Volume 7, Issue 1 pp. 12-20

Original Article

Open Access

MRI tracking/detection of bone marrow mesenchymal stromal cells transplantation for treatment of ischemic cerebral infarction

Nan Zhao,

Nan Zhao

Animal Zoology Department, Kunming Medical University, Kunming, Yunnan, China

Department of Anesthesiology, Affiliated Stomatology Hospital of Zunyi Medical University, Zunyi, Guizhou, China

These authors contributed equally to this article.Search for more papers by this author

Rui-Ze Niu,

Rui-Ze Niu

Animal Zoology Department, Kunming Medical University, Kunming, Yunnan, China

These authors contributed equally to this article.Search for more papers by this author

Yu-Hang Zhu,

Yu-Hang Zhu

Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China

Search for more papers by this author

Chang-Yin Yu,

Corresponding Author

Chang-Yin Yu

[email protected]

Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China

These authors contributed equally to this article.

Corresponding author:

Chang-Yin Yu, Department

of Neurology, Affiliated

Hospital of Zunyi Medical

University, Zunyi, Guizhou,

China.

E-mail: [email protected].

Search for more papers by this author

Nan Zhao,

Nan Zhao

Animal Zoology Department, Kunming Medical University, Kunming, Yunnan, China

Department of Anesthesiology, Affiliated Stomatology Hospital of Zunyi Medical University, Zunyi, Guizhou, China

These authors contributed equally to this article.Search for more papers by this author

Rui-Ze Niu,

Rui-Ze Niu

Animal Zoology Department, Kunming Medical University, Kunming, Yunnan, China

These authors contributed equally to this article.Search for more papers by this author

Yu-Hang Zhu,

Yu-Hang Zhu

Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China

Search for more papers by this author

Chang-Yin Yu,

Corresponding Author

Chang-Yin Yu

[email protected]

Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China

These authors contributed equally to this article.

Corresponding author:

Chang-Yin Yu, Department

of Neurology, Affiliated

Hospital of Zunyi Medical

University, Zunyi, Guizhou,

China.

E-mail: [email protected].

Search for more papers by this author

First published: March 2021

https://doi.org/10.1002/j.2769-2795.2021.tb00059.x

Citations: 1

Share a link

Email
Wechat
Bluesky

Abstract

Background

Cerebral stroke is the second leading cause of death with high mortality and morbidity worldwide, currently it lacks effective therapies to improve the prognosis. This study was aimed to explore the role of bone marrow mesenchymal stem cells (BMSCs) transplantation in the recovery of brain structure and function after ischemic cerebral infarction by magnetic resonance imaging (MRI).

Methods

By applying internal carotid artery embolization, the ischemic cerebral infarction model in rats was established. MRI was performed to detect the imaging changes in the brain tissue after modeling, and the successful modeling was evidenced by the presence of obvious high-signal infarct areas in the brain. BMSCs were then injected into the lateral ventricles of rats, and the recovery of brain tissue and function were quantitatively evaluated by T2-weighted image (T2WI) and voxel-based morphology (VBM) after 28 days.

Results

The results showed that BMSCs were cell subsets with multiple differentiation potentials. Deficits caused by Ischemic cerebral infarction were relieved by BMSCs transplantation, including increase in damaged cerebral tissue and recovery of cerebral function. In addition, the combined imaging technology of VBM and T2WI quantitatively revealed the effectiveness of BMSCs in repairing damaged brain tissue structure and function.

Conclusion

Taken together, the results revealed that the transplantation of BMSCs into the lateral ventricle was beneficial to repair the structure and function of the damaged brain tissue after ischemic cerebral infarction. Moreover, the combination of VBM and T2WI technology can detect the level of brain injury in ischemic cerebral infarction dynamically and noninvasively, and evaluate the recovery of structure and function of damaged brain tissue.

Introduction

Cerebral infarction (CI), also known as cerebral ischemic stroke (CIS), refers to the localized ischemic necrosis or softening of brain tissue caused by brain blood supply disorders, ischemia, and hypoxia. Cerebral stroke is the second leading cause of death in the world according to the latest data published by the World Health Organization. Among them, ischemic cerebral infarction accounts for more than 70% of all cerebrovascular diseases (Gorelick PB, et al., 2020; Kuriakose D, et al., 2020). Mounting studies have shown that interruption of blood supply to the brain for more than 30 minutes would develop irreversible damage to the nerve cells of brain tissue. The longer ischemia time, the more serious reperfusion injury of brain tissue after reperfusion (Sims NR, et al., 2010). The consequences of cerebral ischemia and hypoxia are far-reaching and lasting, eventually leading to short-term or long-term neurological dysfunction and disability as well as high mortality, which brings heavy burdens on the family and society (Rapsomaniki E, et al., 2014; Naess H, et al., 2010). As a result, how to promote the survival and regeneration of neurons in the injured area, recovery the damaged brain tissue, enhance the neurological function, and improve the prognosis are the major research hot topics in the treatment of ischemic brain infarction (Abeysinghe HCS, et al., 2016; Becerra-Calixto A, et al., 2017; Cui C, et al., 2016). At present, the clinical therapeutic strategies for CI are mainly symptomatic supportive treatments; however, these treatments cannot improve long-term neurological dysfunction. Thus, it is of great significance to explore new detection technologies and treatment methods based on main pathophysiology for CI.

Bone marrow mesenchymal stem cells (BMSCs) are a subset of cells with multipotent differentiation potential (Friedenstein AJ, et al., 1976). Woodbury D et al. proved that BMSCs not only have the ability to differentiate multi-directionally, but also to break the traditional restriction of germ layer differentiation (Woodbury D, et al., 2002). Recently, increasing evidences showed that BMSCs transplanted into the brain infarction model can migrate to the injured site and differentiate into neurons, which promoted angiogenesis, anti-glial cell proliferation and anti-apoptosis at the injured site (Jiang W, et al., 2014; Nakajima M, et al., 2017). Many reports demonstrated that BMSCs play an important role in the development of the nervous system and even the survival or repair of neuronal cells (Bonsack B, et al. 2020; Li C, et al. 2019; Shen H, et al., 2020). In addition, the animal experiments have shown that BMSCs transplantation can notably improve the neurological function and prognosis in rats with acute ischemic brain injury (Xie P, et al., 2019; Sammali E, et al., 2017).

In the evaluation of the mechanism and efficacy of BMSCs in the repair of cerebral ischemia injury, most of the literature in China and abroad explored the repair mechanism and efficacy through immunohistochemistry, immunofluorescence, Western blot and cell pathology. In recent years, with the rapid development of medical imaging, Magnetic resonance imaging (MRI) technology has been used to dynamically and noninvasively observe the changes of functional magnetic resonance imaging (fMRI) efficacy evaluation of cerebral ischemic injury area after stem cell intervention, which provided an imaging basis for the mechanism of stem cell treatment and clinical efficacy evaluation (Korbakis G, et al., 2016; Rimmele DL, et al., 2014; Karunamuni RA, et al. 2019; Visser MM, et al., 2019; Nael K, et al., 2015). Among them, Voxel-based morphological (VBM) analysis allows brain region segmentation and post-processing of MRI images, thus the individual data of each brain region can be analyzed with individual data in voxels. Based on the different intensities of voxels, the brain tissue is divided into grey matter, white matter and cerebrospinal fluid, then the density or volume of these parts is measured to quantitatively analyze the morphological changes in brain tissue (Gauthier LV, et al., 2008; Yin D, et al., 2013). So, with the popularity of high magnetic field intensity MRI and the development of brain imaging technology, this safe and non-invasive method can be used to conduct non-invasive and efficient brain structure and function research on living bodies, expecting that it would help early clinical stage with diagnosis, early intervention and early treatment by providing useful information and efficient support.

The present research explored the exact role of BMSCs in CI by establishing CI model in rats. The BMSCs were injected into rats at the lateral ventricle. Afterwards, combined with MRI technology to detect the structure and function recovery of the damaged brain tissue in rats. The present study was designed to validate the specific significance of BMSCs in CI-induced neurological deficits and to research the value of MRI in evaluating the damage and cell apoptosis of ischemic cerebral infarction in rats.

Materials and methods

Animals and grouping

The animal experimental design of this study has been approved by the Animal Care & Welfare Committee of Kunming Medical University. All experimental processes complied with the guidelines for the care and use of laboratory animals published by the National Institutes of Health. The Sprague-Dawley (SD) rats aged 8-week (300 ± 20 g, male) were provided by Animal Centre of Kunming Medical University, and housed with alternate 12/12 light/dark environment at humidity of 40-70% and temperature of 22-24°C. A total of 12 SD rats were randomly divided into Sham group (rats were only subjected to same anesthesia and arterial exposure), Control group (CI rats were injected with the same dose of normal saline at the same site) and BMSC group (CI rats were injected BMSCs, 2x10⁵ cells, totaling 5 μl).

Establishment model of CI

SD rats were anesthetized with an intraperitoneal injection of 2% pentobarbital sodium (0.3 ml/100 g), and then fixed on the operating table in the supine position. After disinfected the skin, an incision was made in the middle of the neck, followed by the left common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA). Silk sutures were tied around the CCA distal and proximal ends and ECA for use. ICA was clamped with an arteriole clip temporarily, and then CCA and ECA were ligated proximal to the heart. A beveled incision was cut from the CCA ligature and the knot, while a strand plug was inserted through the ICA, and tied the tethering wire with a thin wire around the distal end of the CCA gently. The thread was gently put with ophthalmic tweezers, and calculated distance from the arterial bifurcation. When the insertion depth reached 18 mm, the slimline at the distal end of CCA was tightly fastened. The aseptic environment was maintained strictly during surgical procedures.

BMSCs cell culture

One-month-old adult rats were used for primary BMSCs extraction. Briefly, adult rats were sacrificed by intraperitoneal anesthesia with 2% pentobarbital sodium (0.3 ml/100 g) and sterilized in 75% ethanol for 3 minutes (min). Then, the femur was taken out aseptically, the remaining muscle was removed and the end was cut off. Afterwards, the culture fluid was injected into the bone marrow cavity with a 1 ml needle and rinsed three times, the cell suspension was collected, filtered through a 200-mesh syringe and inoculated in a bottle. Then, the cells were incubated with SD rats BMSCs special medium under the condition of 5% carbon dioxide. On the 5th day, half of the fluid was changed, 5 passages of cells were harvested for subsequent experiments after observing the growth and morphology of the cells.

Transplantation of BMSCs into the lateral ventricle

BMSCs were injected into lateral ventricle 5 min after cerebral artery embolization, and the injection dose of BMSC group was 2x10⁵ cells, totaling 5 μl. The control group was injected with the same dose of normal saline at the same site. The injection coordinates were 1.0 mm from the bregma, 1.5 mm on the left side, and 4 mm depth of needle insertion, the process was operated under warm and sterile conditions.

MRI scan of rats' brain

All RI scans were performed by a 7.0 T magnetic resonance scanner (Bruker Biospec 70/30, Ettlingen, Germany) to collect rat brain MRI images. The general procedure is as follows: The rats were anesthetized with 2% pentobarbital sodium (0.3 ml/100 g) using a 16 cm horizontal scanning frame and a volume or surface coil. The rats were placed in an organic glass scanning bed to fix the brain and the body temperature, heart rate and respiration were continuously monitored. Moreover, the heating blanket was used to maintain the body temperature of rats at about 37°C. MRI scanning parameters of rat brain structure were: T2 weighted image, coronal T2WI scanning, parameter setting, Rapid Imaging with Refocused Echoes (RIRE) was 4; Time Repetition (TR) was3000 ms; Echo Time (ET) was 12 ms, Field of View (FOV) was 3.2 cm*3.2 cm; layer thickness was 0.5 mm; layer spacing was 0.75 mm and 25 layers; matrix size was 384*384, spatial resolution was 0.083*0.083*0.75, and the scanning time was 12 min.

VBM image analysis technique

VBM analysis is based on Matlab R2020a software platform. All structural image data are first expanded 10 times by DPABI software, which is convenient for SPM12 toolbox (http://www.fil.ion.ucl.ac.uk/spm/software/spm12/) for subsequent processing (Yan CG, et al., 2016). SPM12 toolbox is used to preprocess the collected extended structural images, including: 1. Manual correction: manual correction of all 3D images according to the pre-and post-joint; 2. Tissue segmentation and standardization: SPM12 was used to convert all individual T2WI to standard three-dimensional space according to the rat brain structure template (Valdés-Hernández PA, et al., 2011), and then divided into grey matter, white matter and cerebrospinal fluid. After the optimal template is generated by DARTEL registration method, the segmented image is averaged to obtain the grey and white template of the sample. The segmented image is standardized to the template again, and then segmented and extracted again. The grey and white images of all individuals after segmentation are standardized to 1.5 mm*1.5 mm*1.5 mm. Grey matter volume (GMV), white matter volume (WMV), cerebrospinal fluid volume (CSFV) and whole brain volume (WBV) were calculated; 3. Image modulation: The volume change caused by non-linear transformation in the standardization step is adjusted to obtain the relative volume of each voxel after correction; 4. Tissue smoothing: Gaussian kernel (full width at half-maximun (FMWH) = 6 mm) with full width at half-maximun (FMWH) = 6 mm is used for spatial smoothing of the obtained images, so as to reduce the anatomical differences of brain structures of different individuals and improve the signal-to-noise ratio, as well as ensure that the data conform to the normal distribution. The masks and final results in all the analysis processes were presented based on the rat anatomical map and rat standard template made by Valdés-Hernández et al., and the coordinate localization is referred to the rat brain stereotaxic map made by Paxinos and Watson (Paxinos G, et al., 1986).

Statistical analysis

The comparison of GMV between the two groups was using by statistical analysis module of DPABI software for statistical analysis. The comparison between the two groups was using two sample t test, while each voxel test level was set to p < 0.001. By using single tail t test, block test level was set to p < 0.05, cluster > 100 voxels of the brain area, the difference was statistically significant. The final result was rendered by DPABI Viewer. Brainnet Viewer software was used to make brain graphics (Mingrui X, et al., 2013).

Results

MRI manifestations of rats’ brain

Bruker Biospec 7T MRI was used to examine rats in the Sham group, Control group and BMSC group on the 28th day after arterial embolization. The results showed that compared with the Sham group, the Control group rat’s coronal T2WI showed significantly high signal infarct area in the ischemic side of the rat, and the signal intensity of the infarct location increased; compared with the Control group, the T2WI of the coronal surface of the rat brain in the BMSC group showed that the signal intensity of the ischemic side brain tissue increased (Figure 1).

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

**CI model was successfully produced.** T2WI of the coronal surface of the CI model rat’s brain. MRI observes the area of CI. From top to bottom, they are divided into Sham group, Control group and BMSC group. From top to bottom, each group is T2WI and cortical segmentation.

3D reconstruction of rats’ brain MRI

According to the MRI results, the rats brain stereogram reconstruction was performed. The results showed that compared with the Sham group, the CI volume of the Control group increased significantly (Figure 2, p < 0.001); Compared with the Control group, 3D reconstruction showed that the CI volume of rats in the BMSC group did not change significantly (Figure 2).

Effect of BMSCs injection on repairing brain infarction in rats

In order to verify the effects of BMSCs treatment on brain structure and function of rats after CI, VBM examination was performed on 28 d after CI. The results showed that:

(1) Compared with the Sham group, the total brain volume (Figure 3), grey matter volume (Figure 3) and cerebrospinal fluid volume (Figure 3) of rats in the Control group did not change significantly; the brain infarction volume significantly increased (Figure 3, p < 0.001); the white matter volume significantly reduced (Figure 3, p < 0.05).

(2) Compared with the Control group, the total brain volume (Figure 3), brain infarction volume (Figure 3), and grey matter volume (Figure 3) of rats in the BMSC group did not change significantly; the white matter volume increased significantly (Figure 3, p < 0.05); the volume of cerebrospinal fluid increased significantly (Figure 3, p < 0.01).

Brain activation regions based on VBM analysis in BMSC group

Brain activation region based on VBM in two groups of rats: Compared with the Control group, the grey matter volume of BMSC group was significantly increased in the right inferior frontal gyrus, occipital fusiform gyrus, left anterior cingulate, Sub-Gyral, lingual gyrus, and Sub-lobar regions. Compared with the Control group, the grey matter volume of BMSC group significantly decreased in the right postcentral gyrus, the precentral gyrus region and the left precentral gyrus (Figure 4, Table 1, p = 0.001, α < 0.05).

Table 1. Difference of GMV between BMSC group and Control group.

Structure	Brain	Peak MNI Coordinate			Number of Voxels	Peak Intensity
		x	y	z
Inferior Frontal Gyrus	R(right)	17.5	17.5	-18.75	583	10.7201
Occipital Fusiform Gyrus	R	23.75	-50	-11.25	372	7.3901
Anterior Cingulate	L(left)	-5	43.75	5	442	10.8276
Sub-Gyral	L	-31.25	-66.25	-3.75	229	6.5639
Lingual Gyrus	L	-16.25	-58.75	-2.5	546	12.1244
Sub-lobar	L	-31.25	-41.25	1.25	255	8.8189
Postcentral Gyrus	L	55	-17.5	20	188	-6.7186
Precentral Gyrus	L	-50	15	55	114	-7.8315
Precentral Gyrus	R	48	10	56	100	-7.8315

MNI is Montreal coordinates.

Discussion

In this study, we demonstrated that the transplantation of BMSCs through the lateral ventricle was conducive to the survival and regeneration of neurons in the injured area of CI rats, and could boost the repair of damaged brain tissue and the improvement of neurological function. In addition, we also found that VBM imaging examination can sensitively observe the changes of brain tissue structure and functional recovery after ischemic injury in various regions of the brain of CI rats, indicating that VBM is an effective method for in vivo monitoring and evaluation of ischemic brain injury in vitro, and has certain value for the study of neurological diseases in clinical work.

In the present study, we established CI model by using SD rats according to previous studies (Longa EZ, et al., 1989), and used MRI to detect ischemic cerebral infarction caused by CI. As we all know, if the middle cerebral artery occlusion is not reversed in time, it will lead to local brain tissue including nerve cells, glial cells and associated fibers degeneration, necrosis or transient loss of function due to blood supply disorders (Sekerdag E, et al., 2018). Once the organization is damaged, it cannot be saved, and the individual will eventually be affected by long-term disability (Karen J, et al., 2014). Therefore, more forms of treatment are needed to improve the results (Vu Q, et al., 2014). At present, in addition to tissue-type plasminogen activator (t-PA) which can effectively treat very few patients with ischemic stroke in especial short time window, there are no other better treatment drugs for ischemic stroke. Although a lot of drugs have shown good therapeutic effects in animal experiments of ischemic brain injury, the clinical effects are not ideal.

To explore the role of BMSCs in CI, we transplanted BMSCs in the lateral ventricle of CI rats. The experimental results showed that the injection of BMSCs into the lateral ventricle of rats after CI modeling was beneficial to the repair of damaged brain tissue after ischemic cerebral infarction. Transplanted BMSCs mentioned in previous studies have the ability to differentiate into astrocytes and neurons (Yang H, et al., 2020; Xiao QX, et al., 2020). The white matter volume and cerebrospinal fluid volume of CI rats after BMSCs transplantation increased significantly. In recent years, many studies have reported that intracerebroventricular injection of BMSCs is a direct and efficient method for stroke patients, which can avoid a long circulatory system and directly affect the lesion site without crossing the blood-brain barrier, reducing the loss of stem cells and thus playing a better therapeutic role (Cui J, et al., 2017; Shichinohe H, et al., 2017). Evidence suggested that BMSCs can migrate and secrete various cytokines and growth factors (Lotfy A, et al., 2014; Kallmeyer K, et al. 2020; Zakaria DM, et al., 2021). In addition, these characteristics have immune regulation, angiogenesis, anti-inflammatory and anti-apoptotic effects, also help to regulate various acute and chronic pathological states. These mechanisms make BMSCs therapy play an important role in the repair of blood-brain barrier after ischemic stroke (Li Z, et al., 2019; Cunningham CJ, et al. 2018; Zhao XM, et al. 2019; Zachar L, et al., 2016). Thus, combined with our research results, all these mentioned studies suggested that BMSCs can promote the repair of brain tissue structure and function after CI in rats.

In this study, we also confirmed that BMSCs could promote the recovery of injured brain tissue structure and function after CI by using MRI combined with VBM imaging technology. Our results showed that the volume of brain grey matter, white matter and cerebrospinal fluid in CI rats after BMSCs transplantation all significantly increased, and the recovery of sensory and motor function of injured brain tissue was significantly better than that of the control group, indicating that MRI and VBM can be used to detect and quantify the recovery of brain tissue and function of CI rats after BMSCs transplantation. Previous studies have shown that CI not only causes changes in local grey matter structure, but also usually leads to the damage of white matter fiber bundles related to it (Ingo C, et al., 2020; Zuo LJ, et al., 2018). Currently, the mechanism and efficacy evaluation of BMSCs in repairing cerebral ischemic injury are mostly based on in vitro animal experiments or clinical observation, which cannot dynamically monitor the condition or treatment of patients, so its clinical application is limited. In addition, with the development of neuroimaging technology, the use of MRI dynamic, non-invasive observation of cerebral ischemic injury area changes in brain function and efficacy evaluation of the study opened up a new way to study the evolution of CI (Wang D, et al. 2020; Nakajo Y, et al. 2019). VBM, fMRI, DTI and other new technologies have been rapidly developed and popularized in recent years, which provide a powerful means to explore the changes of brain structure and function caused by CI (Wesley UV, et al., 2019; Hao XZ, et al., 2017; Mastropietro A, et al. 2019). VBM is an overall analysis of high-resolution anatomical images of the whole brain at voxel level (Wang X, et al. 2021; Chen G, et al. 2018). Taking the brain as a whole, the differences of brain anatomical structure among different subjects were analyzed (Mu SH, et al., 2017; Chen ZY, et al. 2018). By analyzing the changes of brain parenchymal density, the changes of local grey matter volume, white matter volume and brain tissue density were quantitatively calculated. In addition, since the region of interest does not need to be manually set and has high objectivity and accuracy, it is often used to study brain structural changes caused by central nervous system diseases (Fujimoto H, et al., 2017; Steinke J, et al. 2017). In our study, such new technologies were used to confirm the role of BMSCs in CI rats.

However, the present study has limitations. The main limitation of the study is that only MRI results are used to determine whether the CI model is successful, but no further behavioral score and histopathological examination of the animal model are confirmed. This study is a horizontal study without observing the dynamic evolution of brain structure and function in CI rats. Therefore, it is necessary to conduct longitudinal studies in future studies to increase the understanding of CI injury and recovery mechanism. The concentration of transplanted BMSCs was not tracked. Whether the concentration of BMSCs in different brain injury areas occurred variedly still needs further study.

In conclusion, our study shows that the transplantation of BMSCs in lateral ventricle is beneficial to the repair of damaged brain tissue structure and function after ischemic cerebral infarction. Moreover, VBM combined with MRI technology can realize detection of brain injury level of ischemic CI and evaluation of structural and functional recovery of injured brain tissue. This examination method is expected to be applied to the evaluation of curative effect of brain structural and functional recovery of ischemic injury area after stroke.

Ethical statement

The animal study protocol was legally approved by the Animal Care & Welfare Committee of Kunming Medical University (Approval No: kmmu2021534). All experiments conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

Acknowledgements

We would like to thank Professor Ting-Hua Wang of Institute of Neurobiological Disease, West China Hospital, Sichuan University for the technical support.

Conflict of interest

There is no conflict of interest in this study.

Funding

This study was supported by grant from the National Natural Science Foundation of China (Grant Nos. 82001604, 82060243 and 81960214) and Joint Fund of Zunyi Science and Technology Bureau-Affiliated Hospital of Zunyi Medical University (No. HZ2020250).

Transparency statement

All the authors affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Authors' contribution

Nan Zhao and contributed the central idea; Nan Zhao, Yu-Hang Zhu and Rui-Ze Niu and designed the experiments; Chang-Yin Yu contributed to refining the ideas, carrying out additional analyses and finalizing this paper.

References

Abeysinghe HCS, Phillips EL, Chin-Cheng H, et al. Modulating Astrocyte Transition after Stroke to Promote Brain Rescue and Functional Recovery: Emerging Targets Include Rho Kinase. Int J Mol Sci, 2016, 17: 288.
10.3390/ijms17030288
PubMed Web of Science® Google Scholar
Becerra-Calixto A, Cardona-Gómez GP. The Role of Astrocytes in Neuroprotection after Brain Stroke: Potential in Cell Therapy. Front Mol Neurosci, 2017, 10: 88.
10.3389/fnmol.2017.00088
PubMed Web of Science® Google Scholar
Bonsack B, Corey S, Shear A. Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury. CNS Neurosci Ther, 2020, 26: 603–615.
10.1111/cns.13378
PubMed Web of Science® Google Scholar
Chen G, Zhou B, Zhu H. White matter volume loss in amyotrophic lateral sclerosis: A meta-analysis of voxel-based morphometry studies. Prog Neuropsychopharmacol Biol Psychiatry, 2018, 83: 110–117.
10.1016/j.pnpbp.2018.01.007
PubMed Web of Science® Google Scholar
Chen ZY, Guo YQ, Feng TY, Neuroanatomical correlates of time perspective: A voxel-based morphometry study. Behav Brain Res, 2018, 339: 255–260.
10.1016/j.bbr.2017.11.004
PubMed Web of Science® Google Scholar
Cui C, Ye X, Chopp M. miR-145 Regulates Diabetes-Bone Marrow Stromal Cell-Induced Neurorestorative Effects in Diabetes Stroke Rats. Stem Cells Transl Med, 2016, 5: 1656–1667.
10.5966/sctm.2015-0349
CAS PubMed Web of Science® Google Scholar
Cui J, Cui C, Cui Y. Bone Marrow Mesenchymal Stem Cell Transplantation Increases GAP-43 Expression via ERK1/2 and PI3K/Akt Pathways in Intracerebral Hemorrhage. Cell Physiol Biochem, 2017, 42: 137–144.
10.1159/000477122
CAS PubMed Google Scholar
Cunningham CJ, Redondo-Castro E, Allan SM. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J Cereb Blood Flow Metab, 2018, 38: 1276–1292.
10.1177/0271678X18776802
PubMed Web of Science® Google Scholar
Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol, 1976, 4: 267–274.
CAS PubMed Web of Science® Google Scholar
Fujimoto H, Matsuoka T, Kato Y. Brain regions associated with anosognosia for memory disturbance in Alzheimer's disease: a magnetic resonance imaging study. Neuropsychiatr Dis Treat, 2017, 13: 1753–1759.
10.2147/NDT.S139177
PubMed Web of Science® Google Scholar
Gauthier LV, Taub E, Perkins C. Remodeling the brain: plastic structural brain changes produced by different motor therapies after stroke. Stroke, 2008; 39 (5): 1520–1525.
10.1161/STROKEAHA.107.502229
PubMed Web of Science® Google Scholar
Gorelick PB, Whelton PK, Sorond F. Blood Pressure Management in Stroke. Hypertension, 2020, 76 (6): 1688–1695.
10.1161/HYPERTENSIONAHA.120.14653
CAS PubMed Web of Science® Google Scholar
Hao XZ, Tian JQ, Yin LK. MRI detects protective effects of DAPT treatment with modulation of microglia/macrophages at subacute and chronic stages following cerebral ischemia. Mol Med Rep, 2017, 16: 4493–4500.
10.3892/mmr.2017.7200
CAS PubMed Web of Science® Google Scholar
Ingo C, Lin C, Higgins J. Diffusion Properties of Normal-Appearing White Matter Microstructure and Severity of Motor Impairment in Acute Ischemic Stroke. AJNR Am J Neuroradiol, 2020, 41: 71–78.
10.3174/ajnr.A6357
CAS PubMed Web of Science® Google Scholar
Jiang W, Liang G, Li XM. Intracarotid transplantation of autologous adipose-derived mesenchymal stem cells significantly improves neurological deficits in rats after MCAo. J Mater Sci Mater Med, 2014, 25: 1357–1366.
10.1007/s10856-014-5157-9
CAS PubMed Web of Science® Google Scholar
Kallmeyer K, André-Lévigne D, Baquié M. Fate of systemically and locally administered adipose-derived mesenchymal stromal cells and their effect on wound healing. Stem Cells Transl Med, 2020, 9: 131–144.
10.1002/sctm.19-0091
CAS PubMed Web of Science® Google Scholar
Karen J, Sherita C, Prachi M. Current perspectives on the use of intravenous recombinant tissue plasminogen activator (tPA) for treatment of acute ischemic stroke. Vasc Health Risk Manag, 2014, 10: 75–87.
PubMed Google Scholar
Karunamuni RA, White NS, Fromm A. Improved characterization of cerebral infarction using combined tissue T2 and high b-value diffusion MRI in post-thrombectomy patients: a feasibility study. Acta Radiol, 2019, 60: 1294–1300.
10.1177/0284185118820063
PubMed Web of Science® Google Scholar
Korbakis G, Prabhakaran S, John S. MRI Detection of Cerebral Infarction in Subarachnoid Hemorrhage. Neurocrit Care, 2016, 24: 428–435.
10.1007/s12028-015-0212-z
PubMed Web of Science® Google Scholar
Kuriakose D, Xiao Z. Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives. International Journal of Molecular Sciences, 2020, 21 (20): 7609.
10.3390/ijms21207609
CAS PubMed Web of Science® Google Scholar
Li C, Jiao G, Wu W. Exosomes from Bone Marrow Mesenchymal Stem Cells Inhibit Neuronal Apoptosis and Promote Motor Function Recovery via the Wnt/β-catenin Signaling Pathway. Cell Transplant, 2019, 28: 1373–1383.
10.1177/0963689719870999
PubMed Web of Science® Google Scholar
Li Z, Ye H, Cai X. Bone marrow-mesenchymal stem cells modulate microglial activation in the peri-infarct area in rats during the acute phase of stroke. Brain Res Bull, 2019, 153: 324–333.
10.1016/j.brainresbull.2019.10.001
CAS PubMed Web of Science® Google Scholar
Longa EZ, Weinstein PR, Carlson S. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke; a journal of cerebral circulation, 1989, 20 (1): n84.
10.1161/01.STR.20.1.84
CAS PubMed Web of Science® Google Scholar
Lotfy A, Salama M, Zahran F. Characterization of mesenchymal stem cells derived from rat bone marrow and adipose tissue: a comparative study. Int J Stem Cells, 2014, 7: 135–142.
10.15283/ijsc.2014.7.2.135
CAS PubMed Google Scholar
Mastropietro A, Rizzo G, Fontana L. Microstructural characterization of corticospinal tract in subacute and chronic stroke patients with distal lesions by means of advanced diffusion MRI. Neuroradiology, 2019, 61: 1033–1045.
10.1007/s00234-019-02249-2
PubMed Web of Science® Google Scholar
Mingrui X, Jinhui W, Yong H. BrainNet Viewer: A Network Visualization Tool for Human Brain Connectomics. Plos One, 2013, 8 (7): e68910.
10.1371/journal.pone.0068910
PubMed Web of Science® Google Scholar
Mu SH, Xu M, Duan JX. Localizing Age-Related Changes in Brain Structure Using Voxel-Based Morphometry. Neural Plast, 2017, 2017: 6303512.
10.1155/2017/6303512
PubMed Web of Science® Google Scholar
Nael K, Trouard TP, Lafleur SR. White matter ischemic changes in hyperacute ischemic stroke: voxel-based analysis using diffusion tensor imaging and MR perfusion. Stroke, 2015, 46: 413–418.
10.1161/STROKEAHA.114.007000
PubMed Web of Science® Google Scholar
Naess H, Waje-Andreassen U. Review of long-term mortality and vascular morbidity amongst young adults with cerebral infarction. Eur J Neurol, 2010, 17: 17–22.
10.1111/j.1468-1331.2009.02868.x
CAS PubMed Web of Science® Google Scholar
Nakajima M, Nito C, Sowa K. Mesenchymal Stem Cells Overexpressing Interleukin-10 Promote Neuroprotection in Experimental Acute Ischemic Stroke. Mol Ther Methods Clin Dev, 2017, 6: 102–111.
10.1016/j.omtm.2017.06.005
CAS PubMed Google Scholar
Nakajo Y, Zhao Q, Enmi JI. Early Detection of Cerebral Infarction After Focal Ischemia Using a New MRI Indicator. Mol Neurobiol, 2019, 56: 658–670.
10.1007/s12035-018-1073-1
CAS PubMed Web of Science® Google Scholar
Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. Rat Brain in Stereotaxic Coordinates, 1986, 3 (2): 6.
Google Scholar
Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people. Lancet, 2014, 383: 1899–1911.
10.1016/S0140-6736(14)60685-1
PubMed Web of Science® Google Scholar
Rimmele DL, Thomalla G. Wake-up stroke: clinical characteristics, imaging findings, and treatment option - an update. Front Neurol, 2014, 5: 35.
10.3389/fneur.2014.00035
PubMed Web of Science® Google Scholar
Sammali E, Alia Cl, Vegliante G. Intravenous infusion of human bone marrow mesenchymal stromal cells promotes functional recovery and neuroplasticity after ischemic stroke in mice. Sci Rep, 2017, 7: 6962.
10.1038/s41598-017-07274-w
PubMed Web of Science® Google Scholar
Sekerdag E, Solaroglu I, Gursoy-Ozdemir Y. Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options. Curr Neuropharmacol, 2018, 16: 1396–1415.
10.2174/1570159X16666180302115544
CAS PubMed Web of Science® Google Scholar
Shen H, Gu X, Wei ZZ. Combinatorial intranasal delivery of bone marrow mesenchymal stem cells and insulin-like growth factor-1 improves neurovascularization and functional outcomes following focal cerebral ischemia in mice. Exp Neurol, 2020, 337: 113542.
10.1016/j.expneurol.2020.113542
PubMed Web of Science® Google Scholar
Shichinohe H, Kawabori M, Iijima H. Research on advanced intervention using novel bone marrOW stem cell (RAINBOW): a study protocol for a phase I, open-label, uncontrolled, dose-response trial of autologous bone marrow stromal cell transplantation in patients with acute ischemic stroke. BMC Neurol, 2017, 17: 179.
10.1186/s12883-017-0955-6
PubMed Web of Science® Google Scholar
Sims NR, Muyderman H. Mitochondria, oxidative metabolism and cell death in stroke. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2010, 1802 (1): 80–91.
10.1016/j.bbadis.2009.09.003
CAS PubMed Web of Science® Google Scholar
Steinke J, Gaser C, Langbein K. Hippocampal metabolism and prefrontal brain structure: A combined 1H-MR spectroscopy, neuropsychological, and voxel-based morphometry (VBM) study. Brain Res, 2017, 1677: 14–19.
10.1016/j.brainres.2017.09.004
CAS PubMed Web of Science® Google Scholar
Valdés-Hernández PA, Sumiyoshi A, Nonaka H. An in vivo MRI Template Set for Morphometry, Tissue Segmentation, and fMRI Localization in Rats. Front Neuroinform, 2011, 5: 26.
PubMed Google Scholar
Visser MM, Yassi N, Campbell BCV. White Matter Degeneration after Ischemic Stroke: A Longitudinal Diffusion Tensor Imaging Study. J Neuroimaging, 2019, 29: 111–118.
10.1111/jon.12556
PubMed Web of Science® Google Scholar
Vu Q, Xie K, Eckert M. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke. Neurology, 2014, 82 (14): 1277–1286.
10.1212/WNL.0000000000000278
PubMed Web of Science® Google Scholar
Wang D, Bo Z, Lan T. Application of Magnetic Resonance Imaging Molecular Probe in the Study of Pluripotent Stem Cell-Derived Neural Stem Cells for the Treatment of Posttraumatic Paralysis of Cerebral Infarction. World Neurosurg, 2020, 138: 637–644.
10.1016/j.wneu.2020.01.146
PubMed Web of Science® Google Scholar
Wang X, Cheng B, Wang S. Distinct grey matter volume alterations in adult patients with panic disorder and social anxiety disorder: A systematic review and voxel-based morphometry meta-analysis. J Affect Disord, 2021, 281: 805–823.
10.1016/j.jad.2020.11.057
PubMed Web of Science® Google Scholar
Wesley UV, Bhute VJ, Hatcher JF. Local and systemic metabolic alterations in brain, plasma, and liver of rats in response to aging and ischemic stroke, as detected by nuclear magnetic resonance (NMR) spectroscopy. Neurochem Int, 2019, 127: 113–124.
10.1016/j.neuint.2019.01.025
CAS PubMed Web of Science® Google Scholar
Woodbury D, Reynolds K, Black Ira B. Adult bone marrow stromal stem cells express germline, ectodermal, endodermal, and mesodermal genes prior to neurogenesis. J Neurosci Res, 2002, 69: 908–917.
10.1002/jnr.10365
CAS PubMed Web of Science® Google Scholar
Xiao QX, Wen S, Zhang X. MiR-410-3p overexpression ameliorates neurological deficits in rats with hypoxic-ischemic brain damage. Brain Res Bull, 2020, 162: 218–230.
10.1016/j.brainresbull.2020.06.011
CAS PubMed Web of Science® Google Scholar
Xie P, Deng M, Sun QG. Therapeutic effect of transplantation of human bone marrow derived mesenchymal stem cells on neuron regeneration in a rat model of middle cerebral artery occlusion. Mol Med Rep, 2019, 20: 3065–3074.
CAS PubMed Web of Science® Google Scholar
Yan CG, Wang XD, Zuo XN. DPABI: Data Processing & Analysis for (Resting - State) Brain Imaging. Neuroinformatics, 2016, 14: 339–351.
10.1007/s12021-016-9299-4
PubMed Web of Science® Google Scholar
Yang H, Tian S, Xie L. Intranasal administration of Cytoglobin modifies human umbilical cord derived mesenchymal stem cells and improves hypoxic ischemia brain damage in neonatal rats by modulating p38 MAPK signaling mediated apoptosis. Mol Med Rep, 2020, 22: 3493–3503.
CAS PubMed Web of Science® Google Scholar
Yin D, Yan X, Fan M. Secondary degeneration detected by combining voxel-based morphometry and tract-based spatial statistics in subcortical strokes with different outcomes in hand function. AJNR Am J Neuroradiol, 2013; 34 (7): 1341–1347.
10.3174/ajnr.A3410
CAS PubMed Web of Science® Google Scholar
Zachar L, Bačenková D, Rosocha J. Activation, homing, and role of the mesenchymal stem cells in the inflammatory environment. J Inflamm Res, 2016, 9: 231–240.
10.2147/JIR.S121994
CAS PubMed Web of Science® Google Scholar
Zakaria DM, Zahran NM, Arafa SAA. Histological and Physiological Studies of the Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Bleomycin Induced Lung Fibrosis in Adult Albino Rats. Tissue Eng Regen Med, 2021, 18: 127–141.
10.1007/s13770-020-00294-0
CAS PubMed Web of Science® Google Scholar
Zhao XM, He XY, Liu Jia. Neural Stem Cell Transplantation Improves Locomotor Function in Spinal Cord Transection Rats Associated with Nerve Regeneration and IGF-1 R Expression. Cell Transplant, 2019, 28: 1197–1211.
10.1177/0963689719860128
PubMed Web of Science® Google Scholar
Zuo LJ, Li ZX, Zhu RY. The Relationship between Cerebral White Matter Integrity and Cognitive Function in Mild Stroke with Basal Ganglia Region Infarcts. Sci Rep, 2018, 8: 8422.
10.1038/s41598-018-26316-5
PubMed Web of Science® Google Scholar

Citing Literature

Volume7, Issue1

March 2021

Pages 12-20

MRI tracking/detection of bone marrow mesenchymal stromal cells transplantation for treatment of ischemic cerebral infarction