Cell Therapy for Stroke: A Mechanistic Analysis

Abstract

Cell therapy has been widely recognized as a promising strategy to enhance recovery in stroke survivors. However, despite an abundance of encouraging preclinical data, successful clinical translation remains elusive. As the field continues to advance, it is important to reexamine prior clinical trials in the context of their intended mechanisms, as this can inform future preclinical and translational efforts. In the present work, we review the major clinical trials of cell therapy for stroke and highlight a mechanistic shift between the earliest studies, which aimed to replace dead and damaged neurons, and later ones that focused on exploiting the various neuromodulatory effects afforded by stem cells. We discuss why both mechanisms are worth pursuing and emphasize the means through which cell replacement can still be achieved.

Keywords: Cell therapy; Clinical trial; Stem cells; Stroke; Tissue engineering; Tissue therapy.

FIGURE.

Mechanisms of cell therapy for treating strokes varying in phase and severity. In the acute phase (purple), cells can be administered intravascularly and secrete anti-inflammatory, angiogenic, and neurotrophic factors that limit tissue loss; cell replacement is less applicable since patients are poor surgical candidates and poststroke tissue is unsuited for graft survival. In moderate chronic stroke (green), neuromodulation and stimulation of neurogenesis and angiogenesis can optimize the function of remaining tissue, and cell replacement can expand the neural substrate available for functional processing, making both mechanisms highly relevant. In severe chronic stroke (red), bystander effects are limited by the lack of remaining tissue to modulate and the brain's low regenerative capacity, making cell replacement more likely to meaningfully restore lost function.