Neural Stem Cell Plasticity: Advantages in Therapy for the Injured Central Nervous System

Abstract

The physiological and pathological properties of the neural germinal stem cell niche have been well-studied in the past 30 years, mainly in animals and within given limits in humans, and knowledge is available for the cyto-architectonic structure, the cellular components, the timing of development and the energetic maintenance of the niche, as well as for the therapeutic potential and the cross talk between neural and immune cells. In recent years we have gained detailed understanding of the potentiality of neural stem cells (NSCs), although we are only beginning to understand their molecular, metabolic, and epigenetic profile in physiopathology and, further, more can be invested to measure quantitatively the activity of those cells, to model in vitro their therapeutic responses or to predict interactions in silico. Information in this direction has been put forward for other organs but is still limited in the complex and very less accessible context of the brain. A comprehensive understanding of the behavior of endogenous NSCs will help to tune or model them toward a desired response in order to treat complex neurodegenerative diseases. NSCs have the ability to modulate multiple cellular functions and exploiting their plasticity might make them into potent and versatile cellular drugs.

Keywords: aging; inflammation; metabolism; microenvironment; multiple sclerosis; neural stem cells; plasticity; stroke.

Figure 1

Schematic representation of the interplay among cells of the neural stem cell niche of the subventricular zone (A,B,C), vascular endothelial cells (EC), ependymal cells (E), differentiated oligodendrocytes (O), astrocytes (As), and neurons (N). Green is used for positive regulators of neural stem cell function, red for inhibitory regulators. Mechanisms are in italic. (A) depicts mechanisms and factors in physiological conditions: in steady-state, B cells self renewal is promoted by niche-derived factors such as CNTF, EGF, FGF2, LIF, PGD2, S1P, and TGFα, as well as by systemic-derived factors as VEGF, BDNF and SDF1. The cerebrospinal fluid also contributes actively to niche homeostasis via IGF1, Wnt and Shh that signal to B cells via their apical cilium. Aging increases neurogenesis-inhibitory factors such as B2M, CCL2, CCL11, CCL19, while pro-neurogeneic factors as GDF11 decrease. The hypoxic milieu of the niche favors B cell quiescence, while C and A precursors rely on oxidative phosphorylation. In steady-state, astrogliogenesis is generally inhibited, while growing astrocytes secrete both pro-neurogeneic and anti-neurogeneic mediators. Nonetheless, a basal level of oligodendrogenesis and in particular neurogenesis occurs also during the steady state. (B) depicts mechanisms and factors that are altered in the SVZ niche in the context of stroke. Ischemia increases Epo, Ang2 and VEGF as well as morphogens BMP, RA and SHH, which stimulate neurogenesis. Moreover, chemotactic and growth factors produced within the lesion (e.g. CXCL12, CCL2) guide newly formed glial and neuronal cells toward the ischemic area. Hypoxia and increased nitric oxide inhibit B cell cycling while low O₂ promotes precursor differentiation. Direct transdifferentiation (dashed arrow lines) from ependymal cells and astrocytes to neurons might also contribute to stroke-induced neurogenesis. Stroke per se increases oligodendrogenesis and astrogliogenesis as well. In particular, SVZ-derived, Thbs4 positive astrocytes are pivotal in containing tissue damage and preventing hemorrhagic transformation. (C) depicts mechanisms and factors that are altered in the SVZ niche in the context of MS. Neurogenesis in inhibited by IFNγ, Gal3 and upregulation of phoshorylated-SMAD (pSMAD) in neurogenic precursors. IFNγ also inhibits oligodendrogenesis via upregulation of Gli1. NSCs produce a wide array of soluble mediators, including IL15 that attract NK cells, which in turn contribute to the neurogenic niche dysfunction observed in MS models.