How neural stem cell therapy promotes brain repair after stroke

Abstract

The human brain has a very limited capacity for self-repair, presenting significant challenges in recovery following injuries such as ischemic stroke. Stem cell-based therapies have emerged as promising strategies to enhance post-stroke recovery. Building on a large body of preclinical evidence, clinical trials are currently ongoing to prove the efficacy of stem cell therapy in stroke patients. However, the mechanisms through which stem cell grafts promote neural repair remain incompletely understood. Key questions include whether these effects are primarily driven by (1) the secretion of trophic factors that stimulate endogenous repair processes, (2) direct neural cell replacement, or (3) a combination of both mechanisms. This review explores the latest advancements in neural stem cell therapy for stroke, highlighting research insights in brain repair mechanisms. Deciphering the fundamental mechanisms underlying stem cell-mediated brain regeneration holds the potential to refine therapeutic strategies and advance treatments for a range of neurological disorders.

Keywords: brain regeneration; cell therapy; iPS cells; ischemic stroke; neural progenitor cells; neural stem cells.

Figure 1

Existing and future options to treat ischemic stroke Left: currently, stroke treatment is limited to reperfusion therapy, i.e., the mechanical or enzymatical (rtPA) removal of the blood clot. However, this is effective only within a narrow time window after symptom onset. Right: cell-based therapies could offer a promising future option, with the potential to extend the therapeutic window and improve outcomes for patients who fall outside the time frame for reperfusion therapy. rtPA, recombinant human tissue plasminogen activator.

Figure 2

Potential mechanisms of neural stem cell-based brain regeneration Neuronal degeneration, increased apoptosis, activation of astrocytes and microglia, as well as vascular remodeling are involved in the pathophysiology of ischemic stroke. Cell therapy may reverse these processes through several paracrine mechanisms or by direct cell replacement. (1) Stem cells may release trophic factors, e.g., BMP6 or BDNF, to prevent neuronal cell death, (2) stem cells may inhibit the inflammatory response through the release of anti-inflammatory cytokines, e.g., TSG-6, and the suppression of proinflammatory cytokines, e.g., IL-1β or TNF-α, (3) stem cells can promote angiogenesis through the release of proangiogenic factors and the upregulation of e.g., Ang-1/-2, and (4) stem cells may differentiate into neurons to replace damaged cells and support reconstruction of neural circuits. Ang-1/-2, angiopoietin 1/2; TSG-6, tumor necrosis factor-inducible gene 6 protein; IL-1β, interleukin-1 beta; TNF-α: tumor necrosis factor; IGFBP2, insulin-like growth factor-binding protein 2; BMP7, bone morphogenetic protein 7; BDNF, brain-derived neurotrophic factor.