Mouse Embryonic Stem Cell-Derived Cells Reveal Niches that Support Neuronal Differentiation in the Adult Rat Brain

Abstract

A neurogenic niche can be identified by the proliferation and differentiation of its naturally residing neural stem cells. However, it remains unclear whether "silent" neurogenic niches or regions suitable for neural differentiation, other than the areas of active neurogenesis, exist in the adult brain. Embryoid body (EB) cells derived from embryonic stem cells (ESCs) are endowed with a high potential to respond to specification and neuralization signals of the embryo. Hence, to identify microenvironments in the postnatal and adult rat brain with the capacity to support neuronal differentiation, we transplanted dissociated EB cells to conventional neurogenic and non-neurogenic regions. Our results show a neuronal differentiation pattern of EB cells that was dependent on the host region. Efficient neuronal differentiation of EB cells occurred within an adjacent region to the rostral migratory stream. EB cell differentiation was initially patchy and progressed toward an even distribution along the graft by 15-21 days post-transplantation, giving rise mostly to GABAergic neurons. EB cells in the striatum displayed a lower level of neuronal differentiation and derived into a significant number of astrocytes. Remarkably, when EB cells were transplanted to the striatum of adult rats after a local ischemic stroke, increased number of neuroblasts and neurons were observed. Unexpectedly, we determined that the adult substantia nigra pars compacta, considered a non-neurogenic area, harbors a robust neurogenic environment. Therefore, neurally uncommitted cells derived from ESCs can detect regions that support neuronal differentiation within the adult brain, a fundamental step for the development of stem cell-based replacement therapies. STEM CELLS 2015;33:491-502

Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms

“…Hypoxia pretreatment of ES-NPCs also increased observed neural differentiation and reduced apoptosis and caspase-3 activation in ES-NPCs transplanted in the ischemic brain of rat models as compared to non-pretreated ES-NPC transplants (Maya-Espinosa et al, 2015). The hypoxia-induced neuroregenerative and neuroprotective effects of ES cells may be especially important in the treatment of neuroinflammation, as hypoxic conditions are known to correlate with the development of an inflammatory microenvironment.…”

“…These concerns notwithstanding, ES cells have shown noteworthy therapeutic potential in animal studies of stroke. Direct transplantation of ES cell-derived neuronal progenitor cells in stroke mice coincided with observed repair of neuronal damage, while transplantation of endothelial and mural cells also derived from ES cells was shown to promote cerebral angiogenesis and reduce the infarct area of mice after stroke (Liu et al, 2014; Maya-Espinosa et al, 2015). In addition, cells derived from ES cells are amenable to genetic modification.…”

“…Over the years, a variety of transplantable cells have been examined in laboratory studies, including fetal cells, NT2N cells, CTX0E3, embryonic stem cells, neural stem/progenitor cells, umbilical cord blood, amnion, adipose, and induced pluripotent stem cells (Borlongan et al, 1999; Borlongan et al, 2005; Borlongan, 2009; Borlongan et al, 2010; Antonucci et al, 2011; Tajiri et al, 2012; Dailey et al, 2013; Maya-Espinosa et al, 2015; Stevanato et al, 2016). While some of these cell types have been investigated in clinical trials for ischemic stroke, current preclinical studies and clinical trials have concentrated predominantly on the cellular derivatives of bone marrow.…”

ChAT-positive neurons participate in subventricular zone neurogenesis after middle cerebral artery occlusion in mice

“…The mechanism of NSC proliferation in the SVZ is complex; it was reported to be controlled by cell-intrinsic molecular pathways and significantly affected by the NSC microenvironment [1, 12, 25]. Neurotransmitters can also influence SVZ neurogenesis [26].…”

“…Additionally, treatments that increase SVZ neurogenesis have been correlated with enhanced functional recovery [11, 12]. However, the mechanism of stroke-induced neurogenesis is not clear.…”