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Uncovering the Routes Linking Stroke to Neural Stem Cell Proliferation and Differentiation

Review of “Systemic factors trigger vasculature cells to drive Notch signaling and neurogenesis in neural stem cells in the adult brain” from STEM CELLS by Stuart P. Atkinson 

Experimental stroke from middle cerebral artery occlusion leads to increased neural stem cell proliferation and differentiation towards a neuronal fate (neurogenesis) [1]; however, how injury‐related signals drive this process remains unknown. Interestingly, studies describing extensive close contacts between vascular cells, such as endothelial cells and pericytes, and the cells of the neural stem cell niche [2, 3], suggest that this interaction may represent a potential signaling conduit connecting systemic signals to neural stem cells.

Most neural stem cell niches contain a permeable blood‐brain barrier, and previous research from the laboratory of Lorraine Iacovitti (Thomas Jefferson University, Philadelphia, Pennsylvania, USA) demonstrated that increased blood‐brain barrier leakiness positively correlates with increased neural stem cell proliferation and neurogenesis following stroke [1, 4, 5]. In their new STEM CELLS study, the team now return to investigate the signaling pathways involved, with a focus on the leaky nature of blood‐brain barriers in important neural stem cell niches in the mouse brain [6].

Lin et al. report that the already leaky status of blood‐brain barriers in the subventricular zone- and circumventricular organ-stem cell niches in the mouse brain become even more porous after stroke, thereby allowing the brain to respond to the high levels of circulating vascular endothelial growth factor 165 (VEGF165) associated with experimental stroke from middle cerebral artery occlusion [7]. VEGF165 then drives the induction of the pro-angiogenic Notch ligand DLL4 in VEGF Receptor 2-expressing endothelial cells and pericytes of the neural stem cell niche, leading to enhanced DLL4‐Notch signaling between vasculature cells and neighboring neural stem cells, and a subsequent increase in neural stem cell proliferation and neurogenesis.

The authors highlight this exciting study as the first to demonstrate that vascular cells can regulate the activity of neural stem cells within brain niches when triggered by systemic stroke‐induced factors. For more on neural stem cells, brain niches, and stroke, stay tuned to the Stem Cells Portal!


  1. Lin R, Cai J, Nathan C, et al., Neurogenesis is enhanced by stroke in multiple new stem cell niches along the ventricular system at sites of high BBB permeability. Neurobiology of Disease 2015;74:229-39.
  2. Tavazoie M, Van der Veken L, Silva-Vargas V, et al., A specialized vascular niche for adult neural stem cells. Cell Stem Cell 2008;3:279-88.
  3. Shen Q, Wang Y, Kokovay E, et al., Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 2008;3:289-300.
  4. Lin R and Iacovitti L, Classic and novel stem cell niches in brain homeostasis and repair. Brain Research 2015;1628:327-342.
  5. Lin R, Lang M, Heinsinger N, et al., Stepwise impairment of neural stem cell proliferation and neurogenesis concomitant with disruption of blood-brain barrier in recurrent ischemic stroke. Neurobiology of Disease 2018;115:49-58.
  6. Lin R, Cai J, Kenyon L, et al., Systemic Factors Trigger Vasculature Cells to Drive Notch Signaling and Neurogenesis in Neural Stem Cells in the Adult Brain. STEM CELLS 2019;37:395-406.
  7. Slevin M, Krupinski J, Slowik A, et al., Serial Measurement of Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 in Serum of Patients With Acute Ischemic Stroke. Stroke 2000;31:1863-1870.