Harnessing the Neural Stem Cell Secretome for Regenerative Neuroimmunology

Abstract

Increasing evidence foresees the secretome of neural stem cells (NSCs) to confer superimposable beneficial properties as exogenous NSC transplants in experimental treatments of traumas and diseases of the central nervous system (CNS). Naturally produced secretome biologics include membrane-free signaling molecules and extracellular membrane vesicles (EVs) capable of regulating broad functional responses. The development of high-throughput screening pipelines for the identification and validation of NSC secretome targets is still in early development. Encouraging results from pre-clinical animal models of disease have highlighted secretome-based (acellular) therapeutics as providing significant improvements in biochemical and behavioral measurements. Most of these responses are being hypothesized to be the result of modulating and promoting the restoration of key inflammatory and regenerative programs in the CNS. Here, we will review the most recent findings regarding the identification of NSC-secreted factors capable of modulating the immune response to promote the regeneration of the CNS in animal models of CNS trauma and inflammatory disease and discuss the increased interest to refine the pro-regenerative features of the NSC secretome into a clinically available therapy in the emerging field of Regenerative Neuroimmunology.

Extracellular Vesicles in neural cell interaction and CNS homeostasis

“…The influence on NSC fate, however, may differ depending on the regional origin or the specific developmental state of the NSCs 12,13 . In addition to their impact on neurogenesis, NSC‐EVs exhibit immunomodulatory activity turning them to promising candidates for application in regenerative therapies of brain disease or injuries 14,15 …”

Elucidating the Pivotal Neuroimmunomodulation of Stem Cells in Spinal Cord Injury Repair

“…Studies have shown that the source of these vesicle correlated well with the expression of specific surface antigens [ 235 – 237 ]. Furthermore, several studies have demonstrated that sEVs generated by NSCs had therapeutic efficiency against ischemic, inflammatory, and neurodegenerative diseases [ 238 , 239 ].…”

Dynamics of morphological changes in neural cell culture with a model of neurotrauma under the influence of conditioned media of the rat fetal brain neurogenic cells

“…Recently, the paradigm of regenerative effects of NSCs/NPCs has shifted from the concept of «cell replacement» (remodeling) to the concept of «functional or therapeutic plasticity» (modulation of the microenvironment). This is based on a wide range of regulatory paracrine effects of these cells, so called «bystander effects», that provide neuroprotection, modulation of inflammation and immune response and help to repair damaged neural tissue [10][11][12][13]. In this regard, much attention is paid to the study of factors produced by NSCs/ NPCs and thus enrich the culture media during cultivation as a released molecules or as a extracellular vesicles: neurotrophic, growth factors, morphogens, immunomodulatory cytokines (NGF, BDNF, NT-3, GDNF, TGF-β1, TGF-β2, VEGF, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ TNF-α), chemokines (CXCL12), prostaglandins (PGE2), microRNAs, etc.…”

“…In this regard, much attention is paid to the study of factors produced by NSCs/ NPCs and thus enrich the culture media during cultivation as a released molecules or as a extracellular vesicles: neurotrophic, growth factors, morphogens, immunomodulatory cytokines (NGF, BDNF, NT-3, GDNF, TGF-β1, TGF-β2, VEGF, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ TNF-α), chemokines (CXCL12), prostaglandins (PGE2), microRNAs, etc. [10][11][12][13][14][15][16][17][18][19]. These secreted factors or NSCs/NPCs secretome [11,20] are the mediators of bystander-effects, able to regulate a wide range of processes at the cellular, tissue, organ and systemic levels and are considered a key component of these regulatory mechanisms [12,[21][22][23].…”

“…[10][11][12][13][14][15][16][17][18][19]. These secreted factors or NSCs/NPCs secretome [11,20] are the mediators of bystander-effects, able to regulate a wide range of processes at the cellular, tissue, organ and systemic levels and are considered a key component of these regulatory mechanisms [12,[21][22][23]. Given the limited clinical use of cell therapy in the TBI treatment at this stage, it seems promising to study the effectiveness of regenerative effects of NSCs/NPCs conditioned media as a source of their secretome and a possible alternative to direct cell transplantation.…”