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Review
. 2022 Dec 27;10(1):33.
doi: 10.3390/bioengineering10010033.

Stem Cell Therapy for Acute/Subacute Ischemic Stroke with a Focus on Intraarterial Stem Cell Transplantation: From Basic Research to Clinical Trials

Susumu Yamaguchi  1   2 , Michiharu Yoshida  1   2 , Nobutaka Horie  3 , Katsuya Satoh  4 , Yuutaka Fukuda  1 , Shunsuke Ishizaka  1 , Koki Ogawa  5 , Yoichi Morofuji  1 , Takeshi Hiu  1 , Tsuyoshi Izumo  1 , Shigeru Kawakami  5 , Noriyuki Nishida  6 , Takayuki Matsuo  1
Affiliations
Review

Stem Cell Therapy for Acute/Subacute Ischemic Stroke with a Focus on Intraarterial Stem Cell Transplantation: From Basic Research to Clinical Trials

Susumu Yamaguchi et al. Bioengineering (Basel). .

Abstract

Stem cell therapy for ischemic stroke holds great promise for the treatment of neurological impairment and has moved from the laboratory into early clinical trials. The mechanism of action of stem cell therapy includes the bystander effect and cell replacement. The bystander effect plays an important role in the acute to subacute phase, and cell replacement plays an important role in the subacute to chronic phase. Intraarterial (IA) transplantation is less invasive than intraparenchymal transplantation and can provide more cells in the affected brain region than intravenous transplantation. However, transplanted cell migration was reported to be insufficient, and few transplanted cells were retained in the brain for an extended period. Therefore, the bystander effect was considered the main mechanism of action of IA stem cell transplantation. In most clinical trials, IA transplantation was performed during the acute and subacute phases. Although clinical trials of IA transplantation demonstrated safety, they did not demonstrate satisfactory efficacy in improving patient outcomes. To increase efficacy, increased migration of transplanted cells and production of long surviving and effective stem cells would be crucial. Given the lack of knowledge on this subject, we review and summarize the mechanisms of action of transplanted stem cells and recent advancements in preclinical and clinical studies to provide information and guidance for further advancement of acute/subacute phase IA stem cell transplantation therapy for ischemic stroke.

Keywords: intraarterial transplantation; ischemic stroke; regenerative medicine; stem cell transplantation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Summary of angiogenesis after intraarterial (IA) stem cell transplantation in acute and subacute phases post ischemic stroke. At the border of the infarct core (IC), within 24 h of ischemic stroke, neurons, astrocytes, and microglia secrete vascular endothelial growth factor (VEGF). The level of VEGF from microvessels increases after ischemic stroke, peaks on day 3, and normalizes until day 7 post ischemic stroke. In the periinfarct area (PI), pericytes secrete VEGF, helping endothelial cells (ECs) to proliferate. The expression of VEGF receptors (VEGFRs) on microvessels increases by day 2 post ischemic stroke, peaks on day 3, and normalizes until day 7. The expression of VEGFR and proliferation of ECs spreads from the PI to the IC. Once there is sufficient angiogenesis, pericytes terminate the sprouting proliferation of ECs. In the subacute phase, VEGF and platelet-derived growth factor-BB (PDGF-BB) enhance mature angiogenesis. In acute phase IA stem cell transplantation, stem cells are widely distributed in the IC and PI. In subacute phase IA stem cell transplantation, stem cells are mainly distributed in the PI. Transplanted stem cells secrete various growth factors, including VEGF and PDGF-BB, to promote angiogenesis. Thus, stem cell transplantation can reduce the infarct volume (red arrow, increase or enhancement; blue arrow, decrease or inhibition).
Figure 2
Figure 2
Sprague-Dawley rats were anesthetized with isoflurane, and a 75-min transient middle cerebral artery occlusion (MCAO) was performed with a 4.0 nylon monofilament suture coated with silicone (4039PK10; Doccol). One day after MCAO, the rats underwent stem cell transplantation. Mesenchymal stem cells (1 × 106 cells) or phosphate-buffered saline were injected into the internal carotid artery through a catheter inserted from the stump of the distal external carotid artery to the internal carotid artery through the bifurcation. After deep anesthesia, the brain was excised following perfusion fixation using 4% paraformaldehyde. After adequate fixation, a 40-μm frozen coronal section was made [11]. Three coronal sections of the brain (1.0 ± 0.6 mm before the bregma) were stained using Musashi-1 (rat anti-Musashi-1 [Msi-1]: Medical and Biological Laboratories Co., Ltd., Nagoya, Japan; 1:100). The area of Msi-1-positive neural stem cells was measured using WinRoof software (Mitani Corporation; Tokyo, Japan) in the subventricular zone (SVZ). The Msi-1-positive neural stem cells were measured by counting Msi-1- and TOPRO-3- double positive cells in the corpus callosum (CC). (a) The Msi-1-positive area in the SVZ of the contralateral hemisphere in the stem cell treatment group was significantly larger than that in the control group 2 days after MCAO. (b) Seven days after MCAO, the number of Msi-1-positive cells in the CC in the stem cell treatment group was significantly higher than that in the control group. All data are presented as means ± SEM * p < 0.05, (student t-test). IC; infarct core: LV; lateral ventricle.
Figure 3
Figure 3
Neurogenesis. After ischemic stroke, the proliferation of neural stem cells in the subventricular zone (SVZ) increases. These cells migrate to the injury site via the rostral migratory stream (RMS). Astrocytes and endothelial cells secrete brain-derived neurotrophic factor (BDNF). Three to fifteen days post ischemic stroke, neural stem cells (NSCs) migrate into the periinfarct area along the vessels, with p75NTR on the NSCs binding to BDNF on the vessels. Seven to fifteen days post ischemic stroke, the cells bind to BDNF on astrocytes. NSCs also change the morphology of astrocytes through Slit-1-Robo signaling and migrate into the periinfarct area along astrocytes. Regulatory T cells (Tregs) also control neurotoxic astrogliosis. Intraarterial (IA) transplantation provides stem cells in both hemispheres. Acute phase IA transplantation enhances neural stem cell proliferation in both the ipsilateral and contralateral SVZ and increases the level of BDNF in the periinfarct area 7 days post ischemic stroke. These events enhance neural stem cell migration. In addition, transplanted stem cells also enhance the proliferation of Tregs. IA transplantation could enhance NSC migration to the periinfarct area by control of astrogliosis. Three days post ischemic stroke, the ischemic pericytes express NSC markers (red arrow, increase or enhancement). IC: infarct core; PI: peri-infarct lesion: ipsi: ipsilateral; contra: contralateral.
Figure 4
Figure 4
Summary of anti-inflammatory processes. After an ischemic stroke, the level of damage-associated molecular patterns (DAMPs) increases. DAMPs activate macrophages/microglia (M/M) (M1) and neutrophils. DAMPs also increase vessel permeability by decreasing blood-brain barrier (BBB) integrity, leading to infiltration of inflammatory cells into the infarct area. M/M (M1) secretes interleukin (IL)-1 beta, which injures neurons directly. From 3 days post ischemic stroke, MSR1-expressing macrophages, which scavenge DAMPS, increase up to 7 days post ischemic stroke. As DAMPs start decreasing, BBB integrity improves and neuroinflammation decreases. A few days post ischemic stroke, T cells infiltrate the infarct lesion. CD8+ T cells produce interferon-γ and IL-16, injuring neurons. Regulatory T cells (Tregs) gradually increase from the acute phase to 60 days post ischemic stroke. Tregs produce IL-10, reducing the infarct volume. In acute and subacute phase IA stem cell transplantation, stem cells switch the M/M polarization from M1 to M2, which reduces debris and secretes various trophic/growth factors. Stem cells also secrete IL-10. These effects contribute to reducing the infarct volume (red arrow, increase or enhancement; blue arrow, decrease or inhibition). IC: infarct core; PI: peri-infarct lesion.
Figure 5
Figure 5
Focused ultrasound (FUS)/microbubble-assisted blood-brain barrier (BBB) opening system. (a) Schematic of the experimental setup for BBB opening. The cylindrical FUS transducer was filled with agarose and ultrasound gel. The mouse was placed in the supine position, and the head positioned on ultrasound gel. The irradiation target region in the mouse brain was adjusted using a laser marking device. Then, FUS (frequency, 3 MHz; intensity, 1.5 kW/cm2; duration, 60 s; duty cycle, 5% [1 msec irradiation and 19 msec interval]) was applied to the right striatum after intravenous administration of microbubbles and Evans blue. (b) BBB opening confirmed using Evans blue extravasation.
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