiu, R.; Olaru, A.; Hermann, D.M.; Glavan, D.; Catalin, B.; Popa-Wagner, A. Recent Advances in Mono- and Combined Stem Cell Therapies of Stroke in Animal Models and Humans. Int. J. Mol. Sci. 2019, 20, 6029. https://doi.org/10.3390/ijms20236029
Surugiu R, Olaru A, Hermann DM, Glavan D, Catalin B, Popa-Wagner A. Recent Advances in Mono- and Combined Stem Cell Therapies of Stroke in Animal Models and Humans. International Journal of Molecular Sciences. 2019; 20(23):6029. https://doi.org/10.3390/ijms20236029
Chicago/Turabian StyleSurugiu, Roxana, Andrei Olaru, Dirk M. Hermann, Daniela Glavan, Bogdan Catalin, and Aurel Popa-Wagner. 2019. "Recent Advances in Mono- and Combined Stem Cell Therapies of Stroke in Animal Models and Humans" International Journal of Molecular Sciences 20, no. 23: 6029. https://doi.org/10.3390/ijms20236029