Primate Embryonic Stem Cell-Derived Neuronal Progenitors Transplanted into Ischemic Brain

Abstract

Transplantation of stem cells has the possibility of restoring neural functions after stroke damage. Therefore, we transplanted neuronal progenitors generated from monkey embryonic stem (ES) cells into the ischemic mouse brain to test this possibility. Monkey ES cells were caused to differentiate into neuronal progenitors by the stromal cell-derived inducing activity method. Focal cerebral ischemia was induced by occluding the middle cerebral artery by the intraluminal filament technique. The donor cells were transplanted into the ischemic lateral striatum at 24 h after the start of reperfusion. The cells transplanted into the ischemic brain became located widely around the ischemic area, and, moreover, the transplanted cells differentiated into various types of neurons and glial cells. Furthermore, at 28 days after the transplantation, over 10 times more cells in the graft were labeled with Fluorogold (FG) by stereotactic focal injection of FG into the anterior thalamus and substantia nigra on the grafted side when compared with the number at 14 days. From these results we confirmed the survival and differentiation of, as well as network formation by, monkey ES-cell-derived neuronal progenitors transplanted into the ischemic mouse brain.

Inflammation, plasticity and real-time imaging after cerebral ischemia

“…However, the exact causal link, the factors that can inXuence plasticity and its temporal characteristics have not yet been completely established. To date, most of the research eVorts to enhance spontaneous post-injury plasticity and function recovery after stroke have been oriented towards controlled rehabilitation studies and enriched environment [17,64,100,101], pharmacological and/or indirect electrical and transcranial magnetic stimulation of the brain, [16,56] and more recently, cell based therapies [52,69]. The targeted research in this direction has provided us with some promising results; however, there is a growing line of evidence suggesting that in addition to previously mentioned approaches, the brain inXammatory response to ischemia and glial cells may play an important role in the modulation of post-ischemic synaptic plasticity and brain recovery [49,136].…”

Transplantation of telencephalic neural progenitors induced from embryonic stem cells into subacute phase of focal cerebral ischemia

“…In previous reports, we used SDIA method to induce neural progenitor cells. 12,13 This method is efficiently producing significant numbers of midbrain dopaminergic neurons. 19 Retinoic acid treatment also caudalizes neural progenitors in embryoid bodies.…”

“…This is the same technique as used in our previous xenograft transplantation. 13 Synaptophysin is a synaptic vesicle glycoprotein in synaptic transmission and FG is a retrograde tracer. Synaptophysin-or FG-positive transplanted cells could indicate that these cells form neuronal network, even with infused substantia nigra.…”

“…13 Briefly, at 7 days before perfusion, the mice were anesthetized with 2% halothane and then received an injection of 0.2 ml (0.05 ml/ min) of hydroxystilbamidine into the substantia nigra (from bregma: A, þ 3.0 mm; L, þ 1.5 mm; V, þ 4.25 mm; incisor bar 0) on the grafted side.…”

“…We previously reported that transplanted monkey and mouse ES cells could survive and differentiate into various types of neurons and glial cells, and reconstruct the neuronal network in mouse basal ganglia after middle cerebral artery (MCA) occlusion. 12,13 To establish ES cell-based therapy for clinical applications, it is indispensable to conduct proper cell induction, prevent teratoma formation, and evaluate functional recovery in an animal model. In this report, we transplanted the neural progenitors derived from ES cells into the ischemic mouse putamen after transient MCA occlusion.…”