Brain repair mechanisms after cell therapy for stroke

Abstract

Cell-based therapies hold great promise for brain repair after stroke. While accumulating evidence confirms the preclinical and clinical benefits of cell therapies, the underlying mechanisms by which they promote brain repair remain unclear. Here, we briefly review endogenous mechanisms of brain repair after ischaemic stroke and then focus on how different stem and progenitor cell sources can promote brain repair. Specifically, we examine how transplanted cell grafts contribute to improved functional recovery either through direct cell replacement or by stimulating endogenous repair pathways. Additionally, we discuss recently implemented preclinical refinement methods, such as preconditioning, microcarriers, genetic safety switches and universal (immune evasive) cell transplants, as well as the therapeutic potential of these pharmacologic and genetic manipulations to further enhance the efficacy and safety of cell therapies. By gaining a deeper understanding of post-ischaemic repair mechanisms, prospective clinical trials may be further refined to advance post-stroke cell therapy to the clinic.

Keywords: brain injury; iPSC; ischaemia; regeneration; stem cells; therapy.

Figure 1

Pathophysiology of stroke. An ischaemic stroke usually occurs when a brain artery becomes blocked, leading to a reduction in oxygen and nutrients in the affected brain areas. These regions can be divided into: the stroke core, an area with severe cerebral blood flow reduction and irreversible necrotic cell death (<10 ml/100 g/min); the penumbra, an area with reversible damage (17–10 ml/100 g per min); and normal, intact tissue (>17 ml/100 g per min). Damage to stroke tissue includes necrotic and apoptotic cell death, damage to the blood–brain barrier, activation of resident microglia and infiltration of peripheral immune cells. EC = endothelial cell; olig = oligodendrocyte; TJ = tight junction.

Figure 2

Cell types for cell therapy after stroke. Cell transplants can be derived either from the embryonic/fetal stages or the adult human. Adult stem cells comprise mesenchymal stem cells (MSCs) or differentiated cells from the peripheral blood reprogrammed to generate induced pluripotent stem cells (iPSCs). Both embryonic stem cells (ESC) and iPSCs can be differentiated into neural or glial-enriched stem cells to generate neurons, oligodendrocytes or astrocytes. Pericyte-like cells can be generated from iPSCs through neural crest cell intermediates.

Figure 3

Indirect mechanisms of cell therapy for brain repair. Indirect effects of cell therapy include improved vascular repair and maturation through the release of pro-angiogenic factors in the peri-infarct region. Immunomodulation and an increased anti-inflammatory signature reduce secondary damage and decrease glial scar formation. The release of neurotrophic factors by cell grafts also increases axonogenesis and synaptogenesis in damaged areas.