Angiogenic Factors Stimulate Growth of Adult Neural Stem Cells

Abstract

BackgroundThe ability to grow a uniform cell type from the adult central nervous system (CNS) is valuable for developing cell therapies and new strategies for drug discovery. The adult mammalian brain is a source of neural stem cells (NSC) found in both neurogenic and non-neurogenic zones but difficulties in culturing these hinders their use as research tools [1], [2], [3], [4], [5], [6].Methodology/Principal FindingsHere we show that NSCs can be efficiently grown in adherent cell cultures when angiogenic signals are included in the medium. These signals include both anti-angiogenic factors (the soluble form of the Notch receptor ligand, Dll4) and pro-angiogenic factors (the Tie-2 receptor ligand, Angiopoietin 2). These treatments support the self renewal state of cultured NSCs and expression of the transcription factor Hes3, which also identifies the cancer stem cell population in human tumors. In an organotypic slice model, angiogenic factors maintain vascular structure and increase the density of dopamine neuron processes.Conclusions/SignificanceWe demonstrate new properties of adult NSCs and a method to generate efficient adult NSC cultures from various central nervous system areas. These findings will help establish cellular models relevant to cancer and regeneration.

Hes3 Is Expressed in the Adult Pancreatic Islet and Regulates Gene Expression, Cell Growth, and Insulin Release

“…A key component is the transcription factor Hes3 (10). Several inputs into Hes3 increase its expression and nuclear localization, and promote the growth of NSCs in vitro and in vivo (36,37). In vivo, they increase the number of Hes3ϩ cells and confer powerful neuroprotection in animal models of ischemic stroke and Parkinson disease, likely, in part through the release of trophic factors from Hes3ϩ cells (10,11,15,17,38).…”

Glibenclamide Enhances Neurogenesis and Improves Long-Term Functional Recovery after Transient Focal Cerebral Ischemia

“…Vasculature attracts microglial cells and stimulates them to release angiogenic factors, 35 with subsequent growth stimulation of neural stem cells. 36 Furthermore, angiogenesis is considered a key feature of ischemic stroke recovery and neuronal post-stroke re-organization. 37 Several studies using experimental stroke models have indicated the beneficial effects of glibenclamide administration after reperfusion, such as reversing ischemia-reperfusion injury by halting oxidative stress and inflammation in the hippocampus, 9 preventing cytotoxic edema after cerebral ischemia, 2,3,1,7 and enhancing neuroprotection, which all eventually lead to a better functional outcome.…”

Cancer stem cells and their vascular niche: Do they benefit from each other?

“…When co-cultured, ECs promote NSCs to show increased self-renewal capability but delayed differentiation through direct cell-cell contact and paracrine signaling. The paracrine signals include Notch receptor ligand Dll4, the Notch effectors Hes1 and Hes3, as well as the pro-angiogenic factors angiopoietin 2 and the chemokine axis CXCL12/CXCR4 [24][25][26][27]. Vascular niche also regulates adult stem cells in other organs.…”