Bibliometrics of trends in global research on the roles of stem cells in myocardial fibrosis therapy

Abstract

BACKGROUND

Myocardial fibrosis, a condition linked to several cardiovascular diseases, is associated with a poor prognosis. Stem cell therapy has emerged as a potential treatment option and the application of stem cell therapy has been studied extensively. However, a comprehensive bibliometric analysis of these studies has yet to be conducted.

AIM

To map thematic trends, analyze research hotspots, and project future directions of stem cell-based myocardial fibrosis therapy.

METHODS

We conducted a bibliometric and visual analysis of studies in the Web of Science Core Collection using VOSviewer and Microsoft Excel. The dataset included 1510 articles published between 2001 and 2024. Countries, organizations, authors, references, keywords, and co-citation networks were examined to identify evolving research trends.

RESULTS

Our findings revealed a steady increase in the number of publications, with a projected increase to over 200 publications annually by 2030. Initial research focused on stem cell-based therapy, particularly for myocardial infarction and heart failure. More recently, there has been a shift toward cell-free therapy, involving extracellular vesicles, exosomes, and microRNAs. Key research topics include angiogenesis, inflammation, apoptosis, autophagy, and oxidative stress.

CONCLUSION

This analysis highlights the evolution of stem cell therapies for myocardial fibrosis, with emerging interest in cell-free approaches. These results are expected to guide future scientific exploration and decision-making.

Key Words: Stem cells; Myocardial fibrosis; Cardiovascular diseases; VOSviewer; Bibliometrics

Core Tip: This study presents a comprehensive bibliometric analysis of stem cell-based therapies for myocardial fibrosis from 2001 to 2024, highlighting significant trends and emerging research directions. The analysis reveals a growing interest in cell-free therapies, including extracellular vesicles, exosomes, and microRNAs. The focus of research is shifting from angiogenesis, inflammation, apoptosis, autophagy, and oxidative stress to autophagy. These findings provide valuable insights into future research priorities in myocardial fibrosis treatment.

INTRODUCTION

Cardiovascular diseases (CVDs) are the leading causes of morbidity and mortality worldwide and account for a significant portion of healthcare costs[1,2]. The CVD incidence and prevalence are increasing worldwide. The number of CVD cases has risen from 271 million in 1990 to 775 million in 2022, and CVD-related deaths have increased from 12.1 million in 1990 to 19.8 million in 2022. It is estimated that this number could reach 24.0 million by 2030[3-5].

Myocardial fibrosis is linked to a number of CVDs and conditions, including myocardial infarction (MI), heart failure (HF), hypertension, viral myocarditis, hypertrophic cardiomyopathy, and cardiomyopathies[6-11]. Myocardial fibrosis is a common wound-healing response that occurs following cardiac tissue stress or injury; it is characterized by an imbalance in the extracellular matrix[12,13]. Myocardial fibrosis occurs when fibroblasts become myofibroblasts in the injured heart in order to repair damage; however, excessive myocardial fibrosis reduces heart function and leads to HF with a poor prognosis[14,15]. As standard drugs or surgery cannot repair damaged myocardial tissue or reverse cardiac fibrosis, there is currently no treatment for myocardial fibrosis[16,17]. In this context, stem cells, which have the potential to differentiate into myocardial cells, have emerged as a promising treatment option for myocardial fibrosis[18-20]. The effects of stem cell therapy include attenuated remodeling, improved global and regional functions, decreased scar size, and increased myocardium viability[21].

In bibliometric analyses, the quality and quantity of scientific literature are evaluated. This approach is used in conjunction with mathematical and statistical techniques to identify emerging trends, knowledge structures, research hotspots, research trends, and future research directions as well as to develop clinical guidelines[22]. Here, using a bibliometric approach, we retrieved publications from the Web of Science database between 2001 and 2024 to explore trends and potential research hotspots related to stem cells and myocardial fibrosis therapy.

MATERIALS AND METHODS

Data sources and search strategy

The data were obtained from the Web of Science Core Collection (WOSCC), a curated collection of high-quality scientific information. Studies published from the inception of the database until 2024 were included. All journals that were included were selected for coverage, and details, such as authors, abstracts, keywords, and cited references, were recorded for each paper. When using the Web of Science database, “TS” will return the title, abstract, and author keywords within a record. The search strategy was as follows: “(TS = (cardiac fibrosis OR myocardium fibrosis OR myocardial fibrosis OR endomyocardial fibrosis OR endocardial fibrosis OR heart fibrosis)) AND TS = (stem cell* OR bone marrow OR stromal cell* OR mother cell*)”. Retrieval was completed on June 15, 2024. Only articles and reviews in English were included.

Data analysis and presentation

For the bibliometric analysis, the retrieved publications were imported into VOSviewer version 1.6.18[23] (Science and Technology Research Center, Leiden University, Leiden, The Netherlands) and Microsoft Excel 2019. Maps for visualization were created using VOSviewer, and the countries, organizations, authors, references, and keywords were captured.

RESULTS

Temporal publication trends

A total of 3088 studies on myocardial fibrosis and stem cells published prior to June 15, 2024 were retrieved from the WOSCC. After eliminating inappropriate articles, 1510 publications meeting the inclusion criteria were retained. Among them, 280 (18.5%) were reviews and 1230 (81.5%) were original studies. As shown in Figure 1, there was a general upward trend in the number of publications in the field. However, a change in the trend was observed in 2007. Before 2007, the number of publications annually grew slowly; thereafter, despite an occasional decline, the number of publications per year grew rapidly overall (Figure 1A; the solid line represents the annual quantitative distribution, and the dotted line represents the polynomial fitting function). The curve could be fitted by the equation y = 0.06 × (x - 2000)² + 5.3658 × (x - 2000) - 12.108 (the Y-axis represents the number of articles and the X-axis represents the year). If the current trend continues, the number of publications will exceed 200 annually in 2030. The increase in the number of articles published annually suggests that researchers are placing increasing emphasis on this topic (Figure 1B).

Figure 1 Publication output for myocardial fibrosis and stem cells. A: Annual quantitative distribution of publications (the solid line) and the polynomial fitting function (the dotted line). Y-axis represents the number of articles and X-axis represents the year; B: Cumulative number of publications by year.

Countries

We utilized a geographic visualization analysis (Figure 2A) to investigate the global distribution of studies. Articles identified in the literature search were published in 63 countries. When generating a country collaboration map using VOSviewer, we set the minimum number of documents published by a country to three. In total, 40 countries met the thresholds and were included in the analysis. The United States had the most publications (529, 35.03%), followed by China (478, 31.66%) and Japan (118, 7.81%) (Table 1). There were three times more citations of articles in the United States (30060) than those in China (9811), indicating that the United States had a greater influence than that of China. For example, the article “Bone marrow cells regenerate infarcted myocardium” published in 2001 in Nature from the United States had an impact factor (IF) of 50.5 and citations of 4956 citations across all databases. This study represents a major milestone in the field, demonstrating that the transplantation of bone marrow cells into infarcted mice has the potential to regenerate myocardial tissue, thereby improving outcomes in coronary artery disease[24]. In addition, the total link strength of the United States was 296, ranking first in partnerships with 43 countries, indicating extensive cooperation between researchers in the United States and other countries. The United States had the closest cooperation with China.

Figure 2 Contributions of countries/regions, contributions and collaborations between organizations, and contributions and collaborations of authors in myocardial fibrosis and stem cell research. A: Contributions of countries/regions in myocardial fibrosis and stem cell research. The colors represent different clusters of collaborative relationships, with countries/regions of the same color being more closely connected. The scale of the labels indicates the number of publications, with larger labels representing a higher volume of publications; B: Contributions and collaborations between organizations in myocardial fibrosis and stem cell research. The colors represent different clusters of collaborative relationships, with organizations of the same color being more closely connected. The scale of the labels indicates the number of publications, with larger labels representing a higher volume of publications; C: Contributions and collaborations of authors in myocardial fibrosis and stem cell research. The colors represent different clusters of collaborative relationships, with authors of the same color being more closely connected. The scale of the labels indicates the number of publications, with larger labels representing a higher volume of publications.

Table 1 Top 10 countries with the most publications in myocardial fibrosis and stem cell research.

Rank	Country	Publications (%)	Citations	Total link strength
1	United States	529 (35.03)	30060	280
2	China	478 (31.66)	9811	151
3	Japan	118 (7.81)	4970	48
4	Germany	99 (6.56)	4147	97
5	Italy	82 (5.43)	2245	74
6	United Kingdom	66 (4.37)	3035	68
7	Canada	65 (4.30)	3804	37
8	France	60 (3.97)	1734	59
9	South Korea	47 (3.11)	1508	18
10	Spain	47 (3.11)	1664	40

Organizations and collaborations

A total of 1907 organizations conducted studies on the role of stem cells in myocardial fibrosis therapy. When generating an organization collaboration map using VOSviewer, we set the minimum number of documents published by an organization to 12. In total, 43 organizations met the thresholds and were included in the analysis. Among the top 10 organizations, five were from China, four were from the United States, and one was from Japan. Osaka University (Japan) had the most publications in this research area (i.e., 32 papers), followed by Zhejiang University (China) with 29 papers and Nanjing Medical University (China) with 28 papers (Figure 2B and Table 2). Harvard University had 4308 citations, ranking first among the top 10 organizations with the highest number of publications, thus demonstrating a substantial impact on the field. In 2009, Harvard University published an article titled “Growth factors, matrices, and forces combine and control stem cells” in Science (IF: 44.7, cited: 2455), highlighting the key roles of stem cells in the repair and homeostasis of myocardial fibrosis[25]. In terms of collaboration, the Chinese Academy of Medical Sciences collaborated most frequently with Peking Union Medical College. Emory University collaborated closely with the Georgia Institute of Technology, and Nanjing Medical University collaborated closely with Nanjing University. National institutions frequently collaborated; however, international collaborations were limited and should be strengthened in the future.

Table 2 Top 10 organizations in myocardial fibrosis and stem cell research.

Rank	Organization	Country	Documents	Citations	Total link strength
1	Osaka University	Japan	32	934	3
2	Zhejiang University	China	29	495	10
3	Nanjing Medical University	China	28	542	20
4	Soochow University	China	26	867	6
5	Temple University	United States	26	930	16
6	Harvard University	United States	25	4308	18
7	The Ohio State University	United States	22	669	5
8	Sun Yat-sen University	China	20	544	15
9	University ff Cincinnati	United States	20	1345	9
10	Chinese Academy of Medical Sciences	China	19	452	19

Co-authors and co-cited authors

A total of 9623 authors were involved in research on myocardial fibrosis and stem cells. When generating an author collaboration map using VOSviewer, we set the minimum number of documents published by an author to six. In total, 97 authors met the thresholds and were included in the analysis. Seven of the top 10 co-authors were from the United States, two from Japan, and one from China. Yoshiki Sawa from Osaka University, Japan, had the highest number of publications at 27, followed by Shigeru Miyagawa (Japan) with 25 publications and Zhen-Ya Shen (China) with 15 publications (Table 3). Figure 2C shows a network visualization map; co-authors often had stable collaborative relationships and formed research groups with similar research directions.

Table 3 Top 10 authors in myocardial fibrosis and stem cell research.

Rank	Author	Country	Affiliation	Documents	Total link strength
1	Yoshiki Sawa	Japan	Osaka University	27	61
2	Shigeru Miyagawa	Japan	Osaka University	25	61
3	Zhen-Ya Shen	China	Soochow University	15	22
4	Dinender K Singla	United States	University of Central Florida	15	0
5	Wei Huang	United States	University of Cincinnati Medical Center	14	34
6	Yi-Gang Wang	United States	University of Cincinnati Medical Center	13	30
7	Muhammad Ashraf	United States	University of Cincinnati Medical Center	12	25
8	Er-He Gao	United States	Temple University	12	11
9	Raj Kishore	United States	Temple University	12	17
10	Michael E Davis	United States	Emory University	11	8

A multi-person team from the Osaka University Graduate School of Medicine included leaders in the field (e.g., Yoshiki Sawa and Shigeru Miyagawa). Their research concentrated on discovering innovative methods to boost regeneration, reduce fibrosis, and improve functional recovery in various heart diseases. They found that transplanting stem cell sheets into the host myocardium effectively reduced fibrosis, attenuated ventricular remodeling, promoted stem cell migration, and enhanced neovascularization in the endocardium[26-29]. Additionally, they demonstrated the therapeutic effects and preservation of heart function through the use of mesenchymal stem cells (MSCs) in vivo[30-32]. However, cooperation in this field was mostly limited to authors within the same institution, with a lack of collaborations among authors globally.

Author co-citation refers to the simultaneous citation of an article by two or more authors. When generating a co-cited author network using VOSviewer, we set the minimum number of citations of a co-cited author to 45. In total, 120 co-cited authors met the thresholds and were included in the analysis. The top 10 co-cited authors included seven from the United States, one from Italy, one from France, and one from the United Kingdom. Nikolaos G Frangogiannis from the Albert Einstein College of Medicine (United States) ranked first (302 citations), followed by Massimiliano Gnecchi (248 citations) from the University of Pavia (Italy), and Donald Orlic (164 citations) from the National Human Genome Research Institute/National Institutes of Health (United States) (Figure 3A and Table 4).

Figure 3 Distribution of co-cited authors, journals, co-cited journals, and co-cited references in myocardial fibrosis and stem cell research. A: Distribution of co-cited authors in myocardial fibrosis and stem cell research. The colors represent different clusters of collaborative relationships, with co-cited authors of the same color being more closely connected. The scale of the labels indicates the number of citations, with larger labels representing a higher volume of citations; B: Distribution of journals in myocardial fibrosis and stem cell research. The colors represent different clusters of collaborative relationships, with journals of the same color being more closely connected. The scale of the labels indicates the number of publications, with larger labels representing a higher volume of publications; C: Distribution of co-cited journals in myocardial fibrosis and stem cell research. The colors represent different clusters of collaborative relationships, with co-cited journals of the same color being more closely connected. The scale of the labels indicates the number of citations, with larger labels representing a higher volume of citations; D: Distribution of co-cited references in myocardial fibrosis and stem cell research. The colors represent different clusters of collaborative relationships, with co-cited references of the same color being more closely connected. The scale of the labels indicates the number of citations, with larger labels representing a higher volume of citations.

Table 4 Top 10 co-cited authors in myocardial fibrosis and stem cell research.

Rank	Author	Country	Affiliation	Citations
1	Nikolaos G Frangogiannis	United States	Albert Einstein College of Medicine	302
2	Massimiliano Gnecchi	Italy	University of Pavia	248
3	Donald Orlic	United States	National Human Genome Research Institute/NIH	164
4	Philippe Menasché	France	Université Sorbonne Paris Cité	141
5	Joshua M Hare	United States	University of Miami Miller	129
6	Antonio Paolo Beltrami	United Kingdom	University of Bristol	121
7	Roberto Bolli	United States	University of Louisville	120
8	Dinender K Singla	United States	University of Central Florida	113
9	Mark F Pittinger	United States	University of Maryland	108
10	Elisabeth M Zeisberg	United States	Harvard Medical School	102

Notably, Singla was in the top 10 co-authors and top 10 co-cited authors, implying that he has a major influence in this field. He analyzed the roles of stem cells and exosomes in cardiac repair and discovered that transplantation alone does not significantly enhance cardiac function. Furthermore, he found that factors secreted by stem cells play a crucial role in reducing apoptosis and fibrosis[33]. Singla[34] concluded that exosomes derived from stem cells exhibit significant anti-apoptotic, anti-fibrotic, and pro-angiogenic potential and enhance cardiac differentiation to repair damaged tissue.

Distribution of journals and co-cited journals

The articles included in this study were published in 489 journals. When generating a journal network using VOSviewer, we set the minimum number of documents published in a journal to five. In total, 63 journals met the thresholds and were included in the analysis. The distribution of journals is shown in Figure 3B, and the top 10 journals are listed in Table 5. The most productive journal was Circulation Research, with 48 papers, followed by International Journal of Molecular Sciences (45 papers) and Stem Cell Research & Therapy (41 papers). Circulation had the highest average IF among the top 10 journals (35.5), followed by Circulation Research (16.5) and Cardiovascular Research (10.2).

Table 5 Top 10 journals in myocardial fibrosis and stem cell research.

Rank	Journal	IF	JIF quartile	Documents
1	Circulation Research	16.5	Q1	48
2	International Journal of Molecular Sciences	4.9	Q1	45
3	Stem Cell Research & Therapy	7.1	Q1	41
4	PLoS One	2.9	Q1	40
5	Cardiovascular Research	10.2	Q1	30
6	Circulation	35.5	Q1	30
7	Journal of Molecular and Cellular Cardiology	4.9	Q2	29
8	American Journal of Physiology-Heart and Circulatory Physiology	4.1	Q1	24
9	Frontiers in Cardiovascular Medicine	2.8	Q2	22
10	Frontiers in Cell and Developmental Biology	4.6	Q2	22

IF: Impact factor; JIF: Journal Impact Factor.

A citation analysis can be used to evaluate journal importance, which depends primarily on the number of citations. When generating a co-cited journal network using VOSviewer, we set the minimum number of citations of a co-cited journal to 150. In total, 113 co-cited journals met the thresholds and were included in the analysis. The top 10 journals with the highest number of co-citations are summarized in Table 6. All of the top 10 co-cited journals were cited more than 1000 times. Circulation ranked first with the most citations (5091), followed by Circulation Research (4977) and Nature (1938). Among the top 10 co-cited journals, Nature had the highest average IF of 50.5, followed by Circulation (35.5) and Journal of the American College of Cardiology (21.7). According to the journal IF quartile analysis, the majority of the top 10 cited journals and top 10 co-cited journals were distributed in the Q1 region (Figure 3C).

Table 6 Top 10 co-cited journals in myocardial fibrosis and stem cell research.

Rank	Co-cited journal	Citations	IF	JIF quartile	Total link strength
1	Circulation	5091	35.5	Q1	373781
2	Circulation Research	4977	16.5	Q1	397335
3	Nature	1938	50.5	Q1	169834
4	Proceedings of the National Academy of Sciences of the United States of America-Physical Sciences	1890	9.04	Q1	162817
5	Cardiovascular Research	1832	10.2	Q1	148737
6	Journal of the American College of Cardiology	1754	21.7	Q1	140925
7	Journal of Molecular and Cellular Cardiology	1694	4.9	Q2	134825
8	PLoS One	1552	2.9	Q1	142529
9	Journal of Clinical Investigation	1438	13.3	Q1	124120
10	American Journal of Physiology-Heart and Circulatory Physiology	1311	4.1	Q1	99389

IF: Impact factor; JIF: Journal Impact Factor.

Co-cited references

Two papers establish a co-citation relationship when they appear simultaneously on the reference list of a third paper. Frequently co-cited references indicate the status of development in the research field and can provide advanced support and guidance for scientific decision-making. When generating a co-cited reference network using VOSviewer, we set the minimum number of citations of a co-cited reference to 25. In total, 130 co-cited references met the thresholds and were included in the analysis. The most co-cited article “Bone marrow cells regenerate infarcted myocardium” was published in Nature in 2001 and had 109 citations[24]. This study revealed that lineage-negative (Lin)^- c-kit^POS cells can generate new myocardial tissue in the infarcted area of the ventricle. Next, the co-cited article “Adult cardiac stem cells are multipotent and support myocardial regeneration” was published in Cell in 2003 and had 97 citations[35]. This paper also demonstrated that Lin^- c-kit^POS cells have self-renewal properties, clonogenic capacity, and multipotency and opened new opportunities for myocardial repair. The third top co-cited article “Paracrine mechanisms in adult stem cell signaling and therapy” in Circulation Research was published in 2008 and had 85 citations[36]. The contributions and mechanisms of stem cell-paracrine signaling in cardiac repair and regeneration were reviewed in this article. In addition, two articles among the top five co-cited references were published by Massimiliano Gnecchi[36,37], further supporting his contributions and influence in the field (Figure 3D and Table 7).

Table 7 Top 10 co-cited references with the most citations in myocardial fibrosis and stem cell research.

Rank	Title	First author	Journal	IF	Publication year	Citations
1	Bone marrow cells regenerate infarcted myocardium	Donald Orlic	Nature	50.5	2001	109
2	Adult cardiac stem cells are multipotent and support myocardial regeneration	Antonio P Beltrami	Cell	45.5	2003	97
3	Paracrine mechanisms in adult stem cell signaling and therapy	Massimiliano Gnecchi	Circulation Research	16.5	2008	85
4	Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts	Abeel A Mangi	Nature Medicine	58.7	2003	77
5	Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells	Massimiliano Gnecchi	Nature Medicine	58.7	2005	75
6	Endothelial-to-mesenchymal transition contributes to cardiac fibrosis	Elisabeth M Zeisberg	Nature Medicine	58.7	2007	70
7	Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart	Catalin Toma	Circulation	35.5	2002	66
8	Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement	Massimo Dominici	Cytotherapy	3.7	2006	66
9	Multilineage potential of adult human mesenchymal stem cells	Mark F Pittenger	Science	44.7	1999	66
10	Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury	Ruenn Chai Lai	Stem Cell Research	0.8	2010	64

IF: Impact factor.

Keywords

Different versions of words with the same meaning were combined, such as synonyms (e.g., “engraftment” and “transplantation”), different spelling and hyphenation (e.g., “myocardial-infarction” and “myocardial infarction”), abbreviated terms (e.g., “MSCs” and “mesenchymal stem cells”), and singular/plural terms (e.g., “pathway” and “pathways”), for the analysis of keywords. When generating a keyword network using VOSviewer, we set the minimum number of occurrences of a keyword to 30. In total, 64 keywords met the thresholds and were included in the analysis. The top 20 keywords in this study are listed in Table 8. Among the top 20 keywords, “myocardial infarction” and “heart failure” were associated with heart disease; “mesenchymal stem cells”, “exosome”, “bone marrow”, “extracellular vesicles”, and “miRNA” were associated with stem cell therapy; and “angiogenesis”, “inflammation”, “apoptosis”, “autophagy”, and “oxidative stress” were associated with the mechanism of myocardial fibrosis and stem cell therapy.

Table 8 Top 20 keywords related to myocardial fibrosis and stem cell research.

Rank	Keyword	Occurrences	Average appearing year
1	Myocardial infarction	532	2016.69
2	Mesenchymal stem cells	383	2016.85
3	Heart failure	301	2016.82
4	Angiogenesis	258	2015.52
5	Progenitor cells	182	2015.55
6	Inflammation	180	2018.28
7	Cardiomyocytes	160	2016.38
8	Apoptosis	148	2016.86
9	Exosomes	146	2020.77
10	Acute myocardial infarction	125	2016.85
11	Bone marrow	123	2014.54
12	Cardiac function	102	2016.23
13	Hypertrophy	101	2015.93
14	Extracellular vesicles	99	2021.16
15	Fibroblasts	99	2017.80
16	Autophagy	93	2019.15
17	Oxidative stress	93	2017.59
18	Endothelial progenitor cells	85	2014.65
19	Cardiomyopathy	79	2016.71
20	miRNA	78	2018.73

miRNA: MicroRNA.

Keywords with different average appearing years were used to create an overlay visualization map (Figure 4). Early research focused on the effects of stem cell-based therapies (such as stem cell transendocardial injections, cell infusions, cell sheets, and cell patches). With the development of new treatment methods for heart diseases, cell-free therapy with the extracellular vesicle (EV)-mediated transfer of exosomes and selected microRNAs (miRNAs) between stem cells and fibrotic tissues has gained attention. In early research, the most commonly studied mechanisms were angiogenesis, inflammation, apoptosis, and oxidative stress; however, autophagy gained increasing attention in later studies.

Figure 4 Overlay visualization map of co-occurring keywords related to myocardial fibrosis and stem cells. The colors reflect the research activity or development stages over time, with early studies typically shown in blue and more recent ones in yellow. The scale of the labels indicates the number of occurrences, with larger labels representing a higher volume of occurrences.

DISCUSSION

Basic information

In this study, we used bibliometric mapping to analyze several parameters, including countries, organizations, references, and keywords, providing insight into the current direction of research on stem cells in myocardial fibrosis and predicting future trends[38]. The growing number of publications observed in this study indicates that stem cell therapies for myocardial fibrosis have become a significant focus of research. The United States, China, and Japan contributed the most papers to this field. In particular, the United States had a major impact, with several landmark articles[24,25,39]; it ranked first in total citations, with three times more citations than those for the second-ranked country. There is already significant collaboration within institutions and across the country. However, moving forward, there is a pressing need to bolster international partnerships to address global challenges more effectively.

Yoshiki Sawa, the most prolific author, found that transplanting stem cell sheets into the myocardium improves myocardial fibrosis, reduces remodeling, induces stem cell migration, and increases neovascularization[26-29]. Dinender K Singla is among the top 10 prolific authors and top 10 co-cited authors, indicating his substantial influence in this field. Singla[34] evaluated the roles of stem cells and exosomes in cardiac repair and found that while transplantation does not significantly improve heart function, substances secreted by stem cells inhibit apoptosis and fibrosis[33]. He also discovered that stem cell-derived exosomes enhance cardiac differentiation and repair injured tissues, in addition to their anti-apoptotic, anti-fibrotic, and pro-angiogenic properties.

Myocardial diseases

The keyword analysis indicated that myocardial fibrosis is closely related to two myocardial conditions: MI and HF. MI naturally causes myocardial fibrosis when fibroblasts transform into myofibroblasts, characterized by an imbalance in extracellular matrix synthesis, deposition, and degradation[12,13]. Initially, fibrotic tissue repairs the damaged part of the heart and protects it from rupture; however, the progression of myocardial fibrosis reduces heart function, leading to HF and a poor prognosis[14,15]. Preclinical studies have also implicated myocardial fibrosis in the pathophysiology of HF[40-44], resulting from the persistent exacerbation of myocardial fibers, recurrent myocardial ischemia, and hypoxia[45]. In patients with a preserved ejection fraction, myocardial fibrosis in HF is associated with high mortality and hospitalization rates[46]. In a cohort study, a highly modified Look-Locker inversion recovery-extracellular volume, reflecting diffuse myocardial fibrosis, was independently associated with a higher rate of first HF hospitalization and a poor HF prognosis during a 9-month follow-up[47]. These two diseases are also the primary conditions that stem cell therapy seeks to treat.

Stem cell therapy in myocardial fibrosis

Stem cells possess regeneration potential and can differentiate into smooth muscle cells, endothelial cells, and cardiomyocytes (CMs)[18,19]. In ischemic cardiomyopathy (ICM), a combination of simultaneous revascularization and stem cell therapy appears to be the most effective approach to date for halting the progression of HF after MI[48]. The keyword analysis identified several stem cell types used to treat myocardial fibrosis, including MSCs[31,49,50] and bone marrow-derived stem cells (BMCs)[51-53]. These stem cells attenuate CVD, alleviate myocardial fibrosis, and contribute to cardiac functional recovery[54,55]. MSC injections stimulated neoangiogenesis, increased contractility, reduced fibrosis, and enhanced the quality of life in patients with chronic ICM in several clinical trials[52,56-59]. Intramyocardial MSC injection in patients reduced infarct size, indicating an improvement in myocardial fibrosis[60]. The improvements in regional contractility in the scarred myocardium were followed by reverse remodeling, evidenced by decreased end-diastolic and end-systolic volumes[60]. Transendocardial injection of either 20 million or 100 million allogeneic human MSCs (hMSCs) in 30 patients reduced scar size; however, the higher dose resulted in a greater improvement in cardiac function than that for the lower dose[61]. These findings suggest that MSC therapy may help in the treatment of myocardial fibrosis and lead to better structural recovery and cardiac function in the infarcted myocardium. Consequently, among all types of stem cells, MSCs are emerging as the most promising for treating heart diseases[62,63]. Intracoronary autologous transplantation of BMCs has been found to increase ventricular contractility and restore contractile function to previously nonviable scars[64]. In addition, infarct size reduction and alleviation of cardiac fibrosis have been observed[51,53,65]. Importantly, in a clinical trial, BMC transplantation has not been shown to produce aberrant cardiac rhythms in humans[52], and preoperative mobilization of BMCs followed by revascularization surgery has been deemed safe[66]. In the phase 3 randomized controlled trial PERFECT study, bone marrow hematopoietic stem cells, through SH2B3/LNK gene manipulation, significantly improved myocardial repair and preserved cardiac function, possibly by reducing left ventricular fibrosis[67]. However, mixed results have been obtained. In a single-blind randomized controlled trial, intracoronary autologous MSC transplantation did not improve cardiac function significantly following acute MI[68]. Additionally, low engraftment rates[69,70] and concerns over tumorigenic potential[71] have limited the therapeutic applicability of stem cells for CVD.

Stem cell-free therapy in myocardial fibrosis

The overlay visualization of co-occurring keywords showed that early regeneration research focused on cell-based therapies, such as stem cell injections[72-75], cell infusions[76], cell sheet transplantations[77-79], and cell patches[80]. Recently, stem cell-free therapies, including exosome-, EV-, and miRNA-based therapies, have emerged as candidate therapeutic approaches for myocardial fibrosis. Stem cell-free therapy can avoid some risks of tumor formation[81], as it exerts indirect effects. Stem cell-derived EVs include microvesicles and exosomes, which are cell-derived membrane structures originating from the endosomal system or the plasma membrane[82,83]. There is growing preclinical evidence that stem cells (such as BMCs, MSCs, and human induced pluripotent stem cells) protect against cardiomyopathy through paracrine mechanisms rather than direct differentiation into CMs or new cardiac muscle[84-87]. In a randomized dose-finding clinical trial, transendocardial MSC injections in patients with ICM demonstrated that lower doses lead to more significant improvements in cardiac function and infarct size[88]. The beneficial effect is believed to be linked to reduced myocardial fibrosis and the increased release of paracrine factors.

Exosomes play significant roles in the diagnosis[89,90] and therapy[91-94] of myocardial fibrosis and are promising biotherapeutics and drug delivery vectors[95]. Following cardiac injury, exosomes derived from exogenous stem cells regulate apoptosis, proliferation, angiogenesis, and fibrosis in the infarcted heart[96]. The release of paracrine factors from stem cells creates functional microvascular networks with red blood cell perfusion, which protects the myocardium and may contribute to the mechanism underlying the repair of damaged myocardial tissues[97]. Hypoxia-inducible factor-1 overexpression in exosomes from MSCs decreased myocardial fibrosis by promoting neovessel development in rats with MI[98]. Furthermore, a minimally invasive spray based on MSC exosomes and biomaterials was used to minimize myocardial fibrosis in a rat model of acute MI[99]. Citro et al[100] suggested that hMSCs and human induced pluripotent stem cell-CMs exhibit potent autocrine and paracrine mechanisms that promote cardiac function and prevent myocardial fibrosis in male athymic nude rats. Cell-free therapies and stem cell-mediated paracrine signaling could be significant breakthroughs in the development of cardiac fibrosis treatments. In addition, the concept of selective miRNA transmission between cells via stem cell-derived EVs, which shuttle miRNAs between cells, is appealing[101-103]. MSCs partially reduced MI size by delivering cytoprotective miRNAs[104]. EVs containing several antifibrotic and cardiac-specific miRNAs reversed the phenotype of activated fibroblasts in vitro, reduced fibrosis in vivo, and improved overall cardiac function[105].

Pathological mechanisms underlying myocardial fibrosis and stem cell therapy

As shown in Table 8, the current focal areas of research on the mechanisms related to the pathogenesis and development of myocardial fibrosis include “angiogenesis”, “inflammation”, “apoptosis”, “autophagy”, and “oxidative stress”. Stem cell therapy can counteract multiple pathological mechanisms during the regeneration of myocardial cells, thereby improving myocardial fibrosis and cardiac function.

Angiogenesis refers to the formation of new blood vessels from pre-existing vessels during the early stage of vasculogenesis[106]. Ischemic CVD is associated with angiogenesis and has been treated using angiogenic strategies[107,108]. Certain cell populations, including cardiac-resident macrophages[109], heterogeneous podoplanin-expressing cells[110], and natural killer cells[111], can promote angiogenesis while also inhibiting fibrosis in ischemic heart disease. EVs and exosomes secreted by stem cells can alleviate myocardial fibrosis and improve cardiac function by enhancing angiogenesis[112-114]. However, emerging evidence suggests that a vigorous angiogenic response often results in fibrosis due to a high apoptosis burden[115-118]. Consequently, stem cell therapy may exert only moderate pro-angiogenic effects.

An injectable oxidized hyaluronic acid-polylysine hydrogel was developed to conveniently load adipose-derived MSC exosomes. These exosomes attenuated inflammation in the early phase of MI and, in the later stage, reduced myocardial fibrosis, promoted angiogenesis, and restored electrophysiological function[119]. Reducing inflammation creates a more suitable environment for stem cell therapy, increasing graft cell numbers and thereby treating myocardial fibrosis more effectively[120,121].

Apoptosis is regulated at the genetic level, ensuring the efficient and orderly removal of damaged cells[122]. Cardiac apoptosis plays an important role in the formation of fibrotic scars and severe impairment of heart function[123,124]. Transplanting hMSCs and endothelial colony-forming cells into NOD/SCID mice with acute MI decreased CM apoptosis significantly, which was associated with significant reductions in scar size, myocardial fibrosis, and cardiac remodeling, ultimately improving cardiac function during rehabilitation[125]. Transplanting MSCs with molecular capsules significantly improved the cardiac microenvironment, increased the survival of transplanted cells, promoted angiogenesis, reduced CM apoptosis, and decreased myocardial fibrosis, thereby enhancing cardiac repair[126].

Myocardial ischemia can stimulate autophagy, an intracellular bulk degradation process of cytoplasmic components that leads to cell death[127,128]. While moderate autophagy can protect cardiac myocytes[127-129], excessive autophagy contributes to the progression of myocardial fibrosis[130-134]. Several studies have demonstrated that inhibiting autophagy in CMs can protect the heart from hypertrophy and fibrosis[131,135-139]. In vivo, pretreatment with bradykinin prior to human cardiac progenitor cell transplantation effectively promoted cardiac function and reduced myocardial fibrosis[140]. Bradykinin suppressed H₂O₂-induced cell autophagy by increasing P62 expression while decreasing Beclin1, ATG5, and LC3II/I expression[140].

In rats, inhibiting oxidative stress can alleviate HF and myocardial fibrosis[141]. When sirtuin3-overexpressing hMSCs, which have increased antioxidant capacity, were transplanted into adult rats with MI, the infarct size diminished, the number of apoptotic cells decreased, cardiac function improved, and the survival rate of transplanted cells increased[142]. MSCs exhibit high oxidative stress resistance by regulating the redox microenvironment, which involves increasing heme-oxygenase-1 expression, decreasing the 8-OHdG concentration in tissues, and inhibiting reactive oxygen species-induced apoptosis[143-146]. In our study, the map of co-occurring keywords revealed that early research on the pathogenesis of myocardial fibrosis primarily focused on angiogenesis, inflammation, apoptosis, and oxidative stress. Recently, an increasing number of studies have focused on autophagy to uncover the mechanisms of action and targets of stem cell therapy.

Strengths and limitations

This is the first bibliometric study of stem cell therapy and myocardial fibrosis. Our visual analysis provides insights into research hotspots and developmental trends in these fields. However, this study has some limitations. First, only papers from the WOSCC database were considered, excluding those from PubMed and EMBASE. WOSCC covers most high-impact articles indexed in PubMed and has distinct advantages over other platforms, such as its broad multidisciplinary coverage, advanced search and filtering options, and robust citation tracking tools, making it particularly suitable for interdisciplinary research and bibliometric studies. Second, papers on stem cells and myocardial fibrosis that were not published in English were excluded from the analysis. Nonetheless, most high-impact articles were published in English, and focusing on English-language publications ensures the inclusion of high-quality research, minimizes translation challenges and inaccuracies, and improves the rigor and precision of our analysis through manual screening of potentially irrelevant articles. Third, our study acknowledges the potential influence of citation bias in the field, particularly positive publication bias, where articles with promising results may be cited more frequently than studies with non-confirmatory or negative findings. For example, the high-impact study by Orlic et al[24], “Bone marrow cells regenerate infarcted myocardium”[24], was initially influential but later challenged by subsequent studies, such as those by Murry et al[147] and Balsam et al[148], published in the same journal (Nature). This highlights an important limitation in citation-based studies, where non-confirmatory findings may not achieve similar citation counts and could be underrepresented in analyses. We recognize this limitation and suggest that future research consider methods to systematically account for both positive and negative findings to provide a more comprehensive view of the field. Despite these limitations, our comprehensive review of stem cell therapy in myocardial fibrosis offers valuable guidance. Future research should focus on optimizing the production and isolation of EVs, ensuring their scalability for clinical applications, and assessing their long-term efficacy and safety in clinical trials. Moreover, artificial intelligence and machine learning can play a crucial role in accelerating research on myocardial fibrosis and stem cell therapies. These technologies could help optimize stem cell culture conditions, determine the most effective stem cell sources for individual patients, and enhance the design of clinical trials through predictive modeling.

CONCLUSION

In summary, myocardial fibrosis and stem cells have been a major focus of research for over 20 years, as evidenced by both publications and citations. The United States is the leading country, and Harvard University is the dominant organization in this field. The high-frequency keyword analysis indicated that early research focused on stem cell-based therapy; recently, cell-free therapy using EVs, exosomes, and selected miRNAs has gained increasing attention as an emerging treatment strategy. Angiogenesis, inflammation, apoptosis, and oxidative stress were the most prevalent mechanisms evaluated in early research, while autophagy became more prominent later. These findings highlight current research hotspots and can guide future studies. We conclude that new cell-free therapeutic options for myocardial fibrosis and stem cell-mediated paracrine protection may be key topics in the future.