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In vitro and In vivo Studies on Mesenchymal Stem Cells for Ischemic Stroke Therapy: A Scoping Review of The Therapeutic Effect
Authors Rinendyaputri R , Nainggolan IM, Idrus HH, Noverina R, Ayuningtyas W, Huda F , Faried A
Received 24 January 2025
Accepted for publication 8 May 2025
Published 31 May 2025 Volume 2025:18 Pages 45—61
DOI https://doi.org/10.2147/SCCAA.S519338
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Bernard Binetruy
Ratih Rinendyaputri,1,2 Ita Margaretha Nainggolan,3 Hasta Handayani Idrus,1 Rachmawati Noverina,4 Wireni Ayuningtyas,4 Fathul Huda,5 Ahmad Faried6
1Center for Biomedical Research, Research Organization for Health, National Research and Innovation Agency, Bogor, West Java, Indonesia; 2Doctoral Program, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, 40161, Indonesia; 3Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency, Bogor, West Java, Indonesia; 4Bio Farma Stem Cell Research and Development, Bandung, West Java, 40161, Indonesia; 5Department of Neurology, Faculty of Medicine, Dr Hasan Sadikin Central General Hospital/Universitas Padjadjaran, Bandung, West Java, 40161, Indonesia; 6Neurosurgery Department, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, 40161, Indonesia
Correspondence: Ahmad Faried, Email [email protected]
Introduction: Mesenchymal stem cells (MSCs) have a paracrine impact and may regenerate a variety of tissues. This represents a new prospect in cell-based stroke treatment. Several in vitro and in vivo investigations have demonstrated the neuroprotective and neurogenesis properties of MSCs and their secretome.
Purpose: This review provides a comprehensive analysis of the therapeutic effects of MSCs and their secretome on stroke models in vitro and in vivo.
Methods: A coverage evaluation is undertaken in accordance with PRISMA-ScR principles. The selection procedure includes the identification of items. Scopus site, PubMed and ScienceDirect, are used for in vitro and in vitro research, including electronic searches. The search terms include “ischemic stroke” or “MCAO”, “MSC”, “secretome”, and “neurogenesis” or “angiogenesis”. The searches are limited to English-language articles with full text availability.
Results: After selecting 390 papers from two search engines, 94 publications satisfied the review criteria for using MSCs and secretomes for ischemic stroke treatment. We comprehensively review both in vitro and in vivo studies, analyzing aspects such as the source and treatment of MSCs and secretomes, as well as administration, dosage, and mechanisms of therapeutic effects in stroke models.
Conclusion: MSC and secretome therapy for stroke have shown promising results in both in vitro and in vivo models. Exploration of alternative MSC sources, refining of isolation techniques, transfection of various proteins, and combination with herbal medicine are all efforts to improve the preclinical model. This work can be used as a reference for preclinical researchers to help with research design and translational research in clinical trials.
Keywords: middle cerebral artery occlusion (MCAO), conditioned medium/CM, secretome, mesenchymal stem cells (MSC), stroke ischemic
Introduction
Mesenchymal stem cells (MSCs) can be obtained from various sources such as adipose tissue, umbilical cord, bone marrow, iPSC-MSC and peripheral blood.1–7 Bioactives secreted by MSCs have a paracrine effect because they contain various proteins that play a role in the neurogenesis process such as brain derived neurotrophic factors/BDNF, neurotrophic growth factor/NGF, and stromal derived factor-1/SDF-1.8–10 The angiogenesis process in the penumbral area also helps the neurogenesis process so that vascular endothelial growth factor/VEGF is urgently needed, which can be supplied by MSC secretions.11 The effects of neuroprotection through inflammatory pathways, apoptosis, and autophagy are also important effects to continue researching.12,13 The role of EVs, exosomes and microRNAs contained in MSC secretome/conditioned medium (CM) is a factor in the effectiveness of therapy considering that it is a regulator of various genes.14,15
Mesenchymal stem cells and their secretomes provide paracrine effects, especially for ischemic stroke.16 MSCs play a role in the regeneration of the blood-brain barrier (BBB) linkage in brain tissue, which can suppress inflammation so that the neuroregeneration and neuroprotection processes can take place properly.17,18 The bioactive role of MSC secretomes and methods to increase their potential in angiogenesis, neurogenesis, and neuroprotection in ischemic stroke therapy continue to be carried out in vivo and in vitro.19–21 This is because, while experimental investigations have been successful, systematic review studies looking at clinical trials of MSC treatment in stroke patients have not yielded meaningful benefits. Several systematic reviews of clinical trials found that MSC therapy did not result in substantial improvements in ischemic stroke patients. The heterogeneity of data, including MSC sources, doses, replications, and delivery, as well as patient severity, all contributed to variances in therapeutic success.22–24
Currently, there is a gap in translational research from preclinical trials to clinical trials that must be bridged to address clinical trial issues. This study will examine the literature on the effects of MSC and secretome therapy in vitro and in vivo, numerous efforts to optimize MSC and its secretome to have an impact on the therapeutic effect, as well as its potential pharmacological use in ischemic stroke models. This study is planned to serve as a reference for researchers conducting preclinical trials to support the success of subsequent clinical trials.
Materials and Methods
We conducted this scoping review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) statement and based on the Joanna Briggs Institute/JBBI guidelines.25,26 We formulated the research objectives and questions by referring to the Problem, Concept and Contest (PPC), as problem: model stroke ischemic. Concept: MSC and MSC secretomes for stroke ischemic therapy, and contest: in vitro and in vivo study. The research question was “What types of MSCs and their secretomes have been used for ischemic stroke therapy in preclinical trials?”. The aim of this review was to provide a comprehensive analysis of the therapeutic effects of MSCs and their secretomes on stroke models in vitro and in vivo.
Search Strategy
The article searches strategy takes a thorough approach to finding relevant research articles. Advanced search techniques, including “AND” and “OR” operators, are employed to filter results. The search by PICO is ((((((Ischemic Stroke[MeSH Terms]) OR (stroke[Title/Abstract])) OR (brain ischemic[Title/Abstract])) OR (Middle Cerebral Artery Occlusion[Title/Abstract])) OR (MCAO[Title/Abstract])) AND ((((((((mesenchymal stem cells[MeSH Terms]) OR (mesenchymal stem cell[Title/Abstract])) OR (MSC[Title/Abstract])) OR (secretome[Title/Abstract])) OR (Conditioned medium[Title/Abstract])) OR (Exosomes[Title/Abstract])) OR (Extracellular vesicles[Title/Abstract])) OR (EVs[Title/Abstract]))) AND ((((neuroprotection[MeSH Terms]) OR (angiogenesis[Title/Abstract])) OR (autophagy[Title/Abstract])) OR (neurogenesis[Title/Abstract])). The search focuses on electronic resources like ScienceDirect and PubMed.
Study Selection
Inclusion criteria for this scoping review include in vitro and in vivo research articles, with ischemic stroke models using MSC and/or with MSC secretome in English, last 10 years, and full English text availability. Based on these inclusion criteria, clinical trial research studies with only abstracts are available.
Data Extraction
Two independent reviewers carefully choose articles and extract data based on inclusion criteria to ensure the scoping review is complete and accurate. The table summarizes the evaluation results for further analysis. Journal articles are obtained using both electronic and manual searches. The abstract is initially picked based on its relevance to the study topic. The second stage comprises additional selection based on the article’s substance and adherence to inclusion and exclusion criteria. Finally, data from qualifying articles is extracted and processed for analysis.
Results
Study Inclusion
The PRISMA diagram (Figure 1) illustrates the systematic selection process of articles for a scoping review. Originally, a total of 390 articles were obtained from two search engines: PubMed and ScienceDirect. After undergoing screening and selection based on inclusion and exclusion criteria, as many as 134 articles considered suitable for review. Furthermore, 134 selected articles were thoroughly read and analyzed for extraction relevant data. Characteristics of inclusion were compiled and presented in Tables 1–4.
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Table 1 Characteristic of Included Studies (Administration via Intra Artery) |
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Table 2 Characteristic of Included Studies (Administration via Intravenous) |
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Table 3 Characteristic of Included Studies (Administration via Intranasal) |
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Table 4 Characteristic of Included Studies (Administration via Intracerebral) |
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Figure 1 The study selection flow chart. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review (PRISMA-ScR) flow chart depicts the amount of data identified, included, and eliminated during the various rounds of a systematic review. |
Characteristic of Included Studies
These articles include in vivo test articles, in vitro test studies, and both. In the in vivo test describe allogenic approaches that involve bone marrow-derived MSCs. Meanwhile, the remaining articles used human MSCs (xenografts), primarily using mice as stroke model animals. Most researchers used allogeneic MSCs from adipose and bone marrow, whereas xenografts used human MSCs from umbilical cord and fat tissue. In stroke models, most transplants deliver MSCs, but some also deliver CM (six article) and exosomes/EVs (26 article). The use of MSCs for stroke therapy has been modified in many ways, including hypoxia, gene transfection, and the addition of herbal medicine.80
The in vivo test employs the middle cerebral artery occlusion (MCAO) stroke model, whereas the in vitro test uses the oxygen glucose deprivation (OGD) approach. For in vitro studies, the researchers used cell lines as well as primary cultures from mouse brain tissue. In the in vivo test, various concentrations were delivered intravenously, intra-arterially, intranasally, and intracerebral. Similarly, in vitro testing of therapeutic models using co-culture or growing secretome or EVs at specific doses. The researchers discovered that using MSCs as well as EVs or secretions resulted in angiogenesis, neurogenesis, and neuroprotection. This neuroprotection is demonstrated by the influence on anti-inflammatory, anti-apoptosis, and haemostasis processes via autophagy. Only modest neuroprotective effects, particularly in autophagy, were seen in this investigation (9 studies).
Neuroprotection, Angiogenesis, and Neurogenesis Effect of Therapy
This study used a scoping review to determine the administration method, dose, and therapeutic effects of MSC-CM for stroke therapy. This investigation revealed that there are still a few research reports on intra-arterial delivery, with three articles reporting from various sources of MSC and doses. The dose was 5x105-1x106, and the sources were PBMC, adipose tissue derived mesenchymal stem cells/AD-MSC, and bone marrow derived mesenchymal stem cells/BMMSC from humans and rats. For in vivo testing, use the MCAO rodent model. According to the current review, MSC have been shown in vitro to reduce inflammation, and in vivo, their therapeutic effect can decrease apoptosis, increase angiogenesis, and neurogenesis (Table 1).
Table 2 shows that intravenous injection was more frequently reported in the MCAO model, both transient and permanent. The stroke model was tested in vitro using the oxygen glucose deprivation/OGD approach. Lipopolysaccharide/LPS induction was employed to produce an inflammatory response. Therapies using MSC, MSC-CM and extracellular vesicles/EVs including exosomes at various doses have been reported with intravenous administration.
Intranasal treatment has also been used in stroke models with MCAO in rats and mice. However, analogous research demonstrating therapeutic efficacy in stroke models is still rare. The various cell sources make it challenging to choose the optimum cell type for intranasal MSC therapy (Table 3). Stroke therapy through intracranial has been reported. The use of in vitro models with cell lines such as SH-SY5Y and BV2 can be used to see the effects of neuroinflammation, neuroprotection through apoptotic and autophagy pathways (Table 4).
Mesenchymal stem cell/ MSC treatment and secretome have a neuroprotective impact through paracrine actions, which helps to decrease inflammation and apoptosis while promoting autophagy.29,40,82 In addition to the up and down regulation of gene expression and protein markers, TTC is used to measure the infarct area. Several studies have found that therapy resulted in a reduced infarct area than sham control, indicating a neuroprotective effect.40,45
Neurogenesis and angiogenesis are characterized by several markers of neuronal differentiation and blood vessel development.83–85 In in vitro, it may be demonstrated with HUVEC cells and neural progenitors, as well as other and primary cells.36,50 In in vivo mouse experiments, post-therapy analysis was performed by examining the increase in neuronal differentiation and blood vessel creation using the Y maze, Morris water, and rotarod.40,75,76
Discussion
This scoping review examined the therapeutic effects of employing MSCs, secretome, or EVs in stroke models. The effects on angiogenesis, neurogenesis, and neuroprotection were verified using a variety of indicators. Our scoping review contributes significant discoveries to the present literature. We discovered a small number of papers on neuroprotective benefits via the autophagy pathway.12,29,42,45,67,70,73,74,86,87 Anti-inflammatory is one of the neuroprotective benefits described by various researchers because cytokines, as immunomodulators, help to suppress inflammation.33,39,52,53,79,88,89 Anti apoptosis is more typically associated with neurogenesis effect although it is also related to the anti-inflammation and autophagy process.38,40,44,74,90–92
Interestingly, we discovered a variety of articles reporting diverse methods for increasing the potency of MSCs, including 3D synthesis, hypoxic settings, and gene transfection.31,32,93 This is done to boost the therapeutic efficacy of BDNF, CircAkap7, AxCALacZ-F/RGD, and CCL2 transfection therapy, which is intended to improve migration, neurogenesis, autophagy, and oxidative stress.39,48,77 However, the neuroprotective impact is primarily explained by anti-inflammatory and apoptotic pathways, with little studies on the effects of autophagy and antioxidants. Post-reperfusion in ischemic stroke can cause neuronal cell death owing to oxidative stress, hence further research is needed on the effects of boosting endogenous antioxidants to enhance the neuroprotective impact.42,47,82,94
To stimulate the release of bioactive MSCs, the researchers treated them with hypoxia, stroke patients serum and herbal medicine, which increased the therapeutic efficacy via migration and neurogenesis processes.30,50,60,62,66,95,96 Ferulic acid in the herbal content is supposed to help create a microenvironment that promotes cell survival, migration, and differentiation, as well as tissue connections, making it effective for mending brain tissue and recovering from an ischemic stroke.49,51,61,64,97–99 Herbal or antioxidant administration can be combined, although some practitioners use herbal extracts to boost the secretome’s bioactivity, such as promoting progenitor neuron migration to the infarct location.66,71,72,100–102 Bioactive neurotrophic factors derived by MSCs, like as BDNF, have also been shown to trigger neurogenesis from endogenous progenitor neurons.63,77,103,104 However, Zhang et al (2023) found that MSC therapy induces angiogenesis and oligodendrocytes, which are involved in the axon myelination process, allowing electrical signals to surface swiftly.34
Mesenchymal stem cell/MSC also have a function in post-ischemic angiogenesis in the infarction location, allowing neuroprotection to occur.27,35,36 Inducing angiogenesis with herb administration and exercise to improve post-ischemic stroke healing, which is influenced by enhanced miRNA production or functioning synergistically in endothelial progenitor migration.41,54,68,78,105 Bioactive MSCs also boost the activity of VEGF, MMP-2, and MMP-9, which all contribute to increased blood vessel density.57,58 Although animal research with stroke comorbidities such as hypertension, atau aged revealed that MSC therapy did not produce positive benefits.43,46
Extracellular vesicles produced by MSCs represent a novel biomarker and effective target therapy for ischemic stroke. These vesicles are microscopic particles attached to a lipid bilayer that allow intercellular communication and transport a variety of bioactive substances such as proteins, lipids, and RNA, to increase delivery to target cells, modification is given by adding cholesterol as drug delivery.59 EVs promote neurogenesis by upregulating microRNAs leading to brain tissue regeneration.15,56 Reducing inflammation by modifying the immune response, EVs may help reduce inflammation in the brain following a stroke.69,106 EVs can also pass the blood-brain barrier, which allows them to deliver therapeutic drugs directly to damaged brain tissue, enhancing their effectiveness.81,107 The inflammatory process also initiates the processes of neurogenesis and angiogenesis, thus helping restoration in the penumbra area.15,37,55,56,108,109
This study has significant limitations, including the lack of studies comparing MSC therapy to CM or EVs, as well as control and MCAO treatment. According to prior systematic evaluations, treatment groups using MSC, CM, or EVs had considerably better functional and biomechanical outcomes than control groups. In vitro studies revealed that the treatment group exhibited therapeutic effects in angiogenesis, neurogenesis, and neuroprotection. In vitro research has the benefit of being more controlled than in vivo experiments; yet, the autophagy effect continues to occur in vivo, resulting in discrepancies in outcomes. The fact that they all report varying concentrations and non-uniform delivery routes is concerning. Administration via the cerebral route has the benefit of reaching directly to the target organ, is performed by a specialist, and requires fewer MSCs and secretome.110 The intra-arterial route is also more intrusive than the intravenously approach, although the intra-nasal route may be a possibility if the patient is also comfortable.4,8,28,111–113
This study used the idea of xenografts rather than allogeneic or autologous, hence the variances in outcomes are also distinct.3,65,114 In addition, the use of animal models such as rats and mice, which have very different blood circulation from humans, creates obstacles in becoming a reference for translational research. The limitations of animal models are also a barrier to translational research. Non-human primates can be used as animal models. Administration via intranasal, which is non-invasive but close to the target organ, is also an option for more comfortable delivery.
Finally, more research is needed to investigate the use of animal models such as non-human primates, concentration and dosage of MSC, secretome, and EVs to accomplish effective therapy. Information on the role of MSC-secreted miRNAs as therapeutic targets. Obtaining thorough knowledge regarding these aspects can improve therapy effectiveness, hence contributing to advancement in stroke therapy.
Limitations
This study did not conduct a critical appraisal of the included studies and differences in the way data were reported in the articles. A systematic and comprehensive search was conducted, but only articles written in English were included, which limits the applicability of the review results to the English-speaking world. This study also provides insight into the obstacles and challenges of stem cell therapy research for stroke, especially to be a reference for translational research towards clinical trials. Limitations between articles are variability in sample size, study design, and outcome measures, which may affect the generalizability and comparability of the results. To overcome this, more rigorous future studies with standardized outcome measures are needed so that clinical practice findings can be a strong basis for the success of clinical trials.
Conclusion
In conclusion, MSC and secretome therapy for stroke has significant potential in both in vitro and in vivo models. Current research shows the potential of MSC and its secretome to increase neurogenesis and neuroprotection but the challenge is the gap in understanding to conduct translational research in optimizing stroke treatment. Exploration of various sources of MSC, refining isolation techniques, transfection treatments of various proteins, combinations with herbal medicines are efforts to improve preclinical models. Understanding of signaling pathways, mechanistics, safety, and effectiveness in the preclinical stage has been obtained so that further research is needed for clinical trials.
Acknowledgments
We extend our gratitude to the National Research and Innovation Agency (BRIN) and the Graduate School of Biomedical Sciences, Doctoral Program, Faculty of Medicine, Padjadjaran University, Indonesia, for their support of the Degree by Research program and for covering the APC payments.
Disclosure
The authors state that there is no conflict of interest in this study.
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