Understanding Neural Stem Cell Regulation in Vivo and Applying the Insights to Cell Therapy for Strokes

Abstract

The use of neural stem cell (NSC) therapy for the treatment of stroke patients is successfully paving its way into advanced phases of large-scale clinical trials. To understand how to optimize NSC therapeutic approaches, it is fundamental to decipher the crosstalk between NSC and other cells that comprise the NSC microenvironment (niche) and regulate their function, in vivo; namely, the endothelial cells of the microvasculature. In this mini review, we first provide a concise summary of preclinical findings describing the signaling mechanisms between NSC and vascular endothelial cells and vice versa. Second, we describe the progress made in the development of NSC therapy for the treatment of strokes.

Grafting of electrically stimulated subventricular neural stem cells embedded in a nutritional hydrogel into the stroke cavity improved cell survival and behavioural recovery in mice

“…The object recognition test (ORT) is commonly used to asssess various aspects of learning and memory in mice and re ects the relative health of brain regions involved in short-term memory [25]. We found that the SVZ graft treatment led to an improvement in short-term memory re ecting a better preservation of this function in the brain of treated animals.…”

“…Nestin-positive cells used for scanning were labeled with goat anti-mouse Alexa 488 and slides were scanned as large TIFF les utilizing a Nikon 90i motorized microscope (Nikon Europe BV, Amsterdam, the Netherlands) equipped with plan apochromat objectives, a high-resolution low-noise 16. 25 Counting Of Co-localized Dcx/brdu, Mash1/brdu, And Nestin/brdu DCX + /BrdU + , Nestin + /BrdU + double-labeled cells were analyzed in the region adjacent to the SVZ as previously described [21]. To this end, a sequence of confocal images measuring 161 x 242 µm, was scanned at 0.1 µm steps across the 25 µm-thick sections.…”

Neurogenesis: Gene-Based Strategies for Treating Ischemic Stroke

“…This technique could be used to slow the spread of neural decline or generate a neural niche in regions that did not already express the necessary signals or factors 35 . Vectors are preferred over the delivery of naked DNA because of their greater e ciency, and viral vectors take advantage of viruses' evolved ability to alter gene expression in cells they infect 36 . Viruses deliver genetic information by infecting the cell directly, but in gene therapy, they are modi ed so they are unable to transfer unwanted information and result in pathogenicity.…”

Connexin 43-mediated Neurovascular Interactions Regulate Neurogenesis in the Adult Brain Subventricular Zone

“…Several studies have highlighted the role of paracrine signaling between vascular ECs and NSCs in the SVZ via EC-secreted factors such as, vascular endothelial growth factor (VEGF)-A and -C 19, 20 , betacelluline 21 , pigment epithelium-derived factor (PEDF) 22 and placental growth factor (PlGF) type 2 23 that regulate NSC behavior in the SVZ. Moreover, in the SVZ microvasculature, and unlike other areas of the brain, the ECs that form the blood vessels lack pericyte and astrocyte coverage, enabling direct contact between NSCs and ECs in this niche 18, 24, 25 . This allows for physical interactions between NSCs and ECs to enable juxtacrine signaling via membrane-bound proteins and their associated ligands to enable Notch and Ephrin signaling 25, 26 .…”