Mesenchymal stem cell therapy in atherosclerosis: A bibliometric and visual analysis

Abstract

BACKGROUND

Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation, and extensive studies have demonstrated their therapeutic potential in atherosclerosis (AS).

AIM

To conduct a bibliometric analysis of studies on the use of MSC therapy for AS over the past two decades, assess key trends and provide insights for future research directions.

METHODS

We systematically searched the Web of Science Core Collection database for articles published between 1999 and 2023, yielding a total of 556 articles. Visual representation and bibliometric analysis of information and trends were facilitated using CiteSpace, the R package ‘bibliometrix’ and VOSviewer.

RESULTS

The analyzed articles were predominantly from 52 countries/regions, with prominent contributions from China and the United States. A cohort of 3057 authors contributed to these publications, with the works of Libby P distinguished by their influence and citation count. Int J Mol Sci has emerged as the journal with the highest publication volume, prominently disseminating influential papers and identifying citation outbreaks. Furthermore, our analysis identified current research hotspots within the field, focusing on vascular progenitor cells, inflammatory mechanisms, and extracellular vesicles. Emerging research frontiers, such as extracellular vesicles and oxidative stress, have been highlighted as areas of burgeoning interest. Finally, we offer perspectives on the status of research and future directions of MSC therapy in AS.

CONCLUSION

This comprehensive analysis provides valuable insights for advancing scientific research on MSC therapy for AS. By elucidating pivotal trends and research directions, this study aimed to foster innovation and promote the progress of disciplines in this field, thereby contributing to advancing scientific knowledge and clinical practice.

Key Words: Atherosclerosis; Treatment strategy; Bibliometrics; Visual analysis; CiteSpace

Core Tip: This study provided a comprehensive overview of the research landscape on mesenchymal stem cell therapy in atherosclerosis through detailed bibliometric analysis. It not only collated and presented key studies in this field but also highlighted emerging trends, significant developments, and potential future research directions, providing a valuable foundation for further exploration and application of stem cell therapy in the treatment of atherosclerosis.

INTRODUCTION

Cardiovascular disease (CVD) is a leading cause of mortality and disability worldwide and poses a significant threat to human health. Statistics indicate that approximately 30% of the annual global deaths can be attributed to CVD. Notably, atherosclerosis (AS) is the predominant cause of CVD and is specifically recognized as atherosclerotic CVD, imposing a substantial economic and social burden[1-4]. Effectively curbing the progression of AS is paramount for reducing the morbidity and mortality associated with CVD. AS manifests as a complex interplay of various risk factors, including hypertension, diabetes mellitus, smoking, alcohol consumption, age, sex, and heredity[5]. Elucidating the intricate mechanism and inhibition of AS formation by considering only a single factor is challenging. A hallmark of this disease is the deposition of lipids in the arterial intima, triggering inflammation and plaque formation. This process leads to profound structural and functional disruption of the arterial wall. Consequently, the cumulative effect of plaque accumulation and rupture primarily results in the narrowing and blockage of blood vessels, resulting in serious consequences, such as stroke, coronary heart disease, and heart attack[6]. Therefore, effective strategies to manage lipid levels, control inflammation, and promote a healthy lifestyle are imperative to prevent and treat AS.

Lowering lipid levels, particularly through statin administration, is the cornerstone of AS treatment[7,8]. Despite the significant advancements achieved with statins[9], several comprehensive controlled clinical studies have revealed their suboptimal efficacy in addressing CVD[10]. Moreover, some patients, especially older adults, face challenges in tolerating statin medications, thereby increasing the risk of discontinuation[11]. In addition to pharmacological approaches, alternative interventions such as endovascular stenting are commonly used to manage arterial stenosis or occlusion[12,13]. However, the prevalence of postprocedural complications, including stent restenosis and thrombosis, is high and, in certain instances, can pose life-threatening risks. Considering these challenges, global efforts are underway to explore novel treatment modalities.

Stem cells, characterized by their ability to self-renew and differentiate, represent a promising avenue for their exploration. These cells not only sustain their numbers by generating identical stem cells but also possess the ability to form specific cell types and tissues. Stem cell therapy has emerged as a well-established research methodology for addressing a diverse array of diseases[14-16]. Mesenchymal stem cells (MSCs), also referred to as pluripotent mesenchymal stromal cells, are the predominant stem cell type investigated in AS. These cells, derived from bone marrow, can be isolated from various tissues, including the blood, skin, white adipose tissue, liver, pancreas, spleen, thymus, skeletal muscle, placenta, and human gingiva[17-19]. MSCs are easily cultivated and expanded in vitro, and their surfaces are characterized by the expression of CD73, CD90, and CD105[20]. MSC therapy has significant therapeutic potential. Numerous studies have demonstrated its ability to stimulate vascular neovascularization[21,22], facilitate endothelial and arterial wall repair[23,24], diminish inflammatory responses, modulate macrophages, and inhibit foam cell formation[25,26]. These findings underscore the innovative prospects of MSC therapy for treating AS.

Bibliometric analysis employs statistical methods to qualitatively and quantitatively assess publications in databases. This method enables the extraction of valuable insights from data, facilitating the summarization and analysis of research progress in specific domains[27]. In recent years, the growing sophistication of statistical science has propelled bibliometric analysis into prominence, particularly in medical research. Through the visualization of networks and comprehensive analysis of the current literature, this approach objectively delineates the developmental history and research focal points of a specific field[28,29], and aids researchers in comprehending future research trends, defining research trajectories, and identifying collaborative opportunities[30,31].

This study presents a scientific and comprehensive analysis of the literature on MSC therapy for atherosclerotic diseases. Using visual networks, we statistically examined bibliometrics over the past two decades (1999-2023). This study is significant as a bibliometric analysis related to MSC therapy for atherosclerotic disease. This study is important for its capacity to meet the pressing needs of researchers in related fields, offering a concise and efficient means of comprehending the present state, research focal points, and trends within the field. Moreover, it assists in establishing attainable work objectives and identifying appropriate research directions.

MATERIALS AND METHODS

Source of data and methodology for searching

The Web of Science Core Collection (WoSCC) database, provided by Clarivate Analytics, encompasses over 12000 high-quality international scholarly journals, establishing itself as a comprehensive and authoritative resource[32]. To conduct a bibliometric analysis, we utilized the WoSCC to gather global information, aligning it with established practices in previous studies. The raw data were collected on December 23, 2023, to mitigate potential biases from rapid updates. Employing the search strategy “(TS = (“Stem Cell Treatment”) OR TS = (“Stem Cell Therapy”) OR TS = (“Mesenchymal Stem Cell*”) OR TS = (“Mesenchymal Stromal Cell*”) OR TS = (“Mesenchymal Progenitor Cell*”)) AND (TS = (Atherosclerosis) OR TS = (Atheroscleroses) OR TS = (Atherogenesis))”, with language limited to English, we retrieved a total of 556 articles from WoSCC. Following weighting and data cleaning facilitated by CiteSpace software, 522 articles were retained for subsequent analysis. A schematic representation of the screening process is shown in Figure 1.

Figure 1 Flowchart of the screening process.

Statistical analysis

The initial step involved downloading raw data from the WoSCC, followed by its subsequent import into the WPS Office software. Three authors independently thoroughly screened the final articles, systematically collecting essential information, including the title, authors, keywords, affiliated institutions, country/region of origin, citation metrics, journal of publication, and publication date. The processed data were subsequently imported into VOSviewer 6.2 R6, CiteSpace 1.6.18[33], and the R package ‘bibliometrix’ for the bibliometric analysis.

CiteSpace is a software tool designed for scientific bibliometric research, with analysis and visualization capabilities to discern academic trends and patterns[34]. Furthermore, it constructs a comprehensive knowledge map of the field and provides a clear overview of a specific knowledge domain. Using various dynamic network analysis techniques, the tool reveals the developmental history, prominent research areas, emerging trends, and frontiers within a specific scientific field[35]. CiteSpace aims to assist researchers in making informed decisions and fostering deeper insights for further research and academic exploration.

Bibliometrix is an open-source R package for conducting bibliometric analysis created by Dr. Massimo Aria and Corrado Cuccurullo from the University of Naples, Italy (https://www.bibliometrix.org)[36]. In the present investigation, the bibliometrix, in conjunction with CiteSpace, was employed to scrutinize co-citation relationships within the literature. This approach facilitates a comprehensive examination of scholarly connections, enabling researchers to gain insights into prevailing academic trends and identify leading papers within their respective fields.

In this study, we employed VOSviewer software, developed by the Center for Science and Technology Studies at Leiden University in the Netherlands, to create and analyze bibliometric networks. It provides bibliometric networks, including co-cited journals, countries/regions of origin, and institutions[37]. Furthermore, we visualized publications and their cross-country interrelationships through R language. Finally, we conducted comprehensive co-occurrence and clustering analyses of authors, cited literature, and keyword co-citations via CiteSpace.

RESULTS

Global publishing characteristics

On the basis of the retrieved data, investigations on MSC therapy for AS commenced in 1999. The overall trend in the number of annual publications exhibited a consistent upward trajectory (Figure 2A). Publications peaked in 2021, with 59 articles accounting for 11.3% of the total publications. Furthermore, the mean citation count per article stands at approximately 41, resulting in an average annual citation rate of approximately 2.16. These findings highlight the growing and significant impact of research focused on MSC therapy for AS.

Figure 2 Visual analysis of global publishing characteristics. A: Number of articles published per year and average number of citations per year; B: Areas of research covered by the publications; C: The funding organization of the publications; D: Publishers of the articles.

An analysis of the WoSCC database revealed that the 522 articles spanned 53 research areas (Figure 2B). Predominantly, the articles focused on the fields of cell biology (147, 26.44%) and cardiovascular system cardiology (122, 21.94%), with research experimental medicine (92, 16.55%) and biochemistry molecular biology (77, 13.85%). Within this dataset, 197 articles (37.74%) were classified as review articles. Regarding funding sources (Figure 2C), the National Natural Science Foundation of China (114, 20.5%) emerged as the primary funding agency. The National Institutes of Health, United States (80, 14.39%), the United States Department of Health and Human Services (80, 14.39%), and the American Heart Association (24, 4.32%) subsequently played substantial roles. Additionally, in the publishing landscape (Figure 2D), Elsevier occupied the foremost position (125, 22.48%), followed by Springer Nature (79, 14.21%) and Lippincott Williams & Wilkins (49, 8.81%).

Visual analysis of countries/regions and institutions

Using VOSviewer for analysis (Figure 3A, Table 1), 522 articles were identified from 52 countries/regions of origin, with 24 contributing at least five publications each. China stands out as the leading contributor in this field, with 195 articles, followed by the United States (140) and the United Kingdom (36). Among the top ten countries, China was the sole representative from the developing world. However, in terms of cumulative citations, the United States had the highest number of citations (9989), followed by China (4797). A bibliometric analysis (Figure 3B) highlighted collaborations between China and the United States, as well as China and the United Kingdom as the most prevalent. An examination of the corresponding authors revealed that China had a significant lead over other countries in both single-country and multi-country corresponding author publications (Figure 3C). Notably, since 2019, China has surpassed the United States in the number of published papers (Figure 3D).

Figure 3 Visual analysis of countries/regions and institutions. A: Network of countries/regions; B: Collaboration network of countries/regions; C: Corresponding authors’ nationality; D: Country production over time; E: Collaboration network of institutions. SCP: Single country publications; MCP: Multiple country publications.

Table 1 The top 10 countries/regions and institutions in the field of mesenchymal stem cell therapy for atherosclerosis.

Rank	Country/region	Documents	Citations	Institution	Documents	Centrality
1	China	195	4797	Zhejiang University	16	0.19
2	United States	140	9989	University of London	14	0.03
3	United Kingdom	36	2778	Harvard University	12	0.13
4	Japan	32	1071	Shanghai Jiao Tong University	11	0.05
5	Italy	31	1584	King’s College London	11	0.02
6	Germany	27	1251	Sun Yat Sen University	10	0.04
7	Canada	17	524	Harvard Medical School	9	0.09
8	Korea	17	231	Institut National de la Sante et de la Recherche Medicale (Inserm)	9	0.07
9	Australia	16	667	University of California System	9	0.07
10	France	15	1553	Chinese Academy of Sciences	9	0.04

CiteSpace analysis revealed that the 522 articles sourced from 804 institutions, with 42 institutions contributing at least five publications each (Figure 3E, Table 1). Zhejiang University occupied the top position in terms of the number of publications (16), followed by the University of London (14) and Harvard University (12). Centrality, also known as intermediary centrality, is a metric in which a higher value indicates a more active and integral role in cooperative relationships with other nodes. A centrality exceeding 0.1 is denoted by a purple circle at the node. In terms of research institution cooperation, Zhejiang University (0.19) and Harvard University (0.13) presented the highest centralities.

Visual analysis of journals and co-cited journals

According to the VOSviewer analysis (Figure 4A), 522 of the examined articles were disseminated across 286 journals, with 22 boasting a publication volume of at least five articles each. The preeminent contributor was the International Journal of Molecular Sciences (Int J Mol Sci), with 16 articles and an impact factor (IF) of 5.6, followed by Frontiers in Cardiovascular Medicine (Front Cardiovasc Med), with 15 articles and an IF of 3.6, and Stem Cell Research & Therapy (Stem Cell Res Ther), with 13 articles and an IF of 7.5 (Figure 4B). Of the top ten journals (Table 2), nine ranked at Q2 and above. Bradford’s Law (Figure 4C) further confirmed that the core journals in this field maintained high-quality standards.

Figure 4 Visual analysis of journals and co-cited journals. A and B: Network of article source journals; C: Core sources according to Bradford’s law; D: Network of co-cited journals; E: Dual-map overlay of journals.

Table 2 The top 10 journals and co-cited journals in the field of mesenchymal stem cell therapy for atherosclerosis.

Rank	Journal	Documents	Citations	JCR (2023)	Co-cited journal	Citations	JCR (2023)
1	Int J Mol Sci	16	227	Q1, 5.6	Circulation	1772	Q1, 37.8
2	Front Cardiovasc Med	15	341	Q2, 3.6	Circ Res	1690	Q1, 20.1
3	Stem Cell Res Ther	13	288	Q1, 7.5	Arterioscl Throm Vas	1347	Q1, 8.7
4	Arterioscl Throm Vas	10	699	Q1, 8.7	P Natl Acad Sci Usa	812	Q1, 11.1
5	Cells-Basel	9	81	Q2, 6	J Biol Chem	809	Q2, 4.8
6	Circ Res	9	1348	Q1, 20.1	Nature	743	Q1, 64.8
7	Plos One	9	209	Q2, 3.7	Plos One	724	Q2, 3.7
8	Cardiovasc Res	8	347	Q1, 10.9	J Clin Invest	684	Q1, 15.9
9	Atherosclerosis	7	275	Q2, 5.3	Science	530	Q1, 56.9
10	Biochem Bioph Res Co	6	270	Q3, 3.1	Cardiovasc Res	520	Q1, 10.9

According to the VOSviewer analysis (Figure 4D, Table 2), there were 3880 co-cited journals and 403 with ≥ 20 citations. Circulation led the pack with 1772 citations and an IF of 37.8, followed by Circulation Research with 1690 citations and an IF of 20.1 and Arteriosclerosis, Thrombosis, and Vascular Biology with 1347 citations and an IF of 8.7. Nine of the top ten co-cited journals were positioned in the JCR Q1 category. Both Nature and Science emerged as prominent co-cited journals in the field, underscoring the high quality of the article citations.

The dual plot overlay of journals provided profound insights into topic distribution, citation trajectories, and shifts in centrality. The citing journals are on the left, while the cited journals are on the right. The curves illustrate the citation links, delineating comprehensive citation relationships. In this dual plot overlay of journals, the vertical axis of the ellipse lengthens with the increasing number of articles published by a journal, whereas the horizontal axis lengthens with the growing number of authors. As shown in Figure 4E, two principal citation pathways were evident, highlighting the frequent citation of articles published in journals related to molecular biology and genetics and those in health, nursing, and medicine by journals specializing in Molecular Biology and Immunology. This visualization also elucidated journals that publish research articles on MSC therapy for AS and the primary domains of co-cited journals.

Visual analysis of authors and co-cited authors

CiteSpace analysis (Figure 5A, Table 3) revealed that 3057 authors contributed to the publication of these articles. Among them, Xu Qingbo (9) and Orekhov Alexander N (5) had the highest number of published articles. However, no author stands out with an exceptionally high publication count in this field, indicating a lack of collaboration among authors. This observation implied that the field remains in an exploratory phase.

Figure 5 Visual analysis of authors and co-cited authors. A: Collaboration network of authors; B: Collaboration network of co-cited authors.

Table 3 The top 10 authors and co-cited authors in the field of mesenchymal stem cell therapy for atherosclerosis.

Rank	Author	Documents	Cited author	Documents	Centrality
1	Xu Qingbo	9	Libby P	84	0.08
2	Orekhov Alexander N	5	Ross R	54	0.16
3	Li Song	4	Wang Y	49	0.04
4	Li Mincai	4	Asahara T	48	0.19
5	Colmegna Ines	3	Pittenger MF	48	0.04
6	Broskey Nicholas T	3	Hu YH	41	0.06
7	Zhang Wei	3	Zhang Y	40	0.05
8	Houmard Joseph A	3	Li Q	37	0.03
9	Song Chunli	3	Liu Y	36	0.1
10	Yu Jun	3	Sata M	36	0.07

In the context of the CiteSpace analysis (Figure 5B, Table 3), a substantial network of 27637 co-cited authors emerged. The analysis of co-cited authors revealed that two articles by two authors were concurrently cited by a third article. The magnitude of co-citations indicates the proximity of academic interests among researchers and the density of research in the field. Among these authors, 89 had co-citation counts ≥ 20. The leading co-citation count was Libby P (84), followed by Ross R (54) and Wang Y (49). Asahara (0.19) had the highest centrality. Burst detection, a methodology utilized to identify abrupt changes in authors, articles, keywords, and journal citation information, can signify emerging trends and breakthroughs in a field. In this analysis, Asahara T (9.91) demonstrated the highest burst intensity, followed by Asta M (9.58) and Aicher A (7.75) (Supplementary Figure 1).

Visual analysis of articles and co-cited articles

The analysis of 522 articles included a citation examination (Figure 6A and B), revealing 89 articles with ≥ 20 citations. The ten most frequently cited articles are listed in Table 4. Eight were reviews, and two were articles. The article “Vascular Smooth Muscle Cells in Atherosclerosis” in Nature Reviews Cardiology is the most preeminent. This article presents compelling evidence of vascular smooth muscle cell (VSMC) plasticity and summarizes the roles of VSMCs and VSMC-derived cells in the development and progression of atherosclerotic plaques.

Figure 6 Visual analysis of publications and co-cited references. A and B: Network of publications; C: Reference records for each year; D: Network and cluster analysis of co-cited references; E: Clustering timeline map of co-cited references.

Table 4 The top 10 publications in the field of mesenchymal stem cell therapy for atherosclerosis.

Rank	Title	Journal	Citations	Type	Year	Ref.
1	Vascular smooth muscle cells in atherosclerosis	Nat Rev Cardiol	887	Review	2019	[83]
2	KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis	Nat Med	726	Article	2015	[84]
3	Mechanobiology of YAP and TAZ in physiology and disease	Nat Rev Mol Cell Biol	710	Review	2017	[85]
4	Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease	Annu Rev Physiol	537	Review	2012	[86]
5	Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche	Histol Histopathol	451	Review	2009	[87]
6	Gold nanoparticles for photoacoustic imaging	Nanomedicine (Lond)	417	Review	2015	[88]
7	Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like receptor ligands	Immunity	368	Article	2011	[89]
8	Biomedical applications of photoacoustic imaging with exogenous contrast agents	Ann Biomed Eng	306	Review	2012	[90]
9	Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling	Mediators Inflamm	300	Review	2013	[91]
10	Physical and mechanical regulation of macrophage phenotype and function	Cell Mol Life Sci	296	Review	2015	[92]

A literature co-citation relationship is established when two articles are concurrently cited by a third article. References are widely recognized as repositories of knowledge within a specific field, and the significance of a paper is frequently measured by the frequency of its citations. When Bibliometrix and CiteSpace were used for analysis (Figure 6C, Table 5), 522 articles in question collectively cited a total of 37953 articles, with 111 articles co-cited ten or more times The most frequently cited article, titled “Exosomes Derived from Mesenchymal Stem Cells Attenuate the Progression of Atherosclerosis in ApoE-/- Mice via miR-let7 Mediated Infiltration and Polarization of M2 Macrophage”, was published in Biochemical and Biophysical Research Communications. This study demonstrated that exosomes from MSCs inhibited plaque infiltration of macrophages in mice, suggesting a potential therapeutic avenue for AS treatment and reducing the clinical risk of coronary artery disease.

Table 5 The top 10 co-cited references in the field of mesenchymal stem cell therapy for atherosclerosis.

Rank	Title	Journal	Citations	Type	Year	Ref.
1	Exosomes derived from mesenchymal stem cells attenuate the progression of atherosclerosis in ApoE(-/-) mice via miR-let7 mediated infiltration and polarization of M2 macrophage	Biochem Biophys Res Commun	26	Article	2019	[93]
2	Vascular smooth muscle cells in atherosclerosis	Nat Rev Cardiol	22	Review	2019	[83]
3	Adventitial MSC-like cells are progenitors of vascular smooth muscle cells and drive vascular calcification in chronic kidney disease	Cell Stem Cell	21	Article	2016	[94]
4	Mesenchymal stem cells reduce murine atherosclerosis development	Sci Rep	16	Article	2015	[65]
5	Shedding light on the cell biology of extracellular vesicles	Nat Rev Mol Cell Biol	14	Review	2018	[95]
6	Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines	J Extracell Vesicles	14	Guidelines	2018	[96]
7	Extensive proliferation of a subset of differentiated, yet plastic, medial vascular smooth muscle cells contributes to neointimal formation in mouse injury and atherosclerosis models	Circ Res	13	Article	2016	[97]
8	Vascular smooth muscle cells in atherosclerosis	Circ Res	13	Review	2016	[98]
9	Human gingiva-derived mesenchymal stem cells modulate monocytes/macrophages and alleviate atherosclerosis	Front Immunol	13	Article	2018	[66]
10	Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction	Theranostics	12	Article	2018	[99]
11	Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness	Cardiovasc Res	12	Review	2018	[100]
12	Humoral factors secreted from adipose tissue-derived mesenchymal stem cells ameliorate atherosclerosis in Ldlr-/- mice	Cardiovasc Res	12	Article	2019	[101]
13	Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19	Cardiovasc Res	12	Article	2020	[102]

Burst in cited literature is defined as a sudden increase in the citation count over a given period. CiteSpace analysis identified 15 articles with burst intensity data (Supplementary Figure 2). Among them, the article titled “Mesenchymal Stem Cells Reduce Murine Atherosclerosis Development” presented the highest burst intensity of 6.48. This pioneering study revealed that MSC treatment not only modulated the inflammatory response but also substantially diminished both inflammation and dyslipidemia in mice. These findings suggest that MSCs are robust candidates for the treatment of AS.

The co-cited literature was subjected to clustering analysis via CiteSpace software (Figure 6D) to identify valuable research topics. Nine topics were delineated via the latent semantic indexing algorithm (Q = 0.8176, S = 0.9779). A Q value ranging from 0 to 1 indicates a clear cyclic structure, with a value > 0.3 denoting clarity. A S value > 0.5 suggests reasonable clustering, whereas a value > 0.7 signifies greater accuracy. The clusters were identified as follows: #0 exosomes, #1 adventitia, #2 clinical trials, #3 vascular remodeling, #4 nanotechnology, #5 mesenchymal stromal cells, #6 bone marrow, #7 myocardial infarction, and #8 vascular calcifications. To illustrate research trends over time, a timeline diagram of co-cited literature clustering was plotted (Figure 6E). This figure revealed that cluster #0 exosomes and cluster #3 vascular remodeling currently dominate research priorities in MSC therapy for AS.

Evolution of keywords and hotspots

Keywords serve as crucial reflections of an article’s topic and research content. A rapid comprehension of the prevailing status and focal points of MSC therapy for AS can be achieved through mapping keyword co-occurrence. Using CiteSpace software (Figure 7A, Table 6), a comprehensive collection of 2781 keywords was extracted, with 40 exhibiting a frequency of ≥ 20. Table 6 presents the 25 keywords with the highest frequencies of occurrence. Among these cells, “mesenchymal stem cells” (260) and “atherosclerosis” (132) are predominant. After the exclusion of less meaningful keywords, the more frequently appearing terms included “smooth muscle cells”, “endothelial cells”, “myocardial infarction”, “inflammation”, “bone marrow”, “endothelial progenitor cells”, “oxidative stress”, and “extracellular vesicles”. These keywords underwent burst testing (Figure 7B), revealing that “extracellular vesicles” presented the highest burst intensity, persisting to the present day.

Figure 7 Visual analysis of keywords. A: Network and cluster analysis of keywords; B: Top 8 keywords with the strongest citation bursts; C: Clustering timeline map of keywords; D: Thematic evolution of the field.

Table 6 The top 25 keywords in the field of mesenchymal stem cell therapy for atherosclerosis.

Rank	Keywords	Counts	Centrality	Year
1	Mesenchymal stem cells	260	0.11	2004
2	Atherosclerosis	132	0.1	1999
3	Smooth muscle cells	96	0.15	2003
4	Expression	86	0.04	2007
5	Stem cells	72	0.05	2004
6	Progenitor cells	64	0.06	2007
7	Endothelial cells	63	0.05	2005
8	Differentiation	58	0.06	1999
9	In vitro	52	0.05	2004
10	Myocardial infarction	52	0.06	2004
11	Inflammation	52	0.03	2010
12	Bone marrow	51	0.07	2003
13	Endothelial progenitor cells	48	0.05	2004
14	Stromal cells	48	0.1	2004
15	Oxidative stress	45	0.03	2010
16	Proliferation	42	0.04	2005
17	Cardiovascular disease	39	0.07	2004
18	Disease	37	0.01	2009
19	Mechanisms	36	0.05	2007
20	Extracellular vesicles	34	0.02	2016
21	In vivo	32	0.01	2009
22	Vascular calcification	31	0.02	2004
23	Angiogenesis	30	0.08	2003
24	Gene expression	28	0.02	2009
25	Activation	28	0.02	2012

The latent semantic indexing algorithm clustering of keywords through CiteSpace resulted in 11 clusters (Figure 7A), denoted as follows: #0 cell therapy; #1 oxidative stress; #2 MSCs; #3 MSCs; #4 human umbilical cord; #5 cell-based therapy; #6 VSMCs; #7 CVDs; #8 smooth muscle cells; #9 gold nanoparticles; and #10 thromboangiitis obliterans. An examination of the timeline graphs of these keyword clusters (Figure 7C and D) revealed that #1 oxidative stress and #3 MSCs are currently popular research topics.

DISCUSSION

AS is a chronic progressive vascular disease characterized by complex formation and pathogenic mechanisms. The initiation of AS is often attributed to intima-media injury, which can arise from a singular factor or a combination of factors, including hypertension, diabetes, infection, and smoking[38]. Following intimal injury, lipid components such as cholesterol and low-density lipoprotein (LDL) are deposited at the injury site, forming lipid plaques and thickening of the arterial wall[39]. Lipotoxicity can induce cellular dysfunction and cell death when lipids abnormally accumulate in nonadipose tissues[40]. Lipotoxicity can damage macrophages, leading to premature death of these phagocytes, as manifested by defective clearance of apoptotic cells[41-43]. The accumulation of residual apoptotic cells triggers chronic inflammation and leads to pathological states including AS[44,45]. Interestingly, residual apoptotic cell debris tends to be converted into lipid intermediates, further aggravating lipid deposition, forming a vicious cycle and producing an environment of persistent inflammation. Additionally, these substances undergo oxidation in the inflammatory milieu. Oxidized LDL not only damages the vascular endothelium but also triggers an immune response within the arteries. This immune response promotes monocyte migration and adhesion to endothelial cells[46], induces the production and release of proinflammatory cytokines, and induces persistent infiltration of immune cells into atherosclerotic plaques. Some monocytes further differentiate into diseased macrophages, contributing to the phagocytosis of oxidized lipids and the formation of foam cells[47-49]. To subsequently stabilize the progressively enlarging plaque, smooth muscle cells proliferate and generate collagen, forming a fibrous cap and a stiffer arterial wall. Ultimately, plaque rupture may occur in the arterial wall, leading to a serious vascular event[50,51]. AS encompasses a complex pathological process involving multiple components including intimal damage, inflammation, cholesterol deposition, fibrous tissue proliferation, and plaque rupture.

MSC transplantation technology has gradually emerged as a novel therapeutic approach. Additionally, insights from mechanobiology suggest that the therapeutic efficacy of MSCs can be further enhanced by manipulating mechanical forces at the cellular level[52]. Ongoing animal experimental studies have demonstrated that MSCs exert diverse effects, such as anti-inflammatory and lipid-lowering effects[53,54], promoting vascular repair[55], and enhancing plaque stability in an animal model of AS[56]. This innovative approach holds promise as a new avenue for AS treatment.

As mentioned above, MSC therapy has recently emerged as a novel treatment for AS. This study is the first bibliometric analysis of global studies on using MSC therapy for AS. We reviewed the literature on MSC therapy for AS in the last 20 years. China and the United States have greatly contributed to this field’s research. Libby P’s work is most prominent in terms of influence and citation, with Int J Mol Sci having a greater impact. Research hotspots have focused on vascular progenitor cells, inflammatory mechanisms and extracellular vesicles, and emerging research frontiers, such as cell vesicles and oxidative stress, have gradually attracted increasing attention. These findings provide researchers with a systematic and intuitive overview of general trends in the field.

Function of MSCs in AS

Regulation of vascular endothelial cells by MSCs: Bone marrow MSCs have the potential to regulate vascular endothelial progenitor cell homing repair or directly influence endothelial cell function. Transplantation of bone marrow MSCs has been shown to significantly increase the proliferation and migration of functional endothelial progenitor cells, thereby improving overall endothelial function[57-59]. Vascular endothelial cells, positioned as barriers between the vessel wall and bloodstream, play pivotal roles in maintaining vascular tone, regulating permeability, and engaging in biological responses, such as inflammation and immunity[59-61]. Additionally, coculturing bone marrow MSCs with ox-LDL-stimulated endothelial cells activates the endothelial nitric oxide synthase system, promoting nitric oxide production by increasing interleukin-8 (IL-8) and macrophage inflammatory protein-2 expression, thereby enhancing endothelial cell function[62]. Furthermore, bone marrow MSCs can activate the β-catenin-mediated Wnt signaling pathway through the secretion of Wnt proteins, subsequently reducing endothelial cell apoptosis by mitigating oxidative stress[63,64].

Lipid-lowering effects of MSCs: MSC transplantation effectively ameliorates dyslipidemia in a mouse model of AS[56]. Frodermann et al[65] conducted a study involving the transplantation of bone marrow MSCs into a constructed mouse model lacking the LDL receptor, significantly reducing serum cholesterol and LDL levels after four weeks. Zhang et al[66] transplanted gingival MSCs into ApoE-/- mice and reported decreased serum cholesterol and LDL levels. This lipid-lowering effect of MSCs may be attributed to the downregulation of the scavenger receptors SR-A1 and CD36, coupled with the upregulation of the cholesterol transporter-associated protein ATP-binding cassette transporter A1[66].

Impact of MSCs on inflammation and immunomodulation: In their study, Frodermann et al[65] established the pivotal role of MSC transplantation in inflammation and immunomodulation. MSCs can suppress proinflammatory factors, including tumor necrosis factor-α and IL-6[67], reducing chemokine C-C motif ligand 2 levels and circulating monocyte counts. Concurrently, MSCs increase the levels of anti-inflammatory cytokines such as transforming growth factor-β, IL-1, and IL-10[68]. In vitro investigations have demonstrated that MSCs sourced from diverse tissues (e.g., human gingiva and cardiac adipose tissue) can facilitate the reprogramming of macrophages from a proinflammatory phenotype (M1) to an anti-inflammatory phenotype (M2)[69-71]. The anti-inflammatory efficacy of adipose-derived MSCs has been attributed to the paracrine release of immunomodulatory factors[72].

T lymphocytes, which are pivotal in mediating the adaptive immune response in AS, are modulated by bone marrow MSCs. This modulation promotes the establishment of a favorable immune composition of T cells within atherosclerotic plaques, thereby stabilizing the plaques and reducing the risk of rupture[64]. Notably, regulatory T cells (Tregs) play essential roles in maintaining immune tolerance and homeostasis, as evidenced in several studies[73-75]. Bone marrow MSC transplantation has been shown to increase the production of IL-10, transforming growth factor-β, and prostaglandin E2 in atherosclerotic mice[76]. This intervention upregulates Foxp3 on the surface of CD4+ T lymphocytes, fostering Treg differentiation, increasing the proportion of Treg cells, and diminishing the ability of effector T cells to produce inflammatory cytokines in mice[77]. Additionally, in vitro studies have revealed that bone marrow MSCs inhibit T-cell proliferation by disrupting the cell cycle, suppressing the activation and proliferation of proinflammatory T helper type 1 and T helper type 17 cells and enhancing Treg activity[68], thereby establishing a favorable immune distribution in plaques and mitigating inflammatory responses.

Modulation of plaque stability by MSCs: The effect of MSCs on the stability of AS plaques has been thoroughly investigated. In a study conducted by Wang et al[67], bone marrow MSC transplantation in a rabbit AS model revealed a noteworthy reduction in inflammatory factors within plaques following a single MSC infusion. Furthermore, after four weeks of MSC treatment, the expression levels of nuclear factor-kappaB and matrix metalloproteinases (MMPs) were significantly diminished in plaques. MMPs, particularly MMP2 and MMP9, play crucial roles in late-stage AS by contributing to plaque formation through matrix degradation and rupture. Histological examination further demonstrated an increased presence of neoplastic endothelial cells, collagen fibers, and BrdU-positive cells within atherosclerotic plaques. Moreover, MSC microvesicles enhance plaque stability by suppressing the NLR family pyrin domain containing 3-mediated macrophage apoptosis[78].

Investigations into stem cell therapy for atherosclerotic diseases have focused predominantly on bone marrow MSCs. These cells are widely accessible and amenable to isolation and cultivation. However, understanding the various factors influencing the biological function of bone marrow MSCs remains an ongoing endeavor that requires further elucidation. Comparative studies evaluating bone marrow MSCs from different sources with variations in their immune and inflammatory regulatory capacities are essential for their application in AS treatment. Additionally, while recent studies have underscored the pivotal paracrine role of bone marrow MSCs[79,80], research on specific molecules such as peptides, small noncoding RNAs, or other bioactive products is lacking, indicating a potential avenue for novel therapeutic approaches.

A vision for the future

Despite notable advancements in applying MSC therapies to treat atherosclerotic vascular disease, much of the research remains in the early clinical trial stages[81,82], and significant challenges persist in achieving clinical translation. Primarily, the inherent limitations of animal models in fully mirroring the human condition cast uncertainty on the translational efficacy of stem cell-based therapies on the basis solely of animal findings. Furthermore, the clinical effectiveness of these therapies is contingent on several factors, including safety, cell viability, cell source, administration frequency, and delivery route. While current research has predominantly emphasized the potential benefits, aspects such as safety, side effects, and long-term therapeutic viability have received comparatively less attention. Consequently, further investigation is imperative to advance the clinical implementation of this promising technology.

Limitations of this study

Nevertheless, there are certain limitations associated with this study. First, owing to the limitations of CiteSpace software, the literature search scope of this study was limited to the WoSCC database. This may have resulted in omitting some articles, causing potential selection bias and analysis error. Additionally, we included only papers written in English and excluded a small number of papers published in other languages. Finally, the dynamic nature of new research means that influential and recently published studies may not have been fully considered. In future research, we will further analyze and interpret the data by using other tools, supplementing new studies, etc.

CONCLUSION

MSCs have important research value and wide application prospects in the field of atherosclerotic diseases. With the help of bibliometric and visual analyses, we identified global research trends in MSC therapy for atherosclerotic vascular disease over the past two decades. Our comprehensive review helps researchers identify key authors, journals, and potential collaborators, offering insights into research hotspots. Notably, the keywords and locality clustering analysis highlighted pivotal research frontiers, particularly emphasizing “oxidative stress” and “extracellular vesicles”. Analyzing these results will help researchers understand the current state of research and provide promising directions for future research to ultimately achieve meaningful clinical outcomes. Future research should pay more attention to the different aspects of MSC therapy for AS, aiming to achieve early clinical conversion, improve the quality of life and prolong the survival time of patients.