Abstract
Stroke is a leading cause of death and long-term disability worldwide. Current therapeutic options are limited in terms of their time for implementation and efficacy in promoting recovery. Cell transplantation has been shown to have promise in several animal models however significant challenges remain, including the optimal source of cells to promote neural repair. Here, we report on the use of a population of human ESC derived, cortically specified, neuroepithelial precursor cells (cNEPs) that are neurally restricted in their lineage potential. CNEPs have the potential to give rise to mature neural cell types following transplantation, including neurons, astrocytes and oligodendrocytes. With a view towards translation, we sought to determine whether this human cell source was effective in promoting improved functional outcomes following stroke. Undifferentiated cNEPs were transplanted in a pre-clinical endothelin-1 (ET-1) model of ischemic motor cortical stroke in immunocompromised SCID-beige mice and cellular and functional outcomes were assessed. We demonstrate that cNEP transplantation in the acute phase (4 days post-stroke) improves motor function as early as 20 days post-stroke, compared to stroke-injured, non-transplanted mice. At the time of recovery, a small fraction (<6%) of the transplanted cNEPs are observed within the stroke injury site. The surviving cells expressed the immature neuronal marker, doublecortin, with no differentiation into mature neural phenotypes. At longer survival times (40 days), the majority of recovered, transplanted mice had a complete absence of surviving cNEPS. Hence, human cNEPs grafted at early times post-stroke support the observed functional recovery following ET-1 stroke but their persistence is not required, thereby supporting a by-stander effect rather than cell replacement.
Highlights
Stroke is a leading cause of death and disability in adults (Khoshnam et al, 2017)
We demonstrate that the acute transplantation of cNEPs in an ET-1 motor cortex stroke model can promote functional recovery as early as 16 days post-transplantation
We found that only a small fraction of the transplanted cells survive in the stroke injury site at the time of recovery, and despite their ability to differentiate into mature phenotypes in vitro, FIGURE 3 | Transplanted CNEPs express doublecortin, a marker of immature neurons. (A) Coronal schematic of forebrain at PSD20 HuNu+ or hNestin+ transplanted cNEPs express DCX (i), low levels of NeuN (ii) and are GFAP negative (iii)
Summary
Stroke is a leading cause of death and disability in adults (Khoshnam et al, 2017). Current treatment options are limited and do not promote complete recovery after stroke, leaving patients with poor quality of life and socioeconomic hardship. One potential treatment to improve outcome following stroke involves transplantation of stem and progenitor cells (termed precursor cells). This approach has been shown to be effective in animal models of stroke (Mohamad et al, 2013; Xiong et al, 2017; Payne et al, 2018; Vonderwalde et al, 2019), several hurdles remain, including the identification of an optimal cell source to promote neural repair and functional recovery. CNEPs provide regionally specific brain cells for transplantation in a cortical stroke injury model (Tornero et al, 2017; Payne et al, 2019b) and the opportunity to evaluate whether cNEPs promote improved functional outcomes by examining grafted cell survival, maturation and integration
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