The pharmacological support and stimulation of endogenous and transplanted neural stem cells (NSCs) is a major challenge in brain repair. Trauma to the central nervous system (CNS) results in a distinct inflammatory response caused by local and infiltrating immune cells. This makes NSC-supported regeneration difficult due to the presence of inhibitory immune factors which are upregulated around the lesion site. The continual and dual role of the neuroinflammatory response leaves it difficult to decipher upon a single modulatory strategy. Therefore, understanding the influence of cytokines upon regulation of NSC self-renewal, proliferation and differentiation is crucial when designing therapies for CNS repair. There is a plethora of partially conflicting data in vitro and in vivo on the role of cytokines in modulating the stem cell niche and the milieu around NSC transplants. This is mainly due to the pleiotropic role of many factors. In order for cell-based therapy to thrive, treatment must be phase-specific to the injury and also be personalized for each patient, i.e. taking age, sex, neuroimmune and endocrine status as well as other key parameters into consideration. In this review, we will summarize the most relevant information concerning interleukin (IL)-1, IL-4, IL-10, IL-15, IFN-γ, the neuropoietic cytokine family and TNF-α in order to extract promising therapeutic approaches for further research. We will focus on the consequences of neuroinflammation on endogenous brain stem cells and the transplantation environment, the effects of the above cytokines on NSCs, as well as immunopharmacological manipulation of the microenvironment for potential therapeutic use.
Keywords: BDNF; Brain-derived neurotrophic factor; Brd-Udr; Bromodeoxyuridine; CCR5; CXCR4; Central nervous system regeneration; Central nervous system trauma; Cytokines; C–C chemokine receptor type 5; C–X–C chemokine receptor type 4; DG; ESCs; GABA; JAK–STAT; Janus-activated kinase–signal transducer, activator of transcription; LFA-1; LIF; LPS; Leukemia inhibitory factor; Lipopolysaccharides; MAP-2; MAPK; NF-κβ; NO; NPCs; NSPCs; Neural stem cells; Neurogenesis; Neuroinflammation; Notch1; Prox1; ROS; SC1; SVZ; Schwann cell factor 1; Stat3; TGF-β; TLR; UCN; Urocorticon; dentate gyrus; embryonic stem cells; gamma-aminobutyric acid; homeobox protein 1; lymphocyte function-associated antigen 1; microtubule-associated protein 2; mitogen-activated protein kinase; nNOS; neural precursor cells; neurogenic locus notch homolog protein1; neuronal stem/progenitor cells; nitric oxide; nitric oxide synthase; nuclear factor kappa-light-chain-enhancer of activated B cells; prospero homeobox protein 1; reactive oxygen species; signal transducer and activator of transcription 3; subventricular zone; toll-like receptor; transforming growth factor-beta.
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