Stroke alters behavior of human skin-derived neural progenitors after transplantation adjacent to neurogenic area in rat brain

Abstract

BackgroundIntracerebral transplantation of human induced pluripotent stem cells (iPSCs) can ameliorate behavioral deficits in animal models of stroke. How the ischemic lesion affects the survival of the transplanted cells, their proliferation, migration, differentiation, and function is only partly understood.MethodsHere we have assessed the influence of the stroke-induced injury on grafts of human skin iPSCs-derived long-term neuroepithelial-like stem cells using transplantation into the rostral migratory stream (RMS), adjacent to the neurogenic subventricular zone, in adult rats as a model system.ResultsWe show that the occurrence of an ischemic lesion, induced by middle cerebral artery occlusion, in the striatum close to the transplant does not alter the survival, proliferation, or generation of neuroblasts or mature neurons or astrocytes from the grafted progenitors. In contrast, the migration and axonal projection patterns of the transplanted cells are markedly influenced. In the intact brain, the grafted cells send many fibers to the main olfactory bulb through the RMS and a few of them migrate in the same direction, reaching the first one third of this pathway. In the stroke-injured brain, on the other hand, the grafted cells only migrate toward the ischemic lesion and virtually no axonal outgrowth is observed in the RMS.ConclusionsOur findings indicate that signals released from the stroke-injured area regulate the migration of and fiber outgrowth from grafted human skin-derived neural progenitors and overcome the influence on these cellular properties exerted by the neurogenic area/RMS in the intact brain.

Maturation of neural stem cells and integration into hippocampal circuits – a functional study in an in situ model of cerebral ischemia

“…At 1 day after engraftment, medium was replaced to wash out NSPCs not attached to a host tissue. Quantitative analysis demonstrated that there were a similar number of NSPCs over the time of the experiment (1-2 weeks after engraftment) for the control and the OGD-exposed slices (data not shown), consistent with other reports (Darsalia et al, 2011;Sakata et al, 2012;Hicks et al, 2009;de la Rosa-Prieto et al, 2017).…”

“…The versatile differentiation of NSPCs into, for example, neurons (Kelly et al, 2004;Tornero et al, 2017), astrocytes (Emdad et al, 2012;Jiang et al, 2013), oligodendrocytes (Pluchino et al, 2003) and even endovascular cells (Wurmser et al, 2004) has been firmly shown previously; therefore, it is not surprising here, but the distinct differentiation profile between control and post-ischemic conditions have not been shown to date. The changes in migration and outgrowth of human iPSCs after transplantation in stroke-injured brain have been recently reported, but cell proliferation and differentiation were not altered (de la Rosa-Prieto et al, 2017). By using an electrophysiological approach for functional characterization of embryonic NSPCs, here, we demonstrate enhanced NSPC differentiation towards the glial cell type in the ischemic-impaired tissue, which was accompanied with delayed functional maturation (electrophysiological properties) of NSPC-derived neurons.…”

“…A broad therapeutic potential of stem cells has led to increasing interest in cell-based therapies for cell replacement strategies in neuronal cell loss after stroke, brain injury or in neurodegenerative diseases (Lindvall and Kokaia, 2015;Meamar et al, 2013;Pluchino et al, 2003;Kim et al, 2002). Such strategies include either transplantation of cells that are already differentiated into the injured tissue (Tornero et al, 2017;Kim et al, 2002) or engraftment of stem cells into a host tissue for subsequent differentiation and maturation (de la Rosa-Prieto et al, 2017;Tsupykov et al, 2014;Darsalia et al, 2011;Mine et al, 2013). The latter approach is considered as one promoting multipotent differentiation of neural precursors in an environment of endogenous cells in order to provide 'self-repair' of injured tissue (Gage, 2000), although such a concept remains debatable.…”

Transplantation of feeder‐free human induced pluripotent stem cell–derived cortical neuron progenitors in adult male Wistar rats with focal brain ischemia

“…Several reports indicated that this phenomenon could be mediated by chemoattractants as well as by other soluble factors in the ischemic border (Imitola et al, ; Kelly et al, ). The previous study also indicated that stroke environment alters grafted cells' axonal projection, in which grafted cells prefer the ischemic border rather than the rostral migratory system (De la Rosa Prieto et al, ).…”

“…We did not detect any difference in graft survival upon transplantation either into sham or infarcted brain. Earlier reports also showed that the presence of ischemic damage in rats did not affect the survival of hiPSC‐derived NSCs upon transplantation into the neurogenic zone in the subventricular zone (de la Rosa‐Prieto et al, ). Tremendous migration and axonal outgrowth from the transplanted cells was noted particularly in the infarcted brain, which was directed toward the glial scar.…”