Editorial: Pluripotent Cells for Stroke: From Mechanism to Therapeutic Strategies

Editorial on the Research Topic
Pluripotent Cells for Stroke: From Mechanism to Therapeutic Strategies

Stroke, an acute central nervous system injury caused by cerebral ischemia or cerebral hemorrhage, is one of the major causes of death and the leading cause of long-term disability worldwide (Dalys and Collaborators, 2017; Wang et al., 2020). Thanks to early diagnosis, mini-invasive surgery, and advanced intensive care support, stroke survival rate has increased dramatically (Kim et al., 2020; Wang et al., 2020). Nevertheless, stroke survivors usually suffer from sequelae of neurological impairments and psychiatric disorders, which affect their daily functionality and working capacity. Although extensively studied, the molecular mechanisms underlying stroke pathophysiology remain not fully understood and innovative rehabilitation therapies for neural circuit remodeling after stroke are urgently needed.

Recently, pluripotent cell-based approaches have attracted more attention from scientists and physicians due to their possible neuroprotective and restorative effects on stroke. One major challenge, however, is that injury-induced microenvironments usually lead to obstruction in directional differentiation of pluripotent cells, and failure in reconstruction of neural circuits. Additionally, the conventional neurobehavioral evaluation and diffusion-weighted magnetic resonance imaging (MRI-DWI) cannot monitor the evolution of pluripotent cells differentiation. As a consequence, various pluripotent cell-based strategies exhibited uncertain neuroprotective efficacy in previous clinical trials.

This Research Topic contains 12 manuscripts, highlighting current understanding and future directions in pluripotent cell-based therapies in stroke. Due to their proliferation and differentiation potential, both endogenous and exogenous stem cells are candidates for neural regeneration and neural circuit remodeling. Liu et al. summarize the mechanisms, processes, and challenges of using stem cells in stroke treatment. They conclude that specific cell types, dosages and routes, and other issues for stem cell-based approaches still need to be optimized in the near future. Zhang et al. systemically review stem cell-based therapies for experimental ischemic stroke. They conclude that stem cell-based therapies are able to improve neurological function and reduce infarct volume, but further clinical studies are needed to verify these neuroprotective effects. Mesenchymal stem cells (MSCs) have been proven effective in ischemic stroke (Li et al.), intracerebral hemorrhage (Gong et al.), and neurodegeneration diseases, such as Alzheimer's Disease (Yan et al.). Islam et al. also report that human neuroepithelial precursor cells (cNEPs) grafted early after stroke are able to improve functional recovery. Traditional Chinese medicine monomers, active components extracted from Chinese herbs, also exhibit the potential to activate proliferation and neurogenesis of neural stem cells after stroke (Wang et al.). Mechanistic studies show that canonical Wnt/β-catenin signaling and other molecules play a pivotal role in neural stem/progenitor cell differentiation (Kriska et al.).

Due to the limitations of neural stem cells, induced pluripotent stem cells (iPSCs) have been used as an alternative cell type in stroke treatment. iPSCs, produced by introducing specific transcription factors into somatic cells, exhibit similar differentiation potential as embryonic stem cells. Duan et al. summarize the current applications of iPSC therapy in ischemic stroke. In addition, inspired by iPSC and in vivo reprogramming technology, endogenous and reactive glial cells have been in situ converted to functional neurons for the treatments of stroke, neurodegenerative diseases, retinal diseases, and trauma in central nervous system (Wang et al., 2021).

In the concept of neuro-vascular network (Zhang et al., 2012), non-neuronal cells are equally important and play an essential role in neural circuit remodeling and neurofunctional recovery. Microglial cells, major immune cells in brain, are influenced by low dose of valproic acid after stroke, possibly via interleukin-6- and galectin-3-mediated extracellular matrix remodeling (Kuo et al.). Gan et al. elucidate the regulatory functions of lncRNAs on angiogenesis after stroke, which are important for vascular reconstruction and blood flow support of neural circuit remodeling. In addition, Cao et al. summarize the functions of pericytes as perivascular multi-potent cells and an important component of the blood-brain barrier in the central nervous system (Gautam and Yao, 2018). They discuss how pericyte dysfunction affects the pathophysiological processes of stroke. A subset of pericytes have been shown to trans-differentiate into neurons in the damaged tissue (Karow et al., 2018).

In summary, there are 12 outstanding manuscripts, including both original studies and comprehensive reviews, in this Research Topic. We summarize recent findings and challenges of pluripotent cell-based therapies in stroke, and propose to explore the mechanisms of directed differentiation and optimize pluripotent cells products & in vivo tracking techniques in further studies.

Author Contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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