Neural stem cell therapy for stroke: A multimechanistic approach to restoring neurological function

Abstract

Introduction: Neural stem cells (NSCs) have demonstrated multimodal therapeutic function for stroke, which is the leading cause of long-term disability and the second leading cause of death worldwide. In preclinical stroke models, NSCs have been shown to modulate inflammation, foster neuroplasticity and neural reorganization, promote angiogenesis, and act as a cellular replacement by differentiating into mature neural cell types. However, there are several key technical questions to address before NSC therapy can be applied to the clinical setting on a large scale.

Purpose of review: In this review, we will discuss the various sources of NSCs, their therapeutic modes of action to enhance stroke recovery, and considerations for the clinical translation of NSC therapies. Understanding the key factors involved in NSC-mediated tissue recovery and addressing the current translational barriers may lead to clinical success of NSC therapy and a first-in-class restorative therapy for stroke patients.

Keywords: Neural stem cell; cell replacement; neuroprotection; regenerative medicine; stroke.

Figure 1

Multifunctional therapeutic action of transplanted neural stem cells. Transplanted NSCs derived from ESCs, iPSCs, or fetal brain have demonstrated multimodal therapeutic function after intravenous, intraparenchymal, or intracerebroventricular administration (Kokaia et al., 2012; Lau et al., 2015). NSCs demonstrate immunomodulatory function through the expression of cytokines and chemokines in response pro‐inflammatory signaling from activated microglia and infiltrating circulatory immune cells (Huang et al., 2014; Watanabe et al., 2016). NSCs also promote angiogenesis and stimulate neural repair mechanisms including synaptic reorganization and neurogenesis (Andres et al., 2011; Zhang et al., 2011). Transplanted NSCs can act as a cell replacement therapy by differentiating to mature neural cell types (neurons, astrocytes, and oligodendrocytes) and integrating into the host brain tissue (Baker et al., 2017; Kelly et al., 2004; Oki et al., 2012; Tornero et al., 2013). The prepotency of one mechanism to promote tissue repair over another is not well known. Regardless of therapeutic mechanism, the final outcome after NSC transplantation is improved tissue and functional recovery (Kokaia et al., 2012)