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

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.

Treating Cerebral Ischemia: Novel Therapeutic Strategies from Experimental Stroke Research

“…MSCs, for instance, can also achieve the same effects (51). In contrast to common initial belief, however, the majority of transplanted stem cells are trapped in peripheral organs, suggesting that grafted stem cells stabilize the BBB and promote neural regeneration by indirect means (52). Such indirect means include paracrine factors.…”

Enriched Environment and Exercise Enhance Stem Cell Therapy for Stroke, Parkinson’s Disease, and Huntington’s Disease

“…Interestingly, MSCs have also shown to reduce BBB disruption by inhibiting matrix metallopeptidase 9 (MMP-9) and decreasing ICAM-1 ( Cheng et al, 2018 ). This discrepancy may be due to the different stem cells used and the different stages of these stem cells, which needs to be further studied ( Zhou et al, 2021 ). There seems to be a two-pronged mechanism where stem cells will use BBB permeability to extravasate and migrate to the injured area and then begin to secrete growth factors and therapeutic substances through the bystander effect ( Ao et al, 2018 ).…”

Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke

“…Biomaterials act as scaffolds that mechanically protect stem cells during their migration to the site of action [ 17 , 18 ]. Similar to biomaterials, the use of drugs in combination with stem cell transplantation is being investigated as a potential booster for these therapeutic benefits [ 13 , 19 ]. Concomitant administration with drugs and the usage of biomaterials stand as promising adjuvants for stem cell therapies in stroke [ 20 , 21 ].…”

“…Of note, MSCs, NSCs, and HSCs used for regenerative therapy of stroke can protect against tissue damage, promote injured tissue repair, and increase functional recovery [ 39 , 40 ]. Stem cells provide neuroprotection and restorative properties that ameliorate the loss of astrocytes, neurons, blood vessels, and oligodendrocytes, making their therapeutic potential quite promising [ 19 ]. Multiple preclinical studies have elaborated how stem cells afford functional benefits in animal stroke models.…”