Stem Cell Treatment for Ischemic Stroke Recovery

Abstract

The role of cellular transplantation to promote functional recovery after stroke has been evaluated over the last two decades. Preclinical studies first established the potential for cultured neuronal cells derived from a teratocarcinoma cell line to be tested for safety and efficacy in the treatment of human stroke. In animal models of stroke that caused reproducible learning and motor deficits, injection of neuronal cells resulted in a return of learning behavior, retention time, and motor function. Clinical trials followed. Additional work with cells derived from a bone marrow neuroprogenitor line, fetal cortical stem cells, and other cell sources showed promise in preclinical studies and then these cells were tested in clinical studies. This report reviews the different biological repair approaches using cell implants, discusses clinical trial design and surgical methods, and the current state of research.

Keywords

stroke - stem cell - transplantation - neuroprogenitor

Publication History

Article published online:
27 January 2021

• References

• 1 Zivin JA, Choi DW. Stroke therapy. Sci Am 1991; 265 (01) 56-63
• 2 Borlongan CV, Tajima Y, Trojanowski JQ, Lee VM, Sanberg PR. Transplantation of cryopreserved human embryonal carcinoma-derived neurons (NT2N cells) promotes functional recovery in ischemic rats. Exp Neurol 1998; 149 (02) 310-321
• 3 Li Y, Chen J, Chen XG. et al. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 2002; 59 (04) 514-523
• 4 Vendrame M, Cassady J, Newcomb J. et al. Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke 2004; 35 (10) 2390-2395
• 5 Johansson BB, Grabowski M. Functional recovery after brain infarction: plasticity and neural transplantation. Brain Pathol 1994; 4 (01) 85-95
• 6 Nishino H, Koide K, Aihara N, Kumazaki M, Sakurai T, Nagai H. Striatal grafts in the ischemic striatum improve pallidal GABA release and passive avoidance. Brain Res Bull 1993; 32 (05) 517-520
• 7 Andrews PW, Damjanov I, Simon D. et al. Pluripotent embryonal carcinoma clones derived from the human teratocarcinoma cell line Tera-2. Differentiation in vivo and in vitro. Lab Invest 1984; 50 (02) 147-162
• 8 Pleasure SJ, Lee VM. NTera 2 cells: a human cell line which displays characteristics expected of a human committed neuronal progenitor cell. J Neurosci Res 1993; 35 (06) 585-602
• 9 Kleppner SR, Robinson KA, Trojanowski JQ, Lee VM. Transplanted human neurons derived from a teratocarcinoma cell line (NTera-2) mature, integrate, and survive for over 1 year in the nude mouse brain. J Comp Neurol 1995; 357 (04) 618-632
• 10 Trojanowski JQ, Kleppner SR, Hartley RS. et al. Transfectable and transplantable postmitotic human neurons: a potential “platform” for gene therapy of nervous system diseases. Exp Neurol 1997; 144 (01) 92-97
• 11 Tessler A, Fischer I, Giszter S. et al. Embryonic spinal cord transplants enhance locomotor performance in spinalized newborn rats. Adv Neurol 1997; 72: 291-303
• 12 Borlongan CV, Koutouzis TK, Jorden JR. et al. Neural transplantation as an experimental treatment modality for cerebral ischemia. Neurosci Biobehav Rev 1997; 21 (01) 79-90
• 13 Borlongan CV, Saporta S, Poulos SG, Othberg A, Sanberg PR. Viability and survival of hNT neurons determine degree of functional recovery in grafted ischemic rats. Neuroreport 1998; 9 (12) 2837-2842
• 14 Borlongan CV, Cahill DW, Sanberg PR. Locomotor and passive avoidance deficits following occlusion of the middle cerebral artery. Physiol Behav 1995; 58 (05) 909-917
• 15 Borlongan CV, Sanberg PR. Elevated body swing test: a new behavioral parameter for rats with 6-hydroxydopamine-induced hemiparkinsonism. J Neurosci 1995; 15 (7, Pt 2): 5372-5378
• 16 Saporta S, Borlongan CV, Sanberg PR. Neural transplantation of human neuroteratocarcinoma (hNT) neurons into ischemic rats. A quantitative dose-response analysis of cell survival and behavioral recovery. Neuroscience 1999; 91 (02) 519-525
• 17 Bregman BS, Kunkel-Bagden E, Reier PJ, Dai HN, McAtee M, Gao D. Recovery of function after spinal cord injury: mechanisms underlying transplant-mediated recovery of function differ after spinal cord injury in newborn and adult rats. Exp Neurol 1993; 123 (01) 3-16
• 18 Himes BT, Goldberger ME, Tessler A. Grafts of fetal central nervous system tissue rescue axotomized Clarke's nucleus neurons in adult and neonatal operates. J Comp Neurol 1994; 339 (01) 117-131
• 19 Jakeman LB, Reier PJ. Axonal projections between fetal spinal cord transplants and the adult rat spinal cord: a neuroanatomical tracing study of local interactions. J Comp Neurol 1991; 307 (02) 311-334
• 20 Snyder EY, Park KI, Flax JD. et al. Potential of neural “stem-like” cells for gene therapy and repair of the degenerating central nervous system. Adv Neurol 1997; 72: 121-132
• 21 Bregman BS, Reier PJ. Neural tissue transplants rescue axotomized rubrospinal cells from retrograde death. J Comp Neurol 1986; 244 (01) 86-95
• 22 Meltzer CC, Kondziolka D, Villemagne VL. et al. Serial [18F] fluorodeoxyglucose positron emission tomography after human neuronal implantation for stroke. Neurosurgery 2001; 49 (03) 586-591 , discussion 591–592
• 23 Nelson PT, Kondziolka D, Wechsler L. et al. Clonal human (hNT) neuron grafts for stroke therapy: neuropathology in a patient 27 months after implantation. Am J Pathol 2002; 160 (04) 1201-1206
• 24 Kondziolka D, Steinberg GK, Wechsler L. et al. Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg 2005; 103 (01) 38-45
• 25 Kondziolka D, Wechsler L, Goldstein S. et al. Transplantation of cultured human neuronal cells for patients with stroke. Neurology 2000; 55 (04) 565-569
• 26 Kondziolka D, Steinberg GK, Cullen SB, McGrogan M. Evaluation of surgical techniques for neuronal cell transplantation used in patients with stroke. Cell Transplant 2004; 13 (7–8): 749-754
• 27 Hantson L, De Weerdt W, De Keyser J. et al. The European Stroke Scale. Stroke 1994; 25 (11) 2215-2219
• 28 Brott T, Adams Jr HP, Olinger CP. et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20 (07) 864-870
• 29 Stilley CS, Ryan CM, Kondziolka D, Bender A, DeCesare S, Wechsler L. Changes in cognitive function after neuronal cell transplantation for basal ganglia stroke. Neurology 2004; 63 (07) 1320-1322
• 30 Mahmood A, Lu D, Qu C, Goussev A, Chopp M. Treatment of traumatic brain injury with a combination therapy of marrow stromal cells and atorvastatin in rats. Neurosurgery 2007; 60 (03) 546-553 , discussion 553–554
• 31 Mimura T, Dezawa M, Kanno H, Yamamoto I. Behavioral and histological evaluation of a focal cerebral infarction rat model transplanted with neurons induced from bone marrow stromal cells. J Neuropathol Exp Neurol 2005; 64 (12) 1108-1117
• 32 Dezawa M, Kanno H, Hoshino M. et al. Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest 2004; 113 (12) 1701-1710
• 33 Steinberg GK, Kondziolka D, Wechsler LR. et al. Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study. Stroke 2016; 47 (07) 1817-1824
• 34 Steinberg GK, Kondziolka D, Wechsler LR. et al. Two-year safety and clinical outcomes in chronic ischemic stroke patients after implantation of modified bone marrow-derived mesenchymal stem cells (SB623): a phase 1/2a study. J Neurosurg 2018; 131: 1462-1472
• 35 Kalladka D, Sinden J, Pollock K. et al. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet 2016; 388 (10046): 787-796
• 36 Vahidy FS, Haque ME, Rahbar MH. et al. Intravenous bone marrow mononuclear cells for acute ischemic stroke: safety, feasibility and effect size from a phase 1 clinical trial. Stem Cells 2019; 37 (11) 1481-1491
• 37 Thompson TP, Lunsford LD, Kondziolka D. Restorative neurosurgery: opportunities for restoration of function in acquired, degenerative, and idiopathic neurological diseases. Neurosurgery 1999; 45 (04) 741-752
• 38 Prasad K, Sharma A, Garg A. et al. Intravenous autologous bone marrow mono nuclear stern cell therapy for ischemic stroke: a multicentric radomized trial. Stroke 2014; 45: 3618-3624