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Human iPSC-derived Neural Stem Cells Promote Functional Recovery after Stroke

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Review of “Bystander Effect Fuels Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells to Quickly Attenuate Early Stage Neurological Deficits after Stroke” from Stem Cells Translational Medicine by Stuart P. Atkinson

Ischemic reperfusion events which affect the blood-brain-barrier (BBB) following stroke result in severe injury to the patient and the main strategy to minimize this damage is the dissolution of the stroke-causing clot with the thrombolytic recombinant tissue plasminogen activator (tPA). This however has a short window of opportunity and carries significant hemorrhage-related side-effects [1] and so other therapeutic options are much sought after. Researchers from the laboratory of Jean-Pyo Lee (Tulane University School of Medicine, Louisiana, USA) have shown that human neural stem cells (hNSCs) mediate a significant anti-inflammatory effect [2] and therefore may represent an alternative to tPA or a synergistic therapeutic option alongside tPA. In a study published recently in Stem Cells Translational Medicine, the group have found that transplanting hNSCs derived from induced pluripotent stem cells (iPSC-hNSCs) into neurogenic zones of the hippocampus in a well-defined rodent experimental stroke model can help recover behavioral function and attenuate pathophysiology during the acute phase after stroke [3].

The authors first assessed the neurological effects of hiPSC-NSC transplantation into the hippocampus 24 hours after stroke induced by middle cerebral artery occlusion with subsequent reperfusion (MCAO/R) in male C57BL/6J mice. All three tests used (sensorimotor (adhesive removal test), balance (beam walk test), and motor function (rotarod test)) demonstrated significant improvements in the hiPSC-NSC recipient mice over non-transplanted controls. Immunohistochemical analysis at 24 hours found that hiPSC-NSCs had migrated to the lesion, although transplants after 24 hours led to a decrease in the migratory capacity of the cells and a lack of neurological improvement.

Assessment of the brain responses to ischemic reperfusion associated with stroke found increased expression of pro-inflammatory cytokines (TNF-, IL-6, and IL-1), adhesion molecules (ICAM-1 and VCAM-1), and indicators of microglial/macrophage activation (MCP-1 and MIP-1) which mediate the infiltration process and contribute to ischemic stroke injury. Encouragingly, hiPSC-NSC transplantation reduced the level of these factors following stroke and therefore may act to dampen the inflammatory environment of the brain and thereby inhibit functional loss. hiPSC-NSC transplantation also reduced the level of BBB damage normally seen in stroke, leading to a reduction in the extravasation of fluids and intravascular proteins into the brain parenchyma. This correlated with a reduction in matrix metalloproteinases (MMP-2and MMP-9), which promote the dysfunction of endothelial cell tight junctions and reduce BBB integrity, and reduced degradation of tight junction protein ZO-1. Finally, the authors noted that hiPSC-NSCs reduced the number of activated inflammatory cells (Iba-1 positive and amoeboid shaped) in the brain; the adjoined figure shows that the transplantation of the hiPSC-NSCs (C - labelled green) reduces the amount of Iba-1 staining (B- red label) observed after stroke.

Overall, this exciting study suggests that hiPSC-NSC treatment at 24 hours, a period considerably later than the 5 hours quoted for tPA treatment, can attenuate the adverse effects of stroke in the mouse model system used. The dampening of the inflammatory response and reinforcement of the BBB, known as the “bystander effect”, seems to be the main mechanisms by which hiPSC-NSC convey their beneficial role and inhibit the reduction in neurological function. However, the authors do hint that long term studies should be undertaken to determine whether the engraftment of transplanted cells can enhance neurogenesis and further contribute to the heightened positive outcomes in stroke patients.

References

  1. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. The New England journal of medicine 1995;333:1581-1587.
  2. Lee JP, Jeyakumar M, Gonzalez R, et al. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nature Medicine 2007;13:439-447.
  3. Eckert A, Huang L, Gonzalez R, et al. Bystander Effect Fuels Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells to Quickly Attenuate Early Stage Neurological Deficits After Stroke. Stem Cells Translational Medicine 2015;4:841-851.