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

Abstract

Cerebral ischemia causes neuronal death and disruption of neural circuits in the central nervous system. Various neurological disorders caused by cerebral infarction can severely impair quality of life and are potentially fatal. Functional recovery in the chronic stage mainly depends on physical treatment and rehabilitation. We aim to establish cell therapy for cerebral ischemia using embryonic stem (ES) cells, which have self-renewing and pluripotent capacities. We previously reported that the transplanted monkey and mouse ES cell-derived neural progenitors, by stromal cell-derived inducing activity method, could survive and differentiate into various types of neurons and glial cells, and form the neuronal network in basal ganglia. In this report, we induced the differentiation of the neural progenitors from mouse ES cells using the serum-free suspension culture method and confirmed the expression of various basal ganglial neuronal markers and neurotransmitter-related markers both in vitro and in vivo, which was thought to be suitable for replacing damaged striatum after middle cerebral artery occlusion. This is the first report that used selectively induced telencephalic neural progenitors into ischemia model. Furthermore, we purified the progenitors expressing the neural progenitor marker Sox1 by fluorescence-activated cell sorting and Sox1-positive neural progenitors prevented tumor formation in ischemic brain for 2 months. We also analyzed survival and differentiation of transplanted cells and functional recovery from ischemic damage.

Cell based therapies for ischemic stroke: From basic science to bedside

“…Although one group found teratoma formation was independent of pre-differentiation (Erdo et al, 2003), several other groups have found efficacy of pre-differentiated grafts without evidence of tumor formation. ESCs-derived neural progenitor cells (Takagi et al, 2005; Fujimoto et al, 2012; Hayashi et al, 2006), vascular progenitor cells (Oyamada et al, 2008), and mesenchymal stem cells (MSCs) (Liu et al, 2009) have been shown to exert salutary effects after stroke without noticeable tumorigenesis. …”

Stem cell‐based cell therapy for neuroprotection in stroke: A review

“…35,36 ESCs-derived mesenchymal stem cells, vascular progenitor cells, and neural progenitor cells have been revealed to provide valuable effects without visible tumorigenesis. 37,38 Neuronal progenitor cells derivative from ESCs are capable of decreasing infarct volume, rendering neurogenesis, and improving developmental behavior. 39 Transferred embryonic neural stem cells are able to motivate angiogenic cytokines, through vascular endothelial proliferation within 15 days post cerebral ischemia.…”

“…Human‐derived ESCs have been broadly investigated during current years for generation of different types of neurons . ESCs‐derived mesenchymal stem cells, vascular progenitor cells, and neural progenitor cells have been revealed to provide valuable effects without visible tumorigenesis . Neuronal progenitor cells derivative from ESCs are capable of decreasing infarct volume, rendering neurogenesis, and improving developmental behavior .…”

Neural Stem Cells Derived by Small Molecules Preserve Vision

“…Previous studies have shown that neural stem/ progenitor cells can protect dying neurons in the central nervous system and preserve vision after injecting into eye. 6,[16][17][18][19] The purpose of this study is to investigate whether hESC-derived NSCs induced by small molecules can preserve vision when injected into the Royal College of Surgeons (RCS) rat, a wellestablished retinal degeneration model. In the RCS rat, the retinal pigment epithelial cell (RPE) fails to phagocytose shed outer segment material due to a mutation in the MertK gene.…”