Qian Wang
Weifeng Jiang
Yan Feng1
Lin Li
Lisheng Chu- 1Department of Physiology, Zhejiang Chinese Medical University, Hangzhou, China
- 2Department of Gerontology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
Background: The biological process of neurogenesis involves the production of new and completely functional neurons in two specific regions of the brain: the ventricular-subventricular zone (V-SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus by neural stem cells (NSCs). Interfering with this mechanism harms the brain and may result in neurological disorders. Cell-based therapies are becoming recognized as optimal possibilities for facilitating neurogenesis. To comprehend the many processes and mechanisms of neurogenesis and the role of mesenchymal stem cells (MSCs) as active contributors to pathologic events influencing neurogenesis. We utilized the Web of Science (core collection) as the data source.
Methods: The search was performed in the Web of Science core collection database until April 30, 2024, with the terms “Mesenchymal stem cells” as the title and “neurogenesis” as the topic.
Results: A total of 407 papers about mesenchymal stem cells in neurogenesis published from 2004 to 2024 were retrieved. Further, we performed a bibliometric analysis of these publications, such as generating cooperation maps, co-citation analysis of journals and references, and cluster analysis of keywords. Next, we discussed the mechanism by which MSCs promote neurogenesis during the onset of Alzheimer’s disease (AD) and stroke diseases.
Conclusion: Overall, three aspects primarily reflect the treatment of stroke with MSCs: neural circuit reconstruction, mitochondrial transfer, and extracellular vesicle transfer. The treatment of AD with MSCs is mainly reflected in the five aspects of inhibiting neuroinflammation, microglia changes, amyloid-β removal, functional recovery of autophagy, and blood–brain barrier (BBB) function recovery. Finally, we also made prospects for future research of MSCs.
1 Introduction
Neurogenesis is the biological process through which neural stem cells (NSCs) produce new and fully functional neurons in two specific areas of the brain: the ventricular-subventricular zone (V-SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus (1). This mechanism mediates neuronal plasticity, the maintenance of the central nervous system (CNS), and cognitive function (2). Disrupting this process damages the brain and can lead to neurological diseases (3) like Huntington’s disease (HD) and Parkinson’s disease (PD), as well as psychiatric diseases (4) like depression and schizophrenia. Cell-based remedies emerge as ideal candidates for promoting neurogenesis (5). MSCs are the most used stem cells in biological medical research, and they can also migrate to the sites of injury and inflammation (6). Notwithstanding the intriguing and significant study about the regulation of neurogenesis by MSCs, there are yet no systematic reviews on this subject. To comprehend the many processes and mechanisms of neurogenesis and the role of MSCs as active contributors to pathologic events influencing neurogenesis. We analyzed the literature related to neurogenesis in MSCs using scientometrics.
Scientometrics is a statistical and mathematical approach for forecasting future trends, calculating data correlations, and conducting retrospective analyses (7). Emphasizing quantification, it is an all-encompassing knowledge system that amalgamates statistics, mathematics, and bibliographies. Bibliometrics serves as a supplementary research method extensively utilized across all disciplines (7). These scientometric analyses encapsulate prevailing research focal points and suggest prospective avenues for a certain subject. Consequently, scientometric approaches were employed to investigate and identify the focal points of mesenchymal stem cells in neurogenesis in this work.
2 Scientometric study
2.1 Data and methods
2.1.1 Search and screening of literature
The search was conducted in the Web of Science core collection database until April 30, 2024, using the phrases “Mesenchymal stem cells” as the title and “neurogenesis” as the topic. We limited the sorts of literature to articles and reviews. No limits were imposed on language. The retrieved records were saved as plain text files and named download_txt. The flow chart of the paper is shown in Figure 1.
Figure 1. The workflow of study of MSCs on neurogenesis.
2.1.2 Data download
The raw data were obtained from the Web of Science. The data had complete records and referenced citations. The file was formatted as plain text.
2.1.3 Scientometric analysis and visualization
The raw data were analyzed using Bibliometrix (Version 3.13) in the R project (Version 4.1.0), as previously explained. Bibliometrix was used to extract the main information from the literature, including the publication number per year, nation or region, journal, keyword, and title. The data was visualized using R software and Origin software, respectively.
2.2 General analysis
A total of 407 publications on the therapeutic effects of MSCs on neurogenesis were obtained from the Web of Science core collection database prior to April 30, 2024. The average number of citations per document was 35.14. The first article on the therapeutic effect of MSCs on neurogenesis, which focuses on the bone marrow mesenchymal stem cells and Rett syndrome of apoptosis was published in 2008 (Figure 2a). Most articles were published in the year 2015 and 2020, while the most cited year was 2015. So far, research in the field of the therapeutic effect of MSCs on neurogenesis is increasingly ongoing.
Figure 2. Scientometric study of MSCs on neurogenesis. (a) Number of publications by year. (b) Number of publications by country or region. (c) The cooperation relationships of country or region. (d) Number of publications by the journal.
2.3 Country/region analysis
A total of 46 countries/regions contributed to the publications included in this study. Among them, China published the most articles, followed by USA, South Korea, Iran, Taiwan, India, Japan, Israel, and Germany (Figure 2b). The partnership among countries demonstrated close cooperation between various countries (Figure 2c).
2.4 Journal analysis
All publications were published in 200 types of journals. The top 10 journals are shown in Figure 2d. The most relevant journal was “International journal of molecular sciences.” Stem cell research & therapy has the second highest volume of publications, followed by Cell transplantation, Neural regeneration research, Stem cell reviews and reports, Brain research, and Scientific reports.
2.5 Literature and cited reference
The top 10 most-cited papers about the therapeutic effect of MSCs on neurogenesis are shown in Table 1. The article with the most citations reported a long-term follow-up study of intravenous autologous MSCs transplantation in patients with ischemic stroke (8). The second most-cited article studied the effect of MSCs on angiogenesis and neurogenesis after cerebral ischemia in rats (9), as well as Parkinson’s disease (10) and neuroprotection from traumatic brain injury (11). The top 10 cited references on the therapeutic roles of MSCs in neurogenesis are shown in Table 2. These papers reported significant findings for researchers to discover the most influential studies in the field of therapeutic effect of MSCs on neurogenesis, further guiding in-depth research.
Table 1. The top 10 most-cited papers about the therapeutic effect of MSCs on neurogenesis.
Table 2. The top 10 cited references about the therapeutic effect of MSCs on neurogenesis.
2.6 Keyword analysis
According to the scientometric theory, keywords are indicative of current study trends and focal points within a specific research topic (12). In this review, keyword visualization was presented as keywords with citation bursts (Figure 3a) and a co-occurrence network (Figure 3b). Keywords exhibiting citation bursts imply that certain keywords have a higher number of citations within a specific timeframe. This phenomenon can be used to evaluate the level of interest in a particular study subject during that period and to identify developing ideas (13). Through the observation of keywords such as extracellular vesicles (strength, 6.05; time span, 2018–2024), delivery (strength, 3.8; time span, 2019–2024), inflammation (strength, 3.37; time span, 2013–2024), dopaminergic neurons (strength, 3.28; time span, 2011–2017) and progenitor cells (strength, 5.11; time span, 2008–2012) (Figure 3a), it is inferred that extracellular vesicles was a hotspot in the first ten years. In addition, the study of progenitor neurons by MSCs is also a hot topic. These MSCs’ mechanisms for neurogenesis focused on inflammation and oxidative stress. The co-occurrence network involved categorizing keywords into distinct clusters, each assigned a different color, based on their connection. Remarkably, “cognition” was a crossed keyword in these clusters, suggesting that MSCs may affect cognition. Stroke, traumatic brain injury, Parkinson’s disease and Alzheimer’s disease were among the CNS disorders whose keywords appeared in the co-occurrence network, as Figure 3b illustrates. We speculated that by regulating neurogenesis, MSCs would be beneficial to CNS disorders. Thus, we searched for articles on MSCs treating CNS diseases by regulating neurogenesis. Consequently, we analyzed the diseases involved in these 407 articles and finally found the most articles related to stroke and AD.
Figure 3. Keyword of analysis. (a) Top 10 keywords with strongest citation bursts. (b) Keyword co-occurrence diagram from 2008 to 2024.
3 The mechanism of MSCs in neurogenesis
MSCs are very attractive candidates for regenerative medicine owing to their excellent accessibility, in vivo proliferative capacity, and unique immunogenic properties. Moreover, these multipotent cells demonstrate remarkable environmental adaptability and secretory proficiency. Significant attention has been directed towards the ability of MSCs to move and assimilate into diverse tissues. Our bibliometric study delineated the processes through which MSCs contribute to the treatment of AD and stroke. The mechanism by which MSCs operate in the treatment of stroke and Alzheimer’s disease is illustrated in Figure 4.
Figure 4. Scheme illustrates the mechanism of MSCs in neurogenesis.
3.1 MSCs and stroke
Stroke is a critical cerebrovascular disorder resulting from a disruption in cerebral blood flow, resulting in neurological and cognitive deficits (14). Stroke enhances the proliferation of NSCs and facilitates the migration of newly formed neuroblasts from the SVZ to the area surrounding the ischemic boundary. Moreover, stroke promotes the transformation of these neuroblasts into fully developed neurons (15). The findings suggest that fostering neurogenesis in the brain may serve as a potential target for rehabilitative therapy in individuals with ischemic brain injury (15). Recent studies have demonstrated that the administration of MSCs can diminish the extent of cerebral infarction following ischemia and facilitate the restoration of brain function (16). However, the number and replacement capacity of new neurons produced by the body itself after stroke are limited.
3.1.1 Neural circuit reconstruction
Under suitable conditions, MSCs could differentiate into glial and neuronal cells (17). However, MSCs injected into the cortex surrounding the infarcted region can produce markers specific to neurons, the differentiated neurons are still young, spherical in shape, and have few fiber processes (18). More importantly, they lack the voltage-gated ion channels needed to generate action potentials (19). Therefore, the neural replacement mechanism may not be one of the mechanisms of MSCs in the treatment of ischemic stroke (IS). Endogenous neurogenesis takes place in the hippocampus’s SVZ and SGZ following cerebral ischemia. The recently discovered neural progenitor cells can go towards the damaged area caused by an infarction and undergo further specialization into neurons (20). Unfortunately, most of these neural progenitor cells are prone to rapid death due to the presence of inflammatory mediators and insufficient nourishment following ischemia. This hampers the injured area’s capacity to regenerate its neural network (20). It is reported that MSCs can increase the number of neural progenitor cells and promote endogenous neurogenesis after IS (21, 22). Song et al. observed that mice treated with MSCs had significantly increased neural network activity in the peri-infarct cortex, as determined by electrophysiological recording of evoked field potentials (22). Further investigation has shown that MSCs could improve the movement and survival of neuroblasts towards the area around an ischemia event, as well as increase the number of neurons in that same area (22). The upregulation of SDF-1 and polysialylation enzyme by MSCs facilitates the enhanced migration of neuroblasts towards the site of injury (23).
MSC treatment can weaken the physical and chemical barrier effect of glial scars on axonal regeneration after infarction. MSCs have the potential to increase the interhemispheric and intracortical axonal connections in the motor cortex around the infarction (24). Further research indicated that MSCs could support the rebuilding of neuronal connections by decreasing the thickness of glial scarring and the expression of Nogo-A (24). Furthermore, MSCs transplanted into the lesion may promote axonal growth by downregulating neuron expression and upregulating tPA expression in reactive astrocytes in glial scars (25–27). Transplanted MSCs may potentially enhance axonal development following brain ischemia by releasing nutrients. In mice treated with MSC, the cortex surrounding the infarction revealed an increase in GAP-43 expression, whereas axon growth inhibitory proteins Rock II and NG2 expression was decreased (28). It has been reported that transplanted MSCs can increase the number of oligodendrocyte progenitor cells in the peri-infarct area, corpus callosum, and SVZ (29, 30). The total amount of myelin basic protein increased significantly after MSC treatment, according to the researcher’s measurement of the protein in ipsilateral hemisphere tissue lysates of middle cerebral artery occlusion (MCAO) rats. This research indicates MSCs play a role in stimulating myelin production as well as neuronal circuit rebuilding (31).
3.1.2 Mitochondrial transfer
MSCs could transfer healthy mitochondria to injured cells, potentially treating ischemic stroke. Tunnel nanotubes (TNTs) are tiny tubular structures at the nanoscale that link neighboring cells (32). As a novel method of communication between cells, they facilitate the transfer of cellular components between neighboring cells (33). Liu et al. found that TNTs between MSCs and endothelial cells developed when co-culturally MSCs with human umbilical vein endothelial cells exposed to oxygen glucose deprivation and reoxygenation (OGD/R). Furthermore, when exposed to OGD/R, the functioning mitochondria in MSCs migrate towards endothelial cells in a unidirectional manner, thereby safeguarding the endothelial cells from damage caused by hypoxia (34). The author demonstrated that the transplantation of MSCs following an ischemic stroke can offer protection to cerebral vascular endothelial cells via this intercellular connection. Their empirical research shows that when MSCs are transplanted into the area surrounding the peri-infarct region, they can transmit their functional mitochondria to the damaged microvascular endothelial cells. This procedure promotes the development of new blood vessels, reduces the size of the tissue affected by the infarction, and improves neurological function (35). Furthermore, the use of TNT inhibitors successfully prevented this behavior, suggesting that TNTs play a vital role in the transmission of this activity within mitochondria (35).
MSCs can transfer mitochondria to vascular endothelial cells, as well as to astrocytes and neurons that have been damaged by oxidative stress. This transfer of mitochondria helps to enhance the survival and proliferative growth of these cells (36, 37). The positive impact is contingent upon the direct interaction between cells, as the viability of neurons declined when MSCs and neurons were isolated by a permeable transmembrane (37). Moreover, it was observed that Miro1, a particular variant of Rho-GTPase located in mitochondria, exhibited an elevation in neurons that suffered oxidative damage. This rise in Miro1 promoted the transportation of mitochondria from MSCs to neurons (36). The researchers found that an increased quantity of neurons remained alive when they cultured Miro1 overexpressing MSCs with injured neurons. Conversely, Miro1 inhibition of MSCs resulted in the opposite outcome (37). Further in vivo experiments revealed that the transplantation of MSCs overexpressing Miro1 into rats with cerebral infarction resulted in a significant improvement in neuronal function compared to the transplantation of normal MSCs (37). In summary, after an ischemic stroke, the upregulation of Miro1 in neurons can lead to the transmission of functional mitochondria from transplanted MSCs to injured neurons. This process ultimately improves the metabolic function or viability of neurons.
3.1.3 Extracellular vesicles transfer
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are spherical cytoplasmic components secreted by mesenchymal stem cells, which contain many soluble bioactive components such as lipids, proteins, mRNAs, and microRNAs (38). MSC-EVs serve a crucial role as important messengers between MSCs and damaged cells in the therapy of ischemic stroke. Xin et al. injected rats with MSCs-EVs via the tail vein 24 h after the induction of ischemic stroke (39). In comparison to the control group, the treatment group exhibited an increase in the density of axons and synaptophysin immunoreactive regions (39). Zhao et al. showed that the administration of exosomes produced from MSCs through intravenous injection, 2 h after an ischemic stroke, resulted in a significant decrease in neurological severity score and a notable improvement in motor function after 7 days (40). In vitro, exosomes derived from MSCs were co-cultured with OGD microglia. Researchers found that this might stop the activation of M1 microglia, increase the number of M2 microglia, lower the levels of cytokines that cause inflammation (TNF-α, IL-1β, and IL-12), and raise the levels of cytokines that prevent inflammation (TGF-β and IL-10) (40).
Furthermore, MSC-EVs may play a role in mediating microRNA transfer (41). First, according to Moon et al., the intravenous administration of MSC-EVs resulted in the stimulation of blood vessel formation (angiogenesis) and the generation of new nerve cells (neurogenesis) within 24 h after inducing MCAO. This effect was found to be positively associated with the dosage of MSC-EVs (41). The levels of miR-184 and miR-210 in MSC-EVs were higher than those in fibro EVs (41). Transfecting neural stem cells and human umbilical vein endothelial cells with miR-184 and miR-210 may enhance their proliferation. This means that miR-184 and miR-210 may be used by MSC-EVs to help vascular endothelial cells and neural stem cells multiply after ischemic stroke (41). Secondly, MSCs-derived exosome miR-455-3p targeted PDCD7 to alleviate hippocampal neuronal injury in MCAO/R-treated mice and injury of OGD/R-treated Neuro-2a cells (42). Furthermore, the experimental results of Geng et al. showed that MSC-EVs overexpressing miR-126 significantly increased the number of doublecortin positive and von Willebrand factor positive cells compared with normal exosomes (43), which suggests that miR-126 may be involved in EV-mediated angiogenesis and neurogenesis. Finally, MSC-EVs may play an indirect role in nerve repair after ischemic stroke. In vitro experiments by Xin et al. showed that MSC-EVs overexpressing miR-133b could increase the secretion of exosomes by astrocytes, while the latter could significantly increase the number and length of axons (44).
3.2 MSCs and Alzheimer’s disease
AD is characterized by increased deposition of β-amyloid peptides and aggregation of hyperphosphorylated tau in NFT (45). However, clinical symptoms vary with the region of brain injury. Typical clinical symptoms include progressive decline of episodic memory and executive functions (46). Recently, MSCs have garnered significant interest as possible cell-based therapeutic tools because of their capacity to migrate and facilitate damage repair. MSCs promote the restoration of neurological function and the formation of new blood vessels by releasing neurotrophins and proteins that regulate angiogenesis (47, 48). Next, we summarize the effects of MSCs during AD treatment.
3.2.1 Inhibiting neuroinflammation
The pathological mechanism of AD is known to be active inflammatory reactions, and studies have shown that MSCs transplantation can alleviate brain inflammation by regulating the secretion of inflammatory and therapeutic factors (49). In a senescence-accelerated mouse-prone animal model, Li et al. injected BM-MSCs into bone marrow cavities and demonstrated beneficial effects. The levels of inflammatory cytokines (IL-1β, IL-6, iNOS, and HO-1) were diminished, while the concentration of TGF-β (a therapeutic cytokine) was augmented, resulting in an amelioration of the inflammatory condition, a reduction in oxidative stress, and an enhancement of cognitive function (50). When human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) were transplanted into the brains of mice with the APP/PS1 genetic mutation, the activity of microglia was reduced, resulting in a decrease in the production of inflammatory substances and an increase in the release of therapeutic substances, thereby improving the inflammatory condition (49). In a study involving the transplantation of human menstrual blood-derived stem cells (MenSCs) into the cerebellum of an APP/PS1 mouse model, it was seen that these cells stimulated the activation of microglia. This activation led to the secretion of anti-inflammatory substances through an alternative neuroprotective phenotype (51). Redondo-Castro et al. demonstrated when microglial BV2 cells were activated with bacterial lipopolysaccharide (LPS) and then treated them with BM-MSCs, BM-MSCs-treatment upregulated the expressions of anti-inflammatory and neuroprotective factors (IL- 10, VEGF, BDNF, G-CSF, NGF and IL-1Ra) (52). A rat model of AD was given MSCs through the nose. These cells lowered levels of inflammatory factors (IL-1β, IL-12, TNF-α and IFN-γ) in the hippocampal area (53).
3.2.2 Microglia changes
Reactive microglia play a role in removing proteins from the brain during chronic inflammation. However, their limited surface area hinders their ability to take up extracellular proteins and remove them. Furthermore, reactive microglia stimulate astrocytes to assume detrimental reactive states and enhance oxidative stress through the activation of neurotoxic oxygen and nitrogen compounds (54). When Aβ accumulates in the brain, microglia try to restore brain functions by absorbing proteins and secreting anti-inflammatory factors. However, chronic microglial activation increases microglia numbers and the expression of inflammatory factors and decreases protein clearance. Several authors have documented that administering stem cell injections in animal models of AD suppresses the activation of microglia and decreases the levels of inflammatory factors in the brain (55–58). When BM-MSCs were transplanted into an APP/PS1 mouse model of AD via tail vein, microglial numbers in the cortex, microglia sizes, and pro-inflammatory factor levels (TNF-α and IL-6) were reduced (55). Also, putting Wharton’s jelly-derived MSCs (WJ-MSCs) into an APP/PS1 AD mouse model through the tail vein decreased the number of reactive microglia and levels of pro-inflammatory factors (IL-1β and TNF-α) while increasing levels of IL-10, an anti-inflammatory factor (56). Furthermore, expressions of inflammatory factors were downregulated, an alternative activated phenotype of microglia was induced, and phagocytosis was improved in primary rat microglia cultured in rat MSCs conditioned media. In addition, TGF-β secreted by MSCs blocked the nuclear factor-κB pathway and restored the TGF-β pathway (57). Cho et al. reported when human placenta-MSCs (pMSCs) were intracerebroventricularly or intravenously injected into an AD rat model, AD-associated increases in microglia numbers in brain lesion rapidly returned to normal levels (58).
3.2.3 Amyloid-β removal
The Aβ plaque is a representative characteristic of AD. Stem cell transplantation has been shown to reduce Aβ plaque levels by reducing microglia numbers, activating proteasomes, and enhancing autophagy and β-amyloidase secretion (59–66). β-amyloidase exhibits Aβ -degrading activity such as insulin degrading enzyme. In detail, agouti-related peptide secreted by MSCs increased proteasome activity and decreased Aβ plaque (59). Soluble intracellular adhesion molecule-1 (sICAM-1) secreted by hUCB-MSCs induced the expression of neprilysin (a Aβ -degrading enzyme) (60). Growth differentiation factor-15 (GDF-15) secreted by hUCB-MSCs was found to reduce Aβ plaques and promote hippocampal neurogenesis (61). Furthermore, thrombospondin-1 (TSP-1) secreted by hUCB-MSCs restored neuronal synaptic density impairment caused by Aβ (62). Yang et al. transplanted hUCB-MSCs-derived neuron-like cells into bilateral hippocampus in Aβ-induced AD model and observed they activated microglia, promoted the secretions of anti-inflammatory substances, reduced Aβ accumulation, and restored memory deficits (63). In a mouse model of acute AD, bilateral hippocampus injections of BM-MSCs removed Aβ by activating microglia (64). Shin et al. observed intravenous administration of MSCs improved lysosome-autophagy and removed Aβ by activating autophagy-associated LC3-II and BECN1/Beclin 1 (65). When traumatic brain injury was induced, Aβ plaques aggregated in the mouse model. pMSCs were intravenously double injected at 4 and 24 h post-injury onto the traumatic brain injury mice model, and reduced infarct sizes, inflammatory, oxidative responses, and inhibition of Aβ plaque formation were observed (66). Aβ-induces tau hyperphosphorylation, which leads to cytotoxicity and cell death, forming NFT. Studies have shown that numerous stem cell therapies can prevent tau hyperphosphorylation-induced cytotoxicity (49, 51, 67). Zilka et al. used rat MSCs, or substances released by them to treat cells that had mutated tau proteins. This decreased cell death and increased metabolic activity, but did not change the expression of tau. The authors proposed that MSCs can lessen the cytotoxic effect of modified tau in AD (67). We observed rapid reductions of tau hyperphosphorylation, increases in anti-inflammatory factor levels, and changes in microglial phenotype when we transplanted hUCB-MSCs or MenSCs into the cerebellum of the APP/PS1 mouse model (49, 51). Trypsin-like activity (proteolytic activity) of proteasomes is significantly lower and the activity of immunoproteasomes is significantly higher in neurons from AD patients than in those of normal subjects (59). To recover ubiquitin proteasome system function in AD, Lee et al. administered agouti-related peptide secreted from MSCs or WJ-MSCs to mouse hippocampi and observed a significant increase in proteasome activity and a decrease in ubiquitin-conjugated protein accumulation (59).
3.2.4 Functional recovery of autophagy
Autophagy is typically responsible for maintaining cellular homeostasis by breaking down unneeded or aberrant cellular components. However, when autophagy malfunctions, it can contribute to the development of cancer, inflammation, and neurological disorders. Several authors have documented that the administration of stem cell injections in mouse models of AD suppresses the activation of microglia and decreases the levels of inflammatory factors in the brain (68). Interestingly, Guan et al. showed autophagy plays an important role in maintaining stemness, stem cell expansion, and differentiation (69). Another study performed by Salemi et al. noted autophagy levels were elevated in human skin and blood-derived MSCs and important for maintaining stemness (70). Furthermore, the activation of autophagy via Bcl-xL is known to promote MSCs survival and differentiation (71).
There have been relatively few investigations conducted on the correlation between autophagy and AD. Wang et al. conducted a study where they injected MSCs into the tail vein of rats with vascular dementia. They observed a large rise in the levels of autophagy proteins LC3-II and Beclin-1. This suggests a strong association between autophagy and AD (72). After the transplantation of MSCs, there was a decrease in synaptic damage, mitochondrial aggregation, and damage to the presynaptic area. Additionally, there was an increase in the expression of BDNF and N-methyl-D-aspartate receptor 1 in the hippocampus, resulting in enhanced cognitive function (72). When MSCs were injected through the tail vein in a mouse model of AD, it significantly enhanced autolysosome formation and Aβ clearance (65).
3.2.5 BBB function recovery
Under normal conditions of the BBB, medicines can be transported to the brain through carrier-mediated transport or receptor-mediated transcytosis. Nevertheless, diverse dysfunctions of the BBB are identified in the cortex and hippocampus of patients with AD. Examples are capillary leakage and infiltration of blood cells, pericyte degeneration, endothelial degeneration, and micro vessel reduction and shortening (73). The breakdown of the BBB results in the buildup of harmful substances that are toxic to the nervous system. This breakdown also triggers the activation of astrocytes and microglia, as well as an inflammatory response. Consequently, there is an accumulation of cellular debris, including pericyte and endothelial cells, which hinders the absorption of drugs and the delivery of therapeutic treatments to the brain (73).
MSCs and induced pluripotent stem cells (iPSCs) have been differentiated into endothelial cells to recover BBB functions, and this differentiation has shown to play key roles in the regeneration of blood vessels. MSCs can be differentiated into endothelial cells with differentiation media containing vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), insulin like growth factor (IGF), epidermal growth factor (EGF), ascorbic acid, and heparin (74). In an APP/PS1 mouse model, BM-MSCs transplantation increased VEGF expression levels and improved endothelial dysfunction and synaptic plasticity (75). Moreover, several studies have successfully used stem cells to induce vascular regeneration and functions of vascular endothelial cells for treating ischemic diseases, and this technique could be useful for treating AD.
4 Approaches to enhance therapeutic effects of MSCs
Current routes of administration include intravenous, intraventricular, and nasogastric, but the timing of administration remains to be explored. Although MSCs represent a promising candidate for CNS regeneration, low therapeutic efficacy limits their clinical use. Different cultural conditions may alter MSCs’ survival, homing, and key functional features. It was found by Madrigal et al. that growing cells in low-oxygen environments might have therapeutic effects on MSCs by increasing the production of HGF, TGF-b, VEGF, and TSG-6, all of which are important for CNS regeneration (76). Others demonstrated that pro-inflammatory stimuli and tri-dimensional growth stimulate trophic factors secretion of MSCs (77). It is evident that cultural conditions will considerably affect the therapeutic efficacy of MSCs. Apart from culture medium, developed therapeutic strategies may also enhance the therapeutic effects of MSCs, such as delivery route and timing. Although there is no consensus on the optimum delivery route of MSCs, intracerebroventricular transplantation may be the most efficacious. Park et al. found that intracerebroventricular MSC transplantation may be associated with endogenous enhancement, compared to intravenous and intraparenchymal routes for CNS regeneration, after reviewing previous pre-clinical and clinical studies (78). The intracerebroventricular transplanted MSCs attenuated brain injury in a time-dependent manner. Significant neuroprotection was demonstrated when administered from 2 to 7 days after induction in intraventricular hemorrhage rat models (79).
5 Safety of MSC transplantation
Although using MSCs in animal stroke models was generally safe and had a significant effect on behavioral outcomes, some studies still showed side effects such as embolism infection, and tumor formation (80, 81). Aβ accumulation and calcium in the thalamus also appear (82). Research on rat stroke models suggested that intra-arterial (IA) MSCs delivery can reduce the flow of middle cerebral artery (MCA). However, this side effect appears to be dose dependent. A dosage of 1 × 105 MSCs was shown to be the maximal tolerable dose of IA infusion, making no concessions to the blood flow of MCA. One study also showed that delivering MSCs at 24 h after stroke significantly improved neurological function and reduced the infarct size at 1 month compared with control but delivering 1 h after stroke did not confer such protective effects (83). Wang et al. found that there was no standard dose for stem cell therapy currently associated with the route of administration and disease types. For intracerebral parenchymal transplantation, an excessively large transplant dose affected the nutrition of transplanted cells and could cause micro emboli and vascular occlusion when administered intravascularly (84). Although there is no uniform dose standard, dose control is very important in preventing embolism. Intravenous infusion is thought to be associated with embolization, and embolization can be reduced by intraperitoneal or other routes of transplantation (85).
Many safety problems have emerged with the intracerebral transplantation and interventional neuroradiography in acute stroke settings, such as maintain biological stability of the therapeutic product, larger MSCs doses can potentially affect organ perfusion, and the safety of allogeneic MSCs (80). Another investigation demonstrated that amyloid-beta and calcium accumulation in the thalamus occurred following the intravenous administration of human bone marrow mesenchymal stem cells (MSCs) in a rat model of MCAO. Quantitative analysis revealed a markedly significant increase in amyloid-beta and calcium deposits in the thalamus 48 h post-MSC infusion. Furthermore, a distinct correlation was observed between diminished forelimb performance on postoperative day 42 and the accumulation of amyloid-beta and calcium in the thalamus (82). MSCs transplantation animal experiments found no obvious immune rejection. However, studies had shown that in vitro licensed WJMSCs did not improve experimental autoimmune encephalomyelitis in rats, due to increased immunogenicity resulting in rapid rejection (86).
6 Clinical trials of MSCs transplantation
Cells derived from bone marrow displayed great prospects for safety and initial efficacy (87, 88). Some clinical tests in Phase I and Phase II have already begun, using cell populations originating from MSCs (Table 3). Early results revealed that intravenous injection of MSCs did not give raise to significant adverse effects but could improve functional measurements such as the Barthel Index (BI), the National Institutes of Health Stroke Score (NIHSS) and the modified Rankin Scale (MRS) (87, 89). A long-term follow-up study of intravenous autologous MSCs transplantation in patients with ischemic stroke showed that no significant side effects were observed, and the follow-up MRS score was decreased compared with the control group (8). A meta-analysis from Lalu et al. suggested that MSC therapy appeared safe, but there was a significant association between MSCs, and transient fever based on the current clinical trials, so further larger scale controlled clinical trials with rigorous reporting of adverse events were required to further define the safety profile of MSCs (90). Contradictory data shows that MSC injection may not improve the results of the function (91). These studies used autologous MSCs which were expanded in culture before MSC transplantation (8, 87–91). Although no side effects of the products were reported, the cells were amplified in autologous serum, leading to faster cell expansion and reducing concern of heterogeneous contamination.
Table 3. MSCs transplantation in nervous system disease trials.
7 Conclusion and future perspective
This review proposes a novel method to explore the therapeutic effects of MSCs on neurogenesis through scientometric analysis geared towards identifying new research hotspots. An in-depth and comprehensive review has been performed based on the results of the scientometric study. This is the first review to summarize the therapeutic impacts of MSCs on stroke and AD, thus providing a novel unique perspective for their treatment. It is important to elucidate the mechanisms underlying the regulatory role of MSCs in NSC proliferation and differentiation associated with psychiatric and neurological disorders, including stroke and AD accompanied by deterioration of neurogenic signaling pathways and factors implicated in adult neurogenesis. Unraveling the general profile of complex signaling pathways in different neurological disorders improves the understanding of the functional significance of MSCs.
However, our article also has some limitations: 1. Incomplete database coverage: Bibliometrics relies on Web of Science, but these databases have regional, linguistic, and disciplinary biases; 2. The issue of using quantity instead of quality: Common indicators in bibliometrics (such as citation count and H-index) reflect more “influence” than “quality.” High citation may be due to controversy or negative citations rather than academic value. 3. Ignoring innovation: Lagging citations may underestimate early or disruptive research, while high short-term citations may overestimate trend-following research.
Although mesenchymal stem cells have shown enormous potential in fields such as neurogenesis, their clinical application still faces many challenges, especially the selection of the optimal dose and administration time. The following is the analysis of these two major challenges and possible solutions: The dose-effect relationship is not clear: 1. The dose does not linearly relate to the therapeutic effect of MSCs. Excessive doses may cause side effects (such as immune rejection and pulmonary embolism), while insufficient doses may be ineffective. The dosage requirements vary significantly among different disease types (such as myocardial infarction, osteoarthritis, and graft-versus-host disease); 2. Heterogeneity effect: Differences in the source of MSCs (bone marrow, fat, umbilical cord, etc.), culture conditions, and batches may lead to unstable therapeutic effects and make it difficult to standardize the dosage uniformly. Solution strategy: 1. Dose exploration based on preclinical studies. 1.1 Establish a dose gradient experiment in the animal model and determine the effective window in combination with pathophysiological characteristics (such as injury range and inflammation level); 1.2 Predict the survival, distribution, and mechanism of action of cells in vivo through pharmacokinetic/pharmacodynamic models. 2. Individualized dose adjustment. The dosage is dynamically adjusted based on parameters such as the patient’s weight, the severity of the disease, and the immune status. For example, critically ill patients may require higher doses or multiple infusions. 3. New delivery technologies enhance efficiency. 3.1 Use biomaterial scaffolds or 3D microcarriers to prolong the local retention time of cells and reduce dose requirements; 3.2 Enhance the survival rate and function of MSCs through gene editing (such as overexpression of anti-apoptotic genes) or pretreatment (such as hypoxic culture) and reduce the effective dose. The issue of administration time. 1. Narrow treatment time window: The response to MSCs varies greatly at different disease stages (such as the acute stage vs. the chronic stage). For example, a premature infusion after a myocardial infarction may cause cell death due to the inflammatory microenvironment, while a too- late infusion may miss the repair opportunity. 2. The dynamic microenvironment affects the therapeutic effect: Inflammatory factors, hypoxia, oxidative stress, and others in the local microenvironment may inhibit the survival and function of MSCs. It is necessary to choose a time point when the microenvironment is relatively stable for administration. Solution strategy: 1. Implement a sequential intervention strategy that is based on the mechanisms of the disease. Biomarkers, such as inflammatory factor levels and imaging features, dynamically monitored the disease process to determine the optimal intervention time window. For example: Neurodegenerative diseases: Intervention in the early stage when neurons have not undergone extensive apoptosis; 2. Staged combined treatment. First, the microenvironment is regulated through drugs or biological agents (such as inhibiting excessive inflammation), and then MSCs are infused to improve their survival rate and function. 3. Real-time monitoring and feedback. Develop non-invasive imaging techniques (such as magnetic particle imaging and fluorescence labeling) to track the in vivo distribution of MSCs and dynamically adjust the administration time in combination with therapeutic markers.
We believe that future research directions mainly fall into two aspects: 1. Mechanism-driven research. Identify the target sites of MSCs in specific diseases (such as paracrine factors and exosomes) and develop alternative therapies (such as extracellular vesicles) to reduce the reliance on intact cells. 2. Dynamic control technology. Design “intelligent responsive” MSCs and activate their functions at specific times or in a microenvironment through optogenetic or drug-induced systems.
Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Author contributions
QW: Conceptualization, Visualization, Writing – original draft, Writing – review & editing. WJ: Investigation, Supervision, Validation, Writing – original draft. YFe: Investigation, Supervision, Writing – original draft. LL: Conceptualization, Investigation, Software, Writing – original draft. LC: Funding acquisition, Supervision, Visualization, Writing – original draft, Writing – review & editing. YFa: Conceptualization, Funding acquisition, Visualization, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the National Natural Science Foundation of China (82274122, 82104426, 81903949) and the Natural Science Foundation of Zhejiang Province (LY22H28009, LQ19H290004).
Conflict of interest
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.
Generative AI statement
The authors declare that no Gen AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
MSCs, Mesenchymal stem cells; AD, Alzheimer’s disease; NSCs, neural stem cells; V-SVZ, ventricular-subventricular zone; HD, Huntington’s disease; PD, Parkinson’s disease; OGD/R, Oxygen glucose deprivation and reoxygenation; TNTs, Tunnel nanotubes; MSC-EVs, Mesenchymal stem cell-derived extracellular vesicles; NFT, neurofibrillary tangles; BBB, blood–brain barrier; VEGF, vascular endothelial growth factor; Bfgf, basic fibroblast growth factor; IGF, insulin like growth factor; EGF, epidermal growth factor.
References
1. Apple, DM, Fonseca, RS, and Kokovay, E. The role of adult neurogenesis in psychiatric and cognitive disorders. Brain Res. (2017) 1655:270–6. doi: 10.1016/j.brainres.2016.01.023
2. Luo, X, Xu, M, and Guo, W. Adult neurogenesis research in China. Develop Growth Differ. (2023) 65:534–45. doi: 10.1111/dgd.12900
3. Terreros-Roncal, J, Moreno-Jiménez, EP, Flor-García, M, Rodríguez-Moreno, CB, Trinchero, MF, Cafini, F, et al. Impact of neurodegenerative diseases on human adult hippocampal neurogenesis. Science (New York, NY). (2021) 374:1106–13. doi: 10.1126/science.abl5163
4. Yun, S, Reynolds, RP, Masiulis, I, and Eisch, AJ. Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis. Nat Med. (2016) 22:1239–47. doi: 10.1038/nm.4218
5. Kot, M, Neglur, PK, Pietraszewska, A, and Buzanska, L. Boosting neurogenesis in the adult Hippocampus using antidepressants and mesenchymal stem cells. Cells. (2022) 11:3234. doi: 10.3390/cells11203234
6. Fu, X, Liu, G, Halim, A, Ju, Y, Luo, Q, and Song, AG. Mesenchymal stem cell migration and tissue repair. Cells. (2019) 8:784. doi: 10.3390/cells8080784
7. Xu, D, Wang, YL, Wang, KT, Wang, Y, Dong, XR, Tang, J, et al. A Scientometrics analysis and visualization of depressive disorder. Curr Neuropharmacol. (2021) 19:766–86. doi: 10.2174/1570159X18666200905151333
8. Lee, JS, Hong, JM, Moon, GJ, Lee, PH, Ahn, YH, and Bang, OY. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. (2010) 28:1099–106. doi: 10.1002/stem.430
9. Wei, L, Fraser, JL, Lu, ZY, Hu, X, and Yu, SP. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis. (2012) 46:635–45. doi: 10.1016/j.nbd.2012.03.002
10. Venkataramana, NK, Kumar, SK, Balaraju, S, Radhakrishnan, RC, Bansal, A, Dixit, A, et al. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson's disease. Transl Res. (2010) 155:62–70. doi: 10.1016/j.trsl.2009.07.006
11. Zhang, Y, Chopp, M, Zhang, ZG, Katakowski, M, Xin, H, Qu, C, et al. Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury. Neurochem Int. (2017) 111:69–81. doi: 10.1016/j.neuint.2016.08.003
12. Gorzeń-Mitka, I, Bilska, B, Tomaszewska, M, and Kołożyn-Krajewska, D. Mapping the structure of food waste management research: a co-keyword analysis. Int J Environ Res Public Health. (2020) 17:4798. doi: 10.3390/ijerph17134798
13. Yan, W, Zheng, K, Weng, L, Chen, C, Kiartivich, S, Jiang, X, et al. Bibliometric evaluation of 2000–2019 publications on functional near-infrared spectroscopy. NeuroImage. (2020) 220:117121. doi: 10.1016/j.neuroimage.2020.117121
14. Zheng, Y, Li, R, and Fan, X. Targeting oxidative stress in intracerebral hemorrhage: prospects of the natural products approach. Antioxidants (Basel). (2022) 11:1811. doi: 10.3390/antiox11091811
15. Li, Y, Ma, R, and Hao, X. Therapeutic role of PTEN in tissue regeneration for management of neurological disorders: stem cell behaviors to an in-depth review. Cell Death Dis. (2024) 15:268. doi: 10.1038/s41419-024-06657-y
16. Pinosanu, LR, Wolff, N, Olaru, DG, and Popa-Wagner, A. Stem cell treatments in preclinical relevant stroke models. Curr Health Sci J. (2023) 49:487–94. doi: 10.12865/CHSJ.49.04.02
17. Woodbury, D, Schwarz, EJ, Prockop, DJ, and Black, IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res. (2000) 61:364–70. doi: 10.1002/1097-4547(20000815)61:4<364::AID-JNR2>3.0.CO;2-C
18. Zhao, LR, Duan, WM, Reyes, M, Keene, CD, Verfaillie, CM, and Low, WC. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol. (2002) 174:11–20. doi: 10.1006/exnr.2001.7853
19. Hofstetter, CP, Schwarz, EJ, Hess, D, Widenfalk, J, El Manira, A, Prockop, DJ, et al. Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci USA. (2002) 99:2199–204. doi: 10.1073/pnas.042678299
20. Arvidsson, A, Collin, T, Kirik, D, Kokaia, Z, and Lindvall, O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. (2002) 8:963–70. doi: 10.1038/nm747
21. Bao, X, Wei, J, Feng, M, Lu, S, Li, G, Dou, W, et al. Transplantation of human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and endogenous neurogenesis after cerebral ischemia in rats. Brain Res. (2011) 1367:103–13. doi: 10.1016/j.brainres.2010.10.063
22. Song, M, Mohamad, O, Gu, X, Wei, L, and Yu, SP. Restoration of intracortical and thalamocortical circuits after transplantation of bone marrow mesenchymal stem cells into the ischemic brain of mice. Cell Transplant. (2013) 22:2001–15. doi: 10.3727/096368912X657909
23. Shiota, Y, Nagai, A, Sheikh, AM, Mitaki, S, Mishima, S, Yano, S, et al. Transplantation of a bone marrow mesenchymal stem cell line increases neuronal progenitor cell migration in a cerebral ischemia animal model. Sci Rep. (2018) 8:14951. doi: 10.1038/s41598-018-33030-9
24. Liu, Z, Li, Y, Zhang, ZG, Cui, X, Cui, Y, Lu, M, et al. Bone marrow stromal cells enhance inter- and intracortical axonal connections after ischemic stroke in adult rats. J Cereb Blood Flow Metab. (2010) 30:1288–95. doi: 10.1038/jcbfm.2010.8
25. Shen, LH, Li, Y, Gao, Q, Savant-Bhonsale, S, and Chopp, M. Down-regulation of neurocan expression in reactive astrocytes promotes axonal regeneration and facilitates the neurorestorative effects of bone marrow stromal cells in the ischemic rat brain. Glia. (2008) 56:1747–54. doi: 10.1002/glia.20722
26. Xin, H, Li, Y, Shen, LH, Liu, X, Wang, X, Zhang, J, et al. Increasing tPA activity in astrocytes induced by multipotent mesenchymal stromal cells facilitate neurite outgrowth after stroke in the mouse. PLoS One. (2010) 5:e9027. doi: 10.1371/journal.pone.0009027
27. Shen, LH, Xin, H, Li, Y, Zhang, RL, Cui, Y, Zhang, L, et al. Endogenous tissue plasminogen activator mediates bone marrow stromal cell-induced neurite remodeling after stroke in mice. Stroke. (2011) 42:459–64. doi: 10.1161/STROKEAHA.110.593863
28. Cohen-Cory, S, and Fraser, SE. Effects of brain-derived neurotrophic factor on optic axon branching and remodelling in vivo. Nature. (1995) 378:192–6. doi: 10.1038/378192a0
29. Li, Y, Chen, J, Zhang, CL, Wang, L, Lu, D, Katakowski, M, et al. Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells. Glia. (2005) 49:407–17. doi: 10.1002/glia.20126
30. Shen, LH, Li, Y, Chen, J, Zhang, J, Vanguri, P, Borneman, J, et al. Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke. Neuroscience. (2006) 137:393–9. doi: 10.1016/j.neuroscience.2005.08.092
31. Tobin, MK, Stephen, TKL, Lopez, KL, Pergande, MR, Bartholomew, AM, Cologna, SM, et al. Activated mesenchymal stem cells induce recovery following stroke via regulation of inflammation and Oligodendrogenesis. J Am Heart Assoc. (2020) 9:e013583. doi: 10.1161/JAHA.119.013583
32. Scheiblich, H, Dansokho, C, Mercan, D, Schmidt, SV, Bousset, L, Wischhof, L, et al. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell. (2021) 184:5089–106.e21. doi: 10.1016/j.cell.2021.09.007
33. Rustom, A, Saffrich, R, Markovic, I, Walther, P, and Gerdes, HH. Nanotubular highways for intercellular organelle transport. Science (New York, NY). (2004) 303:1007–10. doi: 10.1126/science.1093133
34. Liu, K, Ji, K, Guo, L, Wu, W, Lu, H, Shan, P, et al. Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia-reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. Microvasc Res. (2014) 92:10–8. doi: 10.1016/j.mvr.2014.01.008
35. Liu, K, Guo, L, Zhou, Z, Pan, M, and Yan, C. Mesenchymal stem cells transfer mitochondria into cerebral microvasculature and promote recovery from ischemic stroke. Microvasc Res. (2019) 123:74–80. doi: 10.1016/j.mvr.2019.01.001
36. Babenko, VA, Silachev, DN, Popkov, VA, Zorova, LD, Pevzner, IB, Plotnikov, EY, et al. Miro1 enhances mitochondria transfer from multipotent mesenchymal stem cells (MMSC) to neural cells and improves the efficacy of cell recovery. Molecules. (2018) 23:687. doi: 10.3390/molecules23030687
37. Tseng, N, Lambie, SC, Huynh, CQ, Sanford, B, Patel, M, Herson, PS, et al. Mitochondrial transfer from mesenchymal stem cells improves neuronal metabolism after oxidant injury in vitro: the role of Miro1. J Cereb Blood Flow Metab. (2021) 41:761–70. doi: 10.1177/0271678X20928147
38. Forsberg, MH, Kink, JA, Hematti, P, and Capitini, CM. Mesenchymal stromal cells and exosomes: Progress and challenges. Front Cell Dev Biol. (2020) 8:665. doi: 10.3389/fcell.2020.00665
39. Xin, H, Li, Y, Cui, Y, Yang, JJ, Zhang, ZG, and Chopp, M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. (2013) 33:1711–5. doi: 10.1038/jcbfm.2013.152
40. Zhao, Y, Gan, Y, Xu, G, Yin, G, and Liu, D. MSCs-derived exosomes attenuate acute brain injury and inhibit microglial inflammation by reversing CysLT2R-ERK1/2 mediated microglia M1 polarization. Neurochem Res. (2020) 45:1180–90. doi: 10.1007/s11064-020-02998-0
41. Moon, GJ, Sung, JH, Kim, DH, Kim, EH, Cho, YH, Son, JP, et al. Application of mesenchymal stem cell-derived extracellular vesicles for stroke: biodistribution and MicroRNA study. Transl Stroke Res. (2019) 10:509–21. doi: 10.1007/s12975-018-0668-1
42. Gan, C, and Ouyang, F. Exosomes released from bone-marrow stem cells ameliorate hippocampal neuronal injury through transferring miR-455-3p. J Stroke Cerebrovasc Dis. (2022) 31:106142. doi: 10.1016/j.jstrokecerebrovasdis.2021.106142
43. Geng, W, Tang, H, Luo, S, Lv, Y, Liang, D, Kang, X, et al. Exosomes from miRNA-126-modified ADSCs promotes functional recovery after stroke in rats by improving neurogenesis and suppressing microglia activation. Am J Transl Res. (2019) 11:780–92.
44. Doeppner, TR, Herz, J, Görgens, A, Schlechter, J, Ludwig, AK, Radtke, S, et al. Extracellular vesicles improve post-stroke Neuroregeneration and prevent Postischemic immunosuppression. Stem Cells Transl Med. (2015) 4:1131–43. doi: 10.5966/sctm.2015-0078
45. Ising, C, and Heneka, MT. Functional and structural damage of neurons by innate immune mechanisms during neurodegeneration. Cell Death Dis. (2018) 9:120. doi: 10.1038/s41419-017-0153-x
46. Tarawneh, R, and Holtzman, DM. The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harb Perspect Med. (2012) 2:a006148. doi: 10.1101/cshperspect.a006148
47. Yuan, O, Lin, C, Wagner, J, Archard, JA, Deng, P, Halmai, J, et al. Exosomes derived from human primed mesenchymal stem cells induce mitosis and potentiate growth factor secretion. Stem Cells Dev. (2019) 28:398–409. doi: 10.1089/scd.2018.0200
48. Deng, P, Anderson, JD, Yu, AS, Annett, G, Fink, KD, and Nolta, JA. Engineered BDNF producing cells as a potential treatment for neurologic disease. Expert Opin Biol Ther. (2016) 16:1025–33. doi: 10.1080/14712598.2016.1183641
49. Lee, HJ, Lee, JK, Lee, H, Carter, JE, Chang, JW, Oh, W, et al. Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation. Neurobiol Aging. (2012) 33:588–602. doi: 10.1016/j.neurobiolaging.2010.03.024
50. Li, M, Inaba, M, Guo, K, Abraham, NG, and Ikehara, S. Amelioration of cognitive ability in senescence-accelerated mouse prone 8 (SAMP8) by intra-bone marrow-bone marrow transplantation. Neurosci Lett. (2009) 465:36–40. doi: 10.1016/j.neulet.2009.09.001
51. Zhao, Y, Chen, X, Wu, Y, Wang, Y, Li, Y, and Xiang, C. Transplantation of human menstrual blood-derived mesenchymal stem cells alleviates Alzheimer's disease-like pathology in APP/PS1 transgenic mice. Front Mol Neurosci. (2018) 11:140. doi: 10.3389/fnmol.2018.00140
52. Redondo-Castro, E, Cunningham, C, Miller, J, Martuscelli, L, Aoulad-Ali, S, Rothwell, NJ, et al. Interleukin-1 primes human mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype in vitro. Stem Cell Res Ther. (2017) 8:79. doi: 10.1186/s13287-017-0531-4
53. Long, Q, Upadhya, D, Hattiangady, B, Kim, DK, An, SY, Shuai, B, et al. Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus. Proc Natl Acad Sci USA. (2017) 114:E3536–45. doi: 10.1073/pnas.1703920114
54. Rizor, A, Pajarillo, E, Johnson, J, Aschner, M, and Lee, E. Astrocytic oxidative/nitrosative stress contributes to Parkinson's disease pathogenesis: the dual role of reactive astrocytes. Antioxidants (Basel). (2019) 8:265. doi: 10.3390/antiox8080265
55. Naaldijk, Y, Jäger, C, Fabian, C, Leovsky, C, Blüher, A, Rudolph, L, et al. Effect of systemic transplantation of bone marrow-derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice. Neuropathol Appl Neurobiol. (2017) 43:299–314. doi: 10.1111/nan.12319
56. Xie, ZH, Liu, Z, Zhang, XR, Yang, H, Wei, LF, Wang, Y, et al. Wharton's jelly-derived mesenchymal stem cells alleviate memory deficits and reduce amyloid-β deposition in an APP/PS1 transgenic mouse model. Clin Exp Med. (2016) 16:89–98. doi: 10.1007/s10238-015-0375-0
57. Noh, MY, Lim, SM, Oh, KW, Cho, KA, Park, J, Kim, KS, et al. Mesenchymal stem cells modulate the functional properties of microglia via TGF-β secretion. Stem Cells Transl Med. (2016) 5:1538–49. doi: 10.5966/sctm.2015-0217
58. Cho, JS, Lee, J, Jeong, DU, Kim, HW, Chang, WS, Moon, J, et al. Effect of placenta-derived mesenchymal stem cells in a dementia rat model via microglial mediation: a comparison between stem cell transplant methods. Yonsei Med J. (2018) 59:406–15. doi: 10.3349/ymj.2018.59.3.406
59. Lee, NK, Park, SE, Kwon, SJ, Shim, S, Byeon, Y, Kim, JH, et al. Agouti related peptide secreted via human mesenchymal stem cells upregulates proteasome activity in an Alzheimer's disease model. Sci Rep. (2017) 7:39340. doi: 10.1038/srep39340
60. Kim, JY, Kim, DH, Kim, JH, Lee, D, Jeon, HB, Kwon, SJ, et al. Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-β plaques. Cell Death Differ. (2012) 19:680–91. doi: 10.1038/cdd.2011.140
61. Kim, DH, Lee, D, Chang, EH, Kim, JH, Hwang, JW, Kim, JY, et al. GDF-15 secreted from human umbilical cord blood mesenchymal stem cells delivered through the cerebrospinal fluid promotes hippocampal neurogenesis and synaptic activity in an Alzheimer's disease model. Stem Cells Dev. (2015) 24:2378–90. doi: 10.1089/scd.2014.0487
62. Kim, DH, Lim, H, Lee, D, Choi, SJ, Oh, W, Yang, YS, et al. Thrombospondin-1 secreted by human umbilical cord blood-derived mesenchymal stem cells rescues neurons from synaptic dysfunction in Alzheimer's disease model. Sci Rep. (2018) 8:354. doi: 10.1038/s41598-017-18542-0
63. Yang, H, Xie, Z, Wei, L, Yang, H, Yang, S, Zhu, Z, et al. Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an AβPP/PS1 transgenic mouse model. Stem Cell Res Ther. (2013) 4:76. doi: 10.1186/scrt227
64. Lee, JK, Jin, HK, and Bae, JS. Bone marrow-derived mesenchymal stem cells reduce brain amyloid-beta deposition and accelerate the activation of microglia in an acutely induced Alzheimer's disease mouse model. Neurosci Lett. (2009) 450:136–41. doi: 10.1016/j.neulet.2008.11.059
65. Shin, JY, Park, HJ, Kim, HN, Oh, SH, Bae, JS, Ha, HJ, et al. Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models. Autophagy. (2014) 10:32–44. doi: 10.4161/auto.26508
66. Kim, C, Park, JM, Kong, T, Lee, S, Seo, KW, Choi, Y, et al. Double-injected human stem cells enhance rehabilitation in TBI mice via modulation of survival and inflammation. Mol Neurobiol. (2018) 55:4870–84. doi: 10.1007/s12035-017-0683-3
67. Zilka, N, Zilkova, M, Kazmerova, Z, Sarissky, M, Cigankova, V, and Novak, M. Mesenchymal stem cells rescue the Alzheimer's disease cell model from cell death induced by misfolded truncated tau. Neuroscience. (2011) 193:330–7. doi: 10.1016/j.neuroscience.2011.06.088
68. Mizushima, N, and Komatsu, M. Autophagy: renovation of cells and tissues. Cell. (2011) 147:728–41. doi: 10.1016/j.cell.2011.10.026
69. Guan, JL, Simon, AK, Prescott, M, Menendez, JA, Liu, F, Wang, F, et al. Autophagy in stem cells. Autophagy. (2013) 9:830–49. doi: 10.4161/auto.24132
70. Chang, NC. Autophagy and stem cells: self-eating for self-renewal. Front Cell Dev Biol. (2020) 8:138. doi: 10.3389/fcell.2020.00138
71. Oliver, L, Hue, E, Priault, M, and Vallette, FM. Basal autophagy decreased during the differentiation of human adult mesenchymal stem cells. Stem Cells Dev. (2012) 21:2779–88. doi: 10.1089/scd.2012.0124
72. Wang, F, Zhang, C, Hou, S, and Geng, X. Synergistic effects of mesenchymal stem cell transplantation and repetitive transcranial magnetic stimulation on promoting autophagy and synaptic plasticity in vascular dementia. J Gerontol A Biol Sci Med Sci. (2019) 74:1341–50. doi: 10.1093/gerona/gly221
73. Sweeney, MD, Sagare, AP, and Zlokovic, BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. (2018) 14:133–50. doi: 10.1038/nrneurol.2017.188
74. Wang, C, Li, Y, Yang, M, Zou, Y, Liu, H, Liang, Z, et al. Efficient differentiation of bone marrow mesenchymal stem cells into endothelial cells in vitro. Eur J Vasc Endovasc Surg. (2018) 55:257–65. doi: 10.1016/j.ejvs.2017.10.012
75. Garcia, KO, Ornellas, FL, Martin, PK, Patti, CL, Mello, LE, Frussa-Filho, R, et al. Therapeutic effects of the transplantation of VEGF overexpressing bone marrow mesenchymal stem cells in the hippocampus of murine model of Alzheimer's disease. Front Aging Neurosci. (2014) 6:30. doi: 10.3389/fnagi.2014.00030
76. Madrigal, M, Rao, KS, and Riordan, NH. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J Transl Med. (2014) 12:260. doi: 10.1186/s12967-014-0260-8
77. Vizoso, FJ, Eiro, N, Cid, S, Schneider, J, and Perez-Fernandez, R. Mesenchymal stem cell Secretome: toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci. (2017) 18:1852. doi: 10.3390/ijms18091852
78. Park, SE, Lee, NK, Na, DL, and Chang, JW. Optimal mesenchymal stem cell delivery routes to enhance neurogenesis for the treatment of Alzheimer's disease: optimal MSCs delivery routes for the treatment of AD. Histol Histopathol. (2018) 33:533–41. doi: 10.14670/HH-11-950
79. Park, HJ, Oh, SH, Kim, HN, Jung, YJ, and Lee, PH. Mesenchymal stem cells enhance α-synuclein clearance via M2 microglia polarization in experimental and human parkinsonian disorder. Acta Neuropathol. (2016) 132:685–701. doi: 10.1007/s00401-016-1605-6
80. Vu, Q, Xie, K, Eckert, M, Zhao, W, and Cramer, SC. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke. Neurology. (2014) 82:1277–86. doi: 10.1212/WNL.0000000000000278
81. Ge, J, Guo, L, Wang, S, Zhang, Y, Cai, T, Zhao, RC, et al. The size of mesenchymal stem cells is a significant cause of vascular obstructions and stroke. Stem Cell Rev Rep. (2014) 10:295–303. doi: 10.1007/s12015-013-9492-x
82. Mitkari, B, Kerkelä, E, Nystedt, J, Korhonen, M, and Jolkkonen, J. Unexpected complication in a rat stroke model: exacerbation of secondary pathology in the thalamus by subacute intraarterial administration of human bone marrow-derived mesenchymal stem cells. J Cereb Blood Flow Metab. (2015) 35:363–6. doi: 10.1038/jcbfm.2014.235
83. Yavagal, DR, Lin, B, Raval, AP, Garza, PS, Dong, C, Zhao, W, et al. Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model. PLoS One. (2014) 9:e93735. doi: 10.1371/journal.pone.0093735
84. Wang, LQ, Lin, ZZ, Zhang, HX, Shao, B, Xiao, L, Jiang, HG, et al. Timing and dose regimens of marrow mesenchymal stem cell transplantation affect the outcomes and neuroinflammatory response after ischemic stroke. CNS Neurosci Ther. (2014) 20:317–26. doi: 10.1111/cns.12216
85. Parys, M, Nelson, N, Koehl, K, Miller, R, Kaneene, JB, Kruger, JM, et al. Safety of intraperitoneal injection of adipose tissue-derived autologous mesenchymal stem cells in cats. J Vet Intern Med. (2016) 30:157–63. doi: 10.1111/jvim.13655
86. Donders, R, Vanheusden, M, Bogie, JF, Ravanidis, S, Thewissen, K, Stinissen, P, et al. Human Wharton's jelly-derived stem cells display immunomodulatory properties and transiently improve rat experimental autoimmune encephalomyelitis. Cell Transplant. (2015) 24:2077–98. doi: 10.3727/096368914X685104
87. Honmou, O, Houkin, K, Matsunaga, T, Niitsu, Y, Ishiai, S, Onodera, R, et al. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. (2011) 134:1790–807. doi: 10.1093/brain/awr063
88. Rodríguez-Frutos, B, Otero-Ortega, L, Gutiérrez-Fernández, M, Fuentes, B, Ramos-Cejudo, J, and Díez-Tejedor, E. Stem cell therapy and administration routes after stroke. Transl Stroke Res. (2016) 7:378–87. doi: 10.1007/s12975-016-0482-6
89. De Keyser, J. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. (2005) 58:653–4. doi: 10.1002/ana.20612
90. Lalu, MM, McIntyre, L, Pugliese, C, Fergusson, D, Winston, BW, Marshall, JC, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. (2012) 7:e47559. doi: 10.1371/journal.pone.0047559
91. Prasad, K, Sharma, A, Garg, A, Mohanty, S, Bhatnagar, S, Johri, S, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke. (2014) 45:3618–24. doi: 10.1161/STROKEAHA.114.007028
92. Hsieh, JY, Wang, HW, Chang, SJ, Liao, KH, Lee, IH, Lin, WS, et al. Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis. PLoS One. (2013) 8:e72604. doi: 10.1371/journal.pone.0072604
93. Wang, LS, Chung, JE, Chan, PP, and Kurisawa, M. Injectable biodegradable hydrogels with tunable mechanical properties for the stimulation of neurogenesic differentiation of human mesenchymal stem cells in 3D culture. Biomaterials. (2010) 31:1148–57. doi: 10.1016/j.biomaterials.2009.10.042
94. Chang, CP, Chio, CC, Cheong, CU, Chao, CM, Cheng, BC, and Lin, MT. Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury. Clin Sci. (2013) 124:165–76. doi: 10.1042/CS20120226
95. van Velthoven, CT, Kavelaars, A, van Bel, F, and Heijnen, CJ. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun. (2010) 24:387–93. doi: 10.1016/j.bbi.2009.10.017
96. Koh, SH, Kim, KS, Choi, MR, Jung, KH, Park, KS, Chai, YG, et al. Implantation of human umbilical cord-derived mesenchymal stem cells as a neuroprotective therapy for ischemic stroke in rats. Brain Res. (2008) 1229:233–48. doi: 10.1016/j.brainres.2008.06.087
97. Pittenger, MF, Mackay, AM, Beck, SC, Jaiswal, RK, Douglas, R, Mosca, JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. (1999) 284:143–7. doi: 10.1126/science.284.5411.143
98. Horita, Y, Honmou, O, Harada, K, Houkin, K, Hamada, H, and Kocsis, JD. Intravenous administration of glial cell line-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat. J Neurosci Res. (2006) 84:1495–504. doi: 10.1002/jnr.21056
99. Dominici, M, Le Blanc, K, Mueller, I, Slaper-Cortenbach, I, Marini, F, Krause, D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. (2006) 8:315–7. doi: 10.1080/14653240600855905
100. Chopp, M, and Li, Y. Treatment of neural injury with marrow stromal cells. Lancet Neurol. (2002) 1:92–100. doi: 10.1016/S1474-4422(02)00040-6
101. Chen, J, Li, Y, Wang, L, Zhang, Z, Lu, D, Lu, M, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke. (2001) 32:1005–11. doi: 10.1161/01.str.32.4.1005
102. Sanchez-Ramos, J, Song, S, Cardozo-Pelaez, F, Hazzi, C, Stedeford, T, Willing, A, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol. (2000) 164:247–56. doi: 10.1006/exnr.2000.7389
103. Chen, J, Li, Y, Katakowski, M, Chen, X, Wang, L, Lu, D, et al. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res. (2003) 73:778–86. doi: 10.1002/jnr.10691
104. Li, Y, Chen, J, Chen, XG, Wang, L, Gautam, SC, Xu, YX, et al. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology. (2002) 59:514–23. doi: 10.1212/WNL.59.4.514
Keywords: neurogenesis, stroke, Alzheimer’s disease, mesenchymal stem cells, scientometric
Citation: Wang Q, Jiang W, Feng Y, Li L, Chu L and Fang Y (2025) Therapeutic role of mesenchymal stem cells in neurogenesis for management of neurological disorders: a scientometric study to an in-depth review. Front. Neurol. 16:1588535. doi: 10.3389/fneur.2025.1588535
Edited by:
Ulises Gomez-Pinedo, Health Research Institute of Hospital Clínico San Carlos, SpainReviewed by:
Alejandro A. Canales-Aguirre, CONACYT Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), MexicoBelén Selma, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Spain
Copyright © 2025 Wang, Jiang, Feng, Li, Chu and Fang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lisheng Chu, Y2xzMjAwNEB6Y211LmVkdS5jbg==; Yan Fang ZmFuZ3lhbkB6Y211LmVkdS5jbg==
†These authors have contributed equally to this work