3.1 Temporal distribution map of the literature
From 2010 to 2018, the number of research publications on MSCs in the cardiovascular field generally showed an upward trend (Figure 1). From 2010 to 2013, the number of articles published in this field rose steadily, with a slight decline in 2014, an increase in 2015, and a decline in 2016. The number of articles increased each year from 2017 to 2018. In 2018, the number of articles reached its peak and then declined in 2019. As shown in Figure 1, documents published between 2010 and 2015 were cited more frequently, and the most cited articles were published in 2011.
3.2 Country/Region distribution
As shown in Table 2, the number of articles published by the USA and China placed them at the top of the ranking, as each accounted for 34.306% and 28.550% of the total, respectively. The total number of studies conducted by both countries comprised more than half of the total, indicating that the two countries had high research interest in this field. The top three countries in terms of ACI values were the Netherlands (40.2288), Spain (34.2771) and the USA (32.5757), suggesting that these three countries had started to conduct research in this field earlier than other countries and that their research results were more mature.
Table 2.
Top 10 productive countries
Rank
|
Country
|
Region
|
Quantity
|
Percentage
|
ACI
|
H-index
|
Total link strength
|
1
|
USA
|
North America
|
1129
|
34.306%
|
32.5757
|
89
|
541
|
2
|
China
|
East Asia
|
919
|
28.550%
|
16.7737
|
53
|
258
|
3
|
Italy
|
South
Europe
|
188
|
5.840%
|
26.766
|
38
|
157
|
4
|
Germany
|
Central Europe
|
184
|
5.716%
|
32.4293
|
43
|
168
|
5
|
South Korea
|
East Asia
|
144
|
4.473%
|
21.4861
|
31
|
68
|
6
|
England
|
Western Europe
|
126
|
3.914%
|
27.2619
|
32
|
143
|
7
|
Netherlands
|
Western Europe
|
118
|
3.555%
|
40.2288
|
40
|
100
|
8
|
Canada
|
North America
|
116
|
3.604%
|
28.2586
|
30
|
78
|
9
|
Japan
|
East Asia
|
115
|
3.573%
|
25.5304
|
30
|
66
|
10
|
Spain
|
Southern
Europe
|
83
|
2.578%
|
34.2771
|
27
|
59
|
*ACI: Average Citations per Item
As shown in Figure 2, Countries with close cooperation can be mainly divided into two types. The USA and China showed the greatest cooperation with South Korea, Japan, Canada and Australia. The Germany and Italy worked more closely with England, Netherlands, France, Switzerland and Spain.
3.3 Distribution of authors and research institutions
As shown in Table 3, Hare JM from the University of Miami in the United States has the highest number of published articles, followed by Wang Y from Shanghai Jiao Tong University in China and Zhang Yu from the Second Military Medical University in China. Seven of the top ten writers are from China, and three are from the United States.
Table 3
Top 15 authors
Rank
|
Author
|
Country
|
Institute
|
TP
|
P
|
h
|
1
|
Hare JM
|
USA
|
Univ Miami
|
64
|
1.941%
|
28
|
2
|
Wang Y
|
China
|
Shanghai Jiao Tong Univ
|
58
|
1.759%
|
21
|
3
|
Zhang, Yu
|
China
|
Second Mil Med Univ
|
42
|
1.274%
|
21
|
4
|
Zhang, Lei
|
China
|
Southeast Univ
|
39
|
1.183%
|
16
|
5
|
Ashraf, Muhammad
|
USA
|
Augusta Univ
|
32
|
0.971%
|
18
|
6
|
Li, Yan
|
China
|
Fourth Mil Med Univ
|
27
|
0.819%
|
11
|
7
|
Li, Xin
|
China
|
Guangdong Acad Med Sci
|
26
|
0.789%
|
11
|
8
|
Liu, Yue
|
China
|
China Acad Chinese Med Sci
|
25
|
0.758%
|
8
|
9
|
Cao, Feng
|
China
|
Fourth Mil Med Univ
|
24
|
0.728%
|
16
|
10
|
Heldman, Alan W.
|
USA
|
Univ Miami
|
24
|
0.728%
|
15
|
TP: total publications; h:H-index
As shown in Figure 3, Ashraf and Muhammad worked closely with Wang Yigang and Huang Wei. Li Ren-ke worked closely with Steinhoff, Gustav, David Robert, Guan Jianjun and Khan Mahmood, and so on.
As shown in Table 4, the institution with the highest number of research publications in this field is the University of Miami with a quantity of 73, followed by the Chinese Academy of Medical Sciences with a quantity of 55 and Harvard University with a quantity of 52. The research institution with the highest ACI value in this field was Harvard University, which had an ACI value of 92.2692, followed by Mayo Clinic with an ACI value of 36.5227 and University of Cincinnati with an ACI value of 34.5455.
Table 4.
Top 10 institutions
Rank
|
Institution
|
Country
|
Quantity
|
Total link strength
|
STC
|
ACI
|
1
|
Univ Miami
|
USA
|
73
|
23
|
3339
|
45.7397
|
2
|
Chinese Acad Med Sci
|
China
|
55
|
57
|
1319
|
23.9818
|
3
|
Harvard Univ
|
USA
|
52
|
24
|
4798
|
92.2692
|
4
|
Sun Yat Sen Univ
|
China
|
51
|
5
|
626
|
12.2745
|
5
|
Fourth Mil Med Univ
|
China
|
48
|
25
|
883
|
18.3958
|
6
|
Peking Union Med Coll
|
China
|
47
|
55
|
1173
|
24.9574
|
7
|
Mayo Clin
|
USA
|
44
|
9
|
1607
|
36.5227
|
8
|
Univ Cincinnati
|
USA
|
44
|
9
|
1520
|
34.5455
|
9
|
Univ Toronto
|
Canada
|
44
|
14
|
1410
|
32.0455
|
10
|
Fudan Univ
|
China
|
42
|
13
|
762
|
18.1429
|
*STC: Sum of the Times Cited, ACI: Average Citations per Item
As shown in Figure 4, the University of Miami cooperated closely with Harvard University, Pittsburgh University and Zhejiang University. Sun Yat-sen University cooperated closely with Fudan University.
3.4 Distribution of disciplines in the literature
As shown in Table 5, the top three disciplines in terms of the number of published articles were cell biology (30.664%), cardiovascular system cardiology (20.534%) and research experimental medicine (20.140%). Additional disciplines represented in the literature were engineering (9.827%), materials science (9.160%), biochemistry and molecular biology (8.280%), biotechnology and applied microbiology (7.158%), pharmacology and pharmacy (6.946%), transplantation (4.974%), chemistry (3.063%) and other disciplines, indicating that the research performed in this field was broad and that the research methods were diverse.
Table 5.
The top 20 subject categories
Rank
|
Quantity
|
WOS Categories
|
Percentage
|
1
|
1011
|
Cell biology
|
30.664%
|
2
|
677
|
Cardiovascular system cardiology
|
20.534%
|
3
|
664
|
Research experimental medicine
|
20.140%
|
4
|
324
|
Engineering
|
9.827%
|
5
|
302
|
Materials science
|
9.160%
|
6
|
273
|
Biochemistry and molecular biology
|
8.280%
|
7
|
236
|
Biotechnology and applied microbiology
|
7.158%
|
8
|
232
|
Science technology—other topics
|
7.073%
|
9
|
229
|
Pharmacology and pharmacy
|
6.946%
|
10
|
222
|
Hematology
|
6.733%
|
11
|
164
|
Transplantation
|
4.974%
|
12
|
159
|
Oncology
|
4.823%
|
13
|
129
|
Physiology
|
3.913%
|
14
|
123
|
Surgery
|
3.731%
|
15
|
101
|
Chemistry
|
3.063%
|
16
|
96
|
General internal medicine
|
2.912%
|
17
|
80
|
Endocrinology and metabolism
|
2.426%
|
18
|
62
|
Respiratory system
|
1.880%
|
19
|
57
|
Biophysics
|
1.729%
|
20
|
57
|
Immunology
|
1.729%
|
As shown in Table 6, the journal with the highest number of articles in this field was Circulation Research, followed by Scientific Reports(42), Biomaterials(40), Molecular Medicine Reports(40), Stem Cells(39) and Tissue Engineering Part A(39). The magazine with the highest ACI value was Biomaterials (17.68), followed by Stem Cells Translational Medicine (17.45), Journal of Cellular and Molecular Medicine (16.48), Circulation Research (15.30), Tissue Engineering Part A (14.8182), Cell Transplantation (14.78) and Scientific Reports (13.9167).
Table 6.
Top 15 journals
Rank
|
Journal Title
|
Quantity
|
ACI
|
1
|
Circulation Research
|
49
|
15.30
|
2
|
Scientific Reports
|
42
|
13.9167
|
3
|
Biomaterials
|
40
|
17.68
|
4
|
Molecular Medicine Reports
|
40
|
12.4091
|
5
|
Stem Cells
|
39
|
8.95
|
6
|
Tissue Engineering Part A
|
39
|
14.8182
|
7
|
Stem Cells And Development
|
28
|
13.66
|
8
|
Cell Transplantation
|
27
|
14.78
|
9
|
Circulation
|
25
|
11.48
|
10
|
Journal of Cellular and Molecular Medicine
|
24
|
16.48
|
11
|
International Journal of Cardiology
|
22
|
2.25
|
12
|
PLOS One
|
22
|
7.02
|
13
|
Stem Cell Research & Therapy
|
18
|
6.16
|
14
|
Stem Cells Translational Medicine
|
17
|
17.45
|
15
|
Stem Cells International
|
11
|
5.15
|
ACI: Average Citations per Item
3.5 Highly cited literature analysis
As shown in Table 7, the article “Pericytes: Developmental, Physiological, and Pathological Perspectives, Problems, and Promises” was cited the most often. Armulik discussed the important roles of pericytes in the processes of organismal development and vascular homeostasis and their relationship with MSCs[23].
Table 7
Top 15 co-cited articles, cited authors and cited references
Rank
|
Title
|
Journal
|
Type
|
Authors
|
Y
|
C
|
IN
|
CN
|
1
|
Pericytes: Developmental, Physiological, and Pathological Perspectives, Problems, and Promises
|
Developmental Cell
|
Review
|
Armulik, Annika.et al.
|
2011
|
1086
|
2
|
2
|
2
|
Comparison of Allogeneic vs Autologous Bone Marrow-Derived Mesenchymal Stem Cells Delivered by Trans
|
Journal of the American Medical Association
|
Article
|
Hare, Joshua M.et al.
|
2012
|
639
|
8
|
1
|
3
|
Whole-Organ Tissue Engineering: Decellularization and Recellularization of Three-Dimensional Matrix
|
Annual Review of Biomedical Engineering
|
Review
|
Badylak, Stephen F.et al.
|
2011
|
516
|
7
|
1
|
4
|
Bone Marrow Mesenchymal Stem Cells Stimulate Cardiac Stem Cell Proliferation and Differentiation
|
Circulation Research
|
Article
|
Hatzistergos, Konstantinos E. et al.
|
2010
|
469
|
5
|
2
|
5
|
Molecular mechanisms of cancer development in obesity
|
Nature Reviews
Cancer
|
Review
|
Khandekar, Melin J. et al.
|
2011
|
467
|
4
|
1
|
6
|
Harnessing the Mesenchymal Stem Cell Secretome for the Treatment of Cardiovascular Disease
|
Cell Stem Cell
|
Review
|
Ranganath, Sudhir H. et al.
|
2012
|
449
|
6
|
2
|
7
|
Conversion of vascular endothelial cells into multipotent stem-like cells
|
Nature Medicine
|
Article
|
Medici, Damian et al.
|
2010
|
444
|
8
|
1
|
8
|
Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate P
|
Stem Cell Research
|
Article
|
Arslan, Fatih
Et al.
|
2013
|
436
|
8
|
2
|
9
|
Clinical Trials With Mesenchymal Stem Cells: An Update
|
Cell Transplantation
|
Review
|
Squillaro, Tiziana et al.
|
2016
|
411
|
4
|
3
|
10
|
Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammat
|
Proceedings of the National Academy of Sciences of the United States of America
|
Article
|
Bartosh, Thomas J. et al.
|
2010
|
411
|
1
|
1
|
11
|
Perivascular Gli1(+) Progenitors Are Key Contributors to Injury-Induced Organ Fibrosis
|
Cell Stem Cell
|
Article
|
Kramann, Rafael. et al.
|
2015
|
337
|
6
|
2
|
12
|
Cell Therapy for Heart Failure: A Comprehensive Overview of Experimental and Clinical Studies, Curren
|
Circulation Research
|
Review
|
Sanganalmath, Santosh K. et al.
|
2013
|
332
|
2
|
1
|
13
|
Immunosuppressive Properties of Mesenchymal Stem Cells: Advances and Applications
|
Current Molecular Medicine
|
Review
|
De Miguel, M. P. et al.
|
2012
|
327
|
4
|
1
|
14
|
The war against heart failure: the Lancet lecture
|
Lancet
|
Review
|
Braunwald, Eugene.
|
2015
|
301
|
2
|
1
|
15
|
Bone Marrow-Derived Cell Therapy Stimulates Endogenous Cardiomyocyte Progenitors and Promotes Cardia
|
Cell Stem Cell
|
Article
|
Loffredo, Francesco S. et al.
|
2011
|
292
|
2
|
1
|
Y=Year; C=Citations; IN=Institute Number; CN=Country Number
The second most cited article was “Comparison of Allogeneic vs Autologous Bone Marrow-Derived Mesenchymal Stem Cells Delivered by Transendocardial Injection in Patients with Ischemic Cardiomyopathy: The POSEIDON Randomized Trial”. In this article, Hare et al confirmed that intracardiac injection of allogeneic and autologous MSCs could treat ischemic cardiomyopathy effectively and relatively safely [24].
The third most cited article was “Whole-Organ Tissue Engineering: Decellularization and Recellularization of Three-Dimensional Matrix”. In this article, Badylak explained that the combination of three-dimensional bioscaffold materials and cell transplantation was a promising tissue engineering strategy and a method for the regeneration of functional organs for medical replacement [25]. The above articles could be regarded as constituting an important theoretical basis and providing clinical evidence for research in this field.
According to the types of the articles, 8 of the most highly cited articles were reviews, and 7 were monographs. Based on the publication dates of the most highly cited articles, the most highly cited articles were published from 2011 to 2013, followed by 2015 to 2016. These periods can be regarded as representing the two stages of the development of this field. Based on the numbers of cooperating institutions and countries, there were 10 articles involving more than three institutions and 6 articles involving groups in at least two countries.
3.6 Research hotspots and frontier analysis
3.6.1 Research hotspot analysis
Keywords reflect the core content of the article and can be used to identify the evolving research frontiers related to the knowledge field [26]. As shown in Table 8, in addition to mesenchymal stem cells and heart, the keywords with a high frequency of occurrence were heart transplantation (582), differentiation (535), myocardial infarction (482), in vitro (473), therapy (472) and progenitor cells (458).
Table 8.
The top 20 keywords
Rank
|
Keywords
|
Occurrences
|
Total link strength
|
Rank
|
Keywords
|
Occurrences
|
Total link strength
|
1
|
mesenchymal stem cells
|
1529
|
6487
|
11
|
myocardial infarction
|
456
|
3032
|
2
|
heart
|
594
|
3166
|
12
|
bone marrow
|
449
|
2468
|
3
|
transplantation
|
582
|
3386
|
13
|
expression
|
362
|
1782
|
4
|
mesenchymal stem cells
|
561
|
3066
|
14
|
acute myocardial infarction
|
331
|
1985
|
5
|
differentiation
|
535
|
2780
|
15
|
angiogenesis
|
304
|
1783
|
6
|
stromal cells
|
486
|
2628
|
16
|
regeneration
|
290
|
1814
|
7
|
myocardial infarction
|
482
|
2707
|
17
|
stem cells
|
283
|
1674
|
8
|
in vitro
|
473
|
2476
|
18
|
cardiomyocytes
|
273
|
1603
|
9
|
therapy
|
472
|
2708
|
19
|
heart failure
|
273
|
1529
|
10
|
progenitor cells
|
458
|
2634
|
20
|
repair
|
272
|
1683
|
As shown in Figure 5, in the keyword cooccurrence network map, the thicker the connection between the nodes is, the more frequently the two keywords appear together. The keywords formed 4 clusters, which represented the four major research directions in the field. Stromal cells, tissue, tissue engineering, regenerative medicine, gene expression, scaffolds and extracellular matrix were the key words that had a high correlation with MSCs, as shown in the blue cluster. This indicates that this clustering was predominated by tissue engineering, genes and material research. The yellow cluster was associated with transplantation, expression, therapy and differentiation in the main body and mainly explored the pathways of cell transplantation and signal transduction. The green cluster was mainly associated with progenitor cells, endothelial progenitor cells and acute myocardial infarction and mostly explored the efficacy of stem cells from different sources in the treatment of acute myocardial infarction, cardiac hypertrophy and heart failure. The red cluster was associated with myocardial infarction, repair and regeneration, which indicated that myocardial infarction, regeneration and repair were the main research topics.
3.6.2 Combined evolutionary path
In Figure 6, the year corresponding to each of the keywords is the first year it appeared in the analyzed data set. The transformation between nodes could reveal the evolution of MSCs in the cardiovascular research hotspot. From 2010 to 2012, cardiovascular MSC research began to focus on apoptosis, left ventricular function, proliferation, bone marrow cells and endothelial cells. In 2013-2015, endothelial progenitor cells, extracellular matrix, ischemic cardiomyopathy and tissue received increased attention in the field. From 2016 to 2017, the field turned to research on injury and oxidative stress. Tissue engineering, exosomes and inflammation became the new focus in 2018-2020.
3.6.3 Research frontier identification
In Table 9, the timeline is depicted as a blue line, while burst detection is shown as a red segment on the blue timeline that indicates the start year, end year, and duration of the burst. In particular, we are interested in the key words with research significance, which reflect the evolutionary trend of this field.
Table 9. Top 15 Keywords with the Strongest Citation Bursts
Endothelial progenitor cells showed the strongest burst strength, followed by ischemic cardiomyopathy, cardiovascular disease and endothelial cells. The terms progenitor cells, marrow stromal cells, and heart function appeared for the first time recently but persisted for a shorter period of time. The burst times of the terms delivery, ischemic heart and ischemic cardiomyopathy were consistent. Tissue is the current research frontier in this field and is currently within the burst period.