pubmed.ncbi.nlm.nih.gov

Potential Mechanisms and Perspectives in Ischemic Stroke Treatment Using Stem Cell Therapies - PubMed

  • ️Fri Jan 01 2021

Review

Potential Mechanisms and Perspectives in Ischemic Stroke Treatment Using Stem Cell Therapies

Guoyang Zhou et al. Front Cell Dev Biol. 2021.

Abstract

Ischemic stroke (IS) remains one of the major causes of death and disability due to the limited ability of central nervous system cells to regenerate and differentiate. Although several advances have been made in stroke therapies in the last decades, there are only a few approaches available to improve IS outcome. In the acute phase of IS, mechanical thrombectomy and the administration of tissue plasminogen activator have been widely used, while aspirin or clopidogrel represents the main therapy used in the subacute or chronic phase. However, in most cases, stroke patients fail to achieve satisfactory functional recovery under the treatments mentioned above. Recently, cell therapy, especially stem cell therapy, has been considered as a novel and potential therapeutic strategy to improve stroke outcome through mechanisms, including cell differentiation, cell replacement, immunomodulation, neural circuit reconstruction, and protective factor release. Different stem cell types, such as mesenchymal stem cells, marrow mononuclear cells, and neural stem cells, have also been considered for stroke therapy. In recent years, many clinical and preclinical studies on cell therapy have been carried out, and numerous results have shown that cell therapy has bright prospects in the treatment of stroke. However, some cell therapy issues are not yet fully understood, such as its optimal parameters including cell type choice, cell doses, and injection routes; therefore, a closer relationship between basic and clinical research is needed. In this review, the role of cell therapy in stroke treatment and its mechanisms was summarized, as well as the function of different stem cell types in stroke treatment and the clinical trials using stem cell therapy to cure stroke, to reveal future insights on stroke-related cell therapy, and to guide further studies.

Keywords: cell therapy; clinical trial; ischemic stroke; regenerative medicine; stem cell; transplantation.

Copyright © 2021 Zhou, Wang, Gao, Fu, Cao, Peng, Zhuang, Hu, Shao and Wang.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

FIGURE 1
FIGURE 1

Mechanisms of stem cell migration. Adhesion between stem cells and endothelial cells increases after IS due to the increased expression of E-selectin, P-selectin, and VACM. CXCL-11 released from stem cells can bind CXCR-3 and increase the permeability of the BBB by opening the TJs under the activation of the ERK1/2 signaling pathway. Administered stem cells can migrate to the ischemic lesion by the gradient of SDF-1 through the activation of the PI3K/AKT signaling pathway. The proliferation and migration of endogenous NSCs increase due to BDNF and EPO after IS. Abbreviations: IS, ischemic stroke; VCAM, vascular cell adhesion molecule; CXCL, C-X-C motif ligand; CXCR, C-X-C motif chemokine receptor; EPO, erythropoietin; HIF, hypoxia-inducible factor; SDF, stromal cell-derived factor; PI3K, phosphoinositide-3-kinase; NSCs, neural stem cells; TJs, tight junctions.

FIGURE 2
FIGURE 2

Modulation of neuroinflammation and immune response. Transplanted stem cells can decrease the expression of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α and secrete anti-inflammatory cytokines including IL-4, IL-10, and transforming growth factor-β1. Transplanted stem cells can modulate the activity of inflammatory cells including microglial cells, astrocytes, and T cells. The infiltration and pro-inflammation effect of leukocytes from peripheral blood decreased under the administration of stem cells. Abbreviations: IS, ischemic stroke; VCAM, vascular cell adhesion molecule; ICAM, intercellular adhesion molecule; IL, interleukin; TNF, tumor necrosis factor; TGF, transforming growth factor; Treg, regulatory T cells; TJs, tight junctions.

FIGURE 3
FIGURE 3

Mechanisms of secretion of protective factors. Stem cells secrete neurotrophic factors or generate EVs mainly containing proteins, lipids, and RNA with multiple neuroprotective effects: inhibiting the activation of microglia and astrocyte, and also promoting microglia shift to the anti-inflammatory phenotype instead of the pro-inflammatory; downregulating Th1 and Th2 and upregulating Th17 and Treg; promoting the migration, differentiation, and secretion of neurotrophic factors to the ischemic periphery; upregulating the content of many factors including VEGF, bFGF, and NGF in the ischemic periphery; and mediating angiogenesis and neuroprotection through the induction of MEK/ERK/MAPK and Notch signaling pathway. Abbreviations: ↑, upregulation; ↓, downregulation; EVs, extracellular vesicles; NSCs, neural stem cells; Th, T helper cells; Treg, regulatory T cells; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; NGF, nerve growth factor; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; MEK, MAP kinase.

FIGURE 4
FIGURE 4

A set of diagrams of angiogenesis, neurogenesis, and axonal outgrowth under the treatment of stem cells following ischemic stroke (modified from the reference of Masato Kanazawa et al., 2019). (A) A proposed diagram depicting the location of angiogenesis and axonal outgrowth after ischemic stroke without intervention. Weak angiogenesis (red lines) occurs at the border of the ischemic core (blue) and peripheral areas, and limited axonal sprouting occurs in the neurons (green cells) of the peripheral areas. (B) A proposed diagram depicting enhanced angiogenesis and evident axonal sprouting and outgrowth under the treatment of stem cells. (C) A representative diagram expanded from a certain area of the diagram in (B). Stem cells (pink) adhering to the newly formed blood vessels to achieve migration. The blood vessels and stem cells themselves secrete a variety of neurotrophic factors including VEGF, BDNF, GDNF, Ang-1, Ang-2, IGF-1, and FGF. In addition, blood vessels release additional oxygen and nutrients to promote the proliferation, migration, and differentiation of stem cells, and axonal outgrowth. Abbreviations: VEGF, vascular endothelial growth factor; BDNF, brain-derived neurotrophic factor; GDNF, glial cell-derived neurotrophic factor; Ang-1, angiotensin 1; Ang-2, angiotensin 2; IGF-1, insulin-like growth factor 1; FGF, fibroblast growth factor.

Similar articles

Cited by

References

    1. Abe T., Aburakawa D., Niizuma K., Iwabuchi N., Kajitani T., Wakao S., et al. (2020). Intravenously transplanted human multilineage-differentiating stress-enduring cells afford brain repair in a mouse lacunar stroke model. Stroke 51 601–611. 10.1161/strokeaha.119.026589 - DOI - PubMed
    1. Acosta S. A., Tajiri N., Hoover J., Kaneko Y., Borlongan C. V. (2015). Intravenous bone marrow stem cell grafts preferentially migrate to spleen and abrogate chronic inflammation in stroke. Stroke 46 2616–2627. 10.1161/strokeaha.115.009854 - DOI - PMC - PubMed
    1. Adibhatla R., Hatcher J. (2010). Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid. Redox Signal. 12 125–169. 10.1089/ars.2009.2668 - DOI - PubMed
    1. Alishahi M., Farzaneh M., Ghaedrahmati F., Nejabatdoust A., Sarkaki A., Khoshnam S. (2019). NLRP3 inflammasome in ischemic stroke: as possible therapeutic target. Int. J. Stroke 14 574–591. 10.1177/1747493019841242 - DOI - PubMed
    1. Allegrucci C., Wu Y., Thurston A., Denning C., Priddle H., Mummery C., et al. (2007). Restriction landmark genome scanning identifies culture-induced DNA methylation instability in the human embryonic stem cell epigenome. Hum. Mol. Genet. 16 1253–1268. 10.1093/hmg/ddm074 - DOI - PubMed

Publication types