Desheng Chen, Zeping Chen, Jiabin Yuan, Guanzi Chen, Yutao Chen, Kaiming He, Yongwei Hu, Linsen Ye & Yang Yang
Stem Cell Research & Therapy volume 16, Article number: 259 (2025) Cite this article
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Abstract
Background
Human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) have gained significant attention for their potential in cellular regeneration and functional rehabilitation. Nevertheless, the rapid expansion of research in this field makes it challenging for emerging trends and strategic priorities, potentially impeding scientific advancement. This study employs bibliometric analysis to systematically evaluate the research landscape and highlight pivotal research trajectories of hUCMSC-Exos.
Methods
Publications on hUCMSC-Exos from 2012 to 2024 were retrieved from the Web of Science Core Collection (WoSCC). Quantitative bibliometric analysis was implemented through integrated utilization of VOSviewer, CiteSpace, and Bibliometrix analytical tools.
Results
China and its institutions led global publication output, with Qian Hui from Jiangsu University identified as the most prolific author. STEM CELL RESEARCH & THERAPY emerged as a high-impact journal in this domain. Current research predominantly focuses on immunomodulation, regenerative medicine, pharmaceutical delivery systems, and clinical model development. Future research directions are expected to explore angiogenesis, spinal cord injury, and immunomodulation.
Conclusions
This study maps the evolving landscape of hUCMSC-Exos research, emphasizing its applications in regenerative medicine. By synthesizing current and emerging paradigms, these findings provide insights into therapeutic potential, novel mechanisms, and pathways for clinical translation.
Introduction
Mesenchymal stem cell (MSC)-based therapy has been widely recognized for its substantial therapeutic potential in various diseases, including hepatic insufficiency, hepatoma, stroke, and spinal cord injury (SCI) [1, 2]. Notably, MSCs, owing to their remarkable self-renewal and multipotency, demonstrate therapeutic efficacy in enhancing split liver transplantation outcomes by mitigating postoperative complications and accelerating graft regeneration [3, 4]. MSCs originating from the human umbilical cord (hUC) demonstrate superior proliferative capacity and enhanced differentiation plasticity, positioning them as a promising candidate for tissue repair [5, 6]. Despite encouraging therapeutic outcomes, the underlying mechanisms of hUC-MSCs-based treatment, specifically their contributions to proliferation, differentiation, immunomodulation, and apoptosis, remain incompletely elucidated [7, 8]. Consequently, most clinical trials employing hUC-MSCs have progressed only to phase I/II stages [9], underscoring the need for robust preclinical validation. Despite these challenges, hUC-MSCs are distinguished by their low immunogenicity, negligible tumorigenicity, minimal graft rejection, and high proliferative capacity, prompting extensive research into their clinical translation [10, 11].
Exosomes (Exos) are a key mechanism by which hUC-MSCs deliver therapeutic benefits in disease management [12]. hUCMSC-derived Exos (hUCMSC-Exos) exhibit superior proliferative capacity and reduced immunogenicity compared to Exos derived from other MSC origins and can be obtained by noninvasive methods [13, 14]. The therapeutic efficacy of hUCMSC-Exos is influenced by disease-tailored cellular dynamics (e.g., regeneration, inflammation, cell death, and oxidative stress) and key intracellular signaling pathways, such as mitogen-activated protein kinase (MAPK), wingless-related integration site (Wnt)/β-catenin, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways [15,16,17,18]. Moreover, hUCMSC-Exos serve as an effective vehicle for therapeutic compounds, enhancing bioavailability and reducing adverse effects [6]. Currently, hUCMSC-Exos are being explored in regenerative medicine for various conditions, including hepatic diseases (e.g., NCT05871463), cardiovascular diseases (e.g., NCT05669144), and SCI (e.g., IRCT20200502047277N1).
Given the growing interest in hUCMSC-Exos, the volume of scholarly publications has increased significantly, complicating the identification of emerging research trends and critical developments. This surge in literature, coupled with the absence of comprehensive reviews and meta-analyses, necessitates a synthesized overview of the field’s current and future directions. A bibliometric synthesis is essential for analyzing and predicting the trajectory of a particular research field, offering a comprehensive landscape of scholarly discourse and employing quantitative methodologies to elucidate research hotspots and emerging trends, a methodology widely used in medical research.
Despite its significance, there is currently no bibliometric study that provides a comprehensive examination of hUCMSC-Exos research. In this study, we aim to fill this gap by conducting a systematic literature search and employing bibliometric methods to highlight key milestones, pinpoint focal points of interest, anticipate forthcoming avenues of inquiry, and encapsulate the evolution of hUCMSC-Exos research through the year 2024.
Materials and methods
Data source
A total of 1066 scholarly publications were systematically retrieved from the Clarivate Analytics of Science Citation Index Expanded (SCI-Expanded) within the Web of Science Core Collection (WoSCC). The search strategy employed was: TS = (“umbilical cord mesenchymal stem cells” OR “umbilical cord mesenchymal stromal cells”) AND TS = (“extracellular vesicles” OR “exosomes”). The temporal scope spanned from September 3, 2012 (the date of the inaugural publication on hUCMSC-Exos) to October 19, 2024. Inclusion criteria were limited to English-language peer-reviewed articles (original research and reviews). Following rigorous screening (Fig. 1), the final dataset was compiled on October 19, 2024. Moreover, this bibliometric study required no ethical approval as it involved no human or animal experimentation.
Fig. 1
figure 1
Flow diagram illustrating the inclusion and exclusion criteria for the study
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Data processing
The bibliometric analysis was systematically conducted using VOSviewer (v1.6.20), CiteSpace (v6.4.R1), and the bibliometrix package in RStudio (v4.1.2). VOSviewer generated bibliometric maps using network, overlay, and density visualizations, facilitating structural and evolutionary analysis of the research networks [19]. Specifically, VOSviewer was employed to analyze international/institutional collaborations, co-citation networks, and keyword clusters. CiteSpace employed citation pattern analysis and burst detection to identify intellectual transitions and disciplinary trends [20]. Additionally, it conducted reference burst detection and keyword emergence analysis, revealing temporal patterns in conceptual evolution. The bibliometrix package performed multidimensional analysis of scholarly datasets through scientific mapping techniques [21], visualizing geographic collaboration patterns to elucidate research network dynamics.
Results
Bibliometric analysis of publication output
Original research articles constituted 78.61% of publications in the hUCMSC-Exos field, outnumbering review articles by a factor of three (Fig. 2A). The inaugural study emerged in 2012, marking the onset of scientific exploration in this domain. Temporal distribution analysis (2012–2024) revealed three developmental epochs: the foundational phase (2012–2014; n = 13), the developmental phase (2015–2018; n = 107), and the exponential growth phase (2019–2024; n = 946). Since 2018, publication output has exhibited sustained exponential growth, reflecting the maturation and increasing significance of the field (Fig. 2B).
Fig. 2
figure 2
(A) Classification of publication types involving human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos); (B) Annual production volume of hUCMSC-Exos
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Bibliometric analysis of countries/regions
China led scholarly output in hUCMSC-Exos research, producing 684 publications (64.17%) with cumulative citations reaching 24,171 (average article citations, AACs = 35.34), thereby solidifying China’s global scientific preeminence (Table 1). This dominance highlights a stark contrast in research investment compared to other nations, with the USA ranking second (n = 96, 9.01%). Network analysis of international collaboration identified China’s centrality despite limited transnational partnerships (Fig. 3A). Citation-based collaboration networks exhibited radial connectivity patterns centered on China (Fig. 3B). Geospatial collaboration network analysis confirmed the strongest China-USA cooperation (Fig. 4), with China exerting intellectual influence across multiple bibliometric indicators.
Table 1 The number of documents published and cited at country level
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Fig. 3
figure 3
Knowledge visualization maps examining country-level collaboration and citation patterns: (A) Collaborative network map of countries; (B) Citedness distribution map of countries
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Fig. 4
figure 4
Knowledge visualization map for international collaboration
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Bibliometric analysis of institutions
Institutional productivity analysis (Table 2) further reinforced Chinese dominance in hUCMSC-Exos research, with Jiangsu University leading both in publications (n = 60) and citation metrics (total citations, TCs = 5,611), followed by Nanjing Medical University (TCs = 1,657; n = 30). Inter-institutional collaboration networks (Fig. 5A) revealed three primary clusters: (1) The dominant blue cluster centered on Jiangsu University; (2) the red cluster featuring Shandong University; and (3) the green cluster anchored by Central South University. Core institutions including Soochow University, Nanjing Medical University, and Shanghai Jiao Tong University exhibited dense co-authorship linkages, while peripheral nodes like Sichuan University, Nantong University, and Capital Medical University demonstrated weaker collaborative ties. Citation network analysis (Fig. 5B) confirmed Jiangsu University’s epistemic authority, maintaining radial connections to other network nodes and indicating its significant impact and collaborative reach within the academic network.
Table 2 Top 10 most productive institutions
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Fig. 5
figure 5
Knowledge visualization maps for institutional collaboration and citation analysis: (A) Institutional collaboration network map; (B) Citedness distribution map of institutions
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Bibliometric analysis of authors
Scholarly output metrics identified Qian Hui as the most prominent contributor (n = 34, TCs = 4,772) among the top 10 authors (Table 3), followed by Xu Wenrong (n = 30, TCs = 4,632) and Yan Yongming (n = 24, TCs = 3,407), respectively. Notably, all leading contributors were affiliated with China, highlighting the country’s dominant role in advancing hUCMSC-Exos research. The co-authorship network (Fig. 6A) revealed distinct clusters led by prominent authors, including Qian Hui, Xu Wenrong, and Yan Yongming. The citation network (Fig. 6B) confirmed Qian Hui’s scholarly influence, indicating both his significant scholarly impact and extensive collaborations in the hUCMSC-Exos research field. Peripheral authors demonstrated limited collaborative propensity, suggesting more independent research trajectories.
Table 3 Productivity based on number of articles at author level
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Fig. 6
figure 6
Knowledge visualization maps focusing on author collaboration and citation trends: (A) Authors’ collaboration network map; (B) Citedness distribution map of authors
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Bibliometric analysis of journals
Journal productivity analysis (Table 4) revealed that STEM CELL RESEARCH & THERAPY is the leading journal in the field (n = 78; TCs = 3,821), thereby demonstrating its scholarly preeminence. While the INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES ranked second in output (n = 40), it paradoxically exhibited the lowest citation frequency (TCs = 639; AACs = 15.98). STEM CELLS secured the second citation rank (TCs = 1,391; AACs = 107.00), with STEM CELLS TRANSLATIONAL MEDICINE closely following in third place (TCs = 1,387; AACs = 115.58), confirming their status as key knowledge repositories. Significantly, the journal citation network analysis (Fig. 7) reinforced the pivotal role of STEM CELL RESEARCH & THERAPY as the central hub, exhibiting extensive connectivity with other major journals, such as the INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES and STEM CELLS INTERNATIONAL. This further emphasized their collective contribution to the hUCMSC-Exos research domain.
Table 4 The number of documents published and cited at journal level
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Fig. 7
figure 7
Knowledge visualization map analyzing journal-level citation patterns
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Bibliometric analysis of references
Table 5 summarized the top 10 most-cited publications in the hUCMSC-Exos domain. The seminal work by Li Tingfen et al. (2013) achieved the highest citation count (n = 661) in STEM CELLS AND DEVELOPMENT, elucidating hUCMSC-Exos’ therapeutic efficacy against hepatic fibrosis. Lee et al. (2012) ranked second (n = 628 citations) in CIRCULATION, investigating MSC-derived exosome-mediated cytoprotection in hypoxic pulmonary hypertension models. These landmark studies collectively underscore the translational potential of MSC research. The citation network visualization (Fig. 8A) employed node sizing proportionate to citation frequency. Moreover, burst detection analysis identified 25 pivotal references (Fig. 8B) with citation bursts, revealing periods of intensified scholarly interest (denoted by red zones). Pioneering researchers such as Li Tingfen, Zhang Bin, Zhou Ying, and Thery Clotilde emerged as leading contributors, laying the foundation for MSC-Exos mechanisms and therapeutic applications [22,23,24,25].
Table 5 Ranking of the top 10 highest cited documents
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Fig. 8
figure 8
Knowledge visualization map of document-level citation metrics: (A) Citedness distribution map of documents; (B) Temporal analysis map of document-level citation bursts
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Bibliometric analysis of keywords
Keyword analysis revealed the shifting academic focus of hUCMSC-Exos research, elucidating prevailing investigative priorities and emerging research directions. Through synonym consolidation, 3,822 distinct keywords were extracted from 1,066 publications, with 20 high-frequency terms (≥ 75 occurrences) identified (Table 6). Network visualization delineated the structural composition of the research domain (Fig. 9A), categorizing keywords into four major clusters: green (predominantly “versus-host-disease” and “immunomodulation”), blue (“angiogenesis”, “cellular proliferation”, and “microRNAs”), yellow (“regeneration” and “wound healing”), and red (“inflammation”, “SCI”, “acute lung injury”, “transplantation”, “fibrosis”, “delivery”, and “therapy”). Notably, key nodal elements including “angiogenesis”, “immunomodulation”, “inflammation”, “regeneration”, “delivery”, “pathway”, and “SCI” exhibited heightened centrality and interconnectivity, reflecting their critical relevance to hUCMSC-Exos research priorities.
Table 6 Ranking of the top 20 keywords
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Fig. 9
figure 9
Knowledge visualization map examining keyword-related research trends: (A) Clustered keywords visualization map; (B) Keywords timeline map
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Temporal mapping enabled chronological analysis of disciplinary progression, revealing phase-specific research priorities and developmental trajectories within hUCMSC-Exos studies (Fig. 9B). Distinct clustering patterns emerged around terms including “cancer”, “autophagy”, “macrophages”, “osteoarthritis”, and “inflammation”, indicating a consistent scholarly emphasis on therapeutic applications and mechanistic explorations across diverse pathologies. Burst detection analysis identified 19 temporally significant keywords (Fig. 10), with “stromal cells” (Strength: 8.64) and “microvesicles” (Strength: 9.06) emerging as prominent focal points. The marked surge in “extracellular vesicle” research since 2021 highlighted its emergence as a contemporary investigative priority with growing academic relevance.
Fig. 10
figure 10
Knowledge visualization map examining keyword-related research trends: Top 19 keywords with the strongest citation bursts
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Discussion
To our current understanding, this investigation marks the inaugural application of bibliometric methodologies to systematically quantify and characterize the hUCMSC-Exos research corpus. We identified pivotal research foci and developmental trajectories of hUCMSC-Exos studies, providing a comprehensive framework that elucidated the evolutionary trends in the domain.
Countries/institutions cooperation
The findings demonstrate that hUCMSC-Exos research represents an emergent scientific frontier, with exponential growth in publication volume. Geographical distribution patterns revealed the top 10 contributing nations spanning three major scientific regions: Asia, Europe, and North America. Strikingly, China has emerged as the leading contributor, surpassing the USA in both productivity and citation influence. While academic engagement continued to intensify, international collaborative efforts remained constrained, indicating substantial potential for enhanced global scientific partnerships. The institutional analysis identified Jiangsu University and Shandong University as key players, both distinguished by their outstanding performance in publication output and academic influence. Notably, all top-tier productive institutions were based in China, which further reinforced the country’s dominance in hUCMSC-Exos research.
Citation landscape
Analysis of author productivity revealed that eight of the top 10 most prolific researchers maintained affiliations with Jiangsu University, underscoring robust intra-institutional collaboration and confirming the university’s leadership position in this field. Xu Wenrong has produced multiple seminal publications that have fundamentally shaped the field’s trajectory. His 2012 breakthrough study in STEM CELLS AND DEVELOPMENT [22] first established the therapeutic potential of hUCMSC-Exos in hepatic fibrosis management, providing the conceptual framework for subsequent mechanistic and translational investigations. This foundational work was expanded in 2013 through STEM CELL RESEARCH & THERAPY [24], where Xu’s team demonstrated hUCMSC-Exos’ efficacy in counteracting cisplatin-induced nephrotoxicity, thereby proposing a novel therapeutic strategy for chemotherapy-associated renal complications. Collaborative research led by Xu has further elucidated hUCMSC-Exos applications across diverse pathologies including cutaneous regeneration [23], SCI [26], type 2 diabetes mellitus [27], and inflammatory bowel disease [28], substantially broadening the technology’s clinical relevance.
Bibliometric evaluation identified stem cell-specific journals as principal knowledge dissemination channels, notably STEM CELL RESEARCH & THERAPY, STEM CELLS INTERNATIONAL, and STEM CELLS. STEM CELLS TRANSLATIONAL MEDICINE, a high-impact journal, has published works with the highest mean citation rates. In contrast, STEM CELL RESEARCH & THERAPY, despite leading in publication volume, has demonstrated comparatively lower citation metrics, highlighting the imperative of focusing on breakthrough research to enhance its academic standing.
Research hotspots and frontiers
The hUCMSC-Exos research domain has witnessed substantial investigation into tissue regeneration [29,30,31,32,33], employing methodologies that span transplantation protocols, cellular therapeutics, and biomaterial applications. Despite these advancements, the development of optimized clinical regimens remains an unresolved challenge, particularly in achieving sustained therapeutic efficacy and safety profiles within complex pathophysiological microenvironments [34,35,36]. Nevertheless, pioneering investigations in this research domain have garnered significant scholarly attention due to their pivotal role in tissue repair mechanisms. The research scope encompasses the following areas: hepatic fibrosis suppression [22], protective mechanisms against hypoxic stress [37], cisplatin-induced cellular damage [24, 37], and promotion of dermal tissue regeneration [23]. These preliminary findings have delineated promising trajectories for clinical translation applications.
While these translational potentials are being explored, hUCMSC-Exos are emerging as a multifaceted regenerative strategy, with key properties such as immunomodulation, angiogenesis, and anti-apoptosis [38]. Angiogenesis serves as a pivotal determinant of tissue repair efficacy [39,40,41,42]. Notably, multiple clinical trials are committed to employing MSCs to ameliorate ischemic diseases, such as ischemic heart disease (NCT01781390 and NCT00877903), ischemic retinopathy (NCT03011541 and NCT01920867), critical limb ischemia (NCT04104451 and NCT05078385), and ischemic stroke (NCT03384433). The proangiogenic attributes of hUCMSC-Exos present a strategic therapeutic avenue to address the persistent clinical challenge of optimizing regenerative responses in ischemic tissue microenvironments.
Burst analysis further identified SCI as a consistent investigative priority within hUCMSC-Exos research. Mechanistic studies demonstrate their multi-target therapeutic actions: microRNA (miR)-146a-5p-mediated nuclear factor kappa-B (NF-κB) axis suppression mitigates post-traumatic neuroinflammation and promotes neural repair, while Wnt/β-catenin pathway modulation reduces apoptosis and enhances locomotor recovery [43,44,45,46]. Clinically, intrathecal administration of UCMSCs/UCMSC-Exos has shown preliminary efficacy in enhancing sensorimotor outcomes in SCI patients, despite the absence of standardized therapeutic protocols [47,48,49]. This therapeutic ambiguity necessitates comprehensive clinical validation through rigorously designed trials to establish evidence-based treatment paradigms.
hUCMSC-Exos have been established as pivotal immunomodulatory agents, with their therapeutic primacy substantiated through our results and experimentally validated multimodal mechanisms. hUCMSC-Exos orchestrate bidirectional immunomodulation in both innate and adaptive immunity across heterogeneous disease models [50,51,52]. Specifically, hUCMSC-Exos exhibit multimodal immunomodulation through: (1) macrophage repolarization via NF-κB inhibition [53], (2) pharmacological synergy (e.g., arsenic trioxide-enhanced macrophage polarization in acute graft-versus-host disease management) [54], (3) neuroinflammatory modulation (regulation of expressed interleukin (IL)-6/IL-1β/IL-10) [55], and (4) regulatory T cell expansion [56]. These coordinated mechanisms collectively validate their therapeutic efficacy across immune disorders.
While methodologically rigorous, this study has limitations including exclusive reliance on WoSCC data (excluding PubMed), which risks selection bias. Through multidimensional analysis (geographic-institutional-author metrics, citation networks, thematic evolution), we mapped hUCMSC-Exos research priorities and forecasted key trajectories: SCI management, vascularization mechanisms, and immune homeostasis regulation. This synthesized overview provides critical guidance for future research and frontier exploration.
Conclusion
This systematic bibliometric mapping delineates the evolutionary trajectory of hUCMSC-Exos research, characterizing its academic influence, conceptual focal points, and disciplinary progression. Contemporary research efforts put emphasis on four aspects: immunomodulatory mechanisms, regenerative medicine, therapeutic delivery systems, and clinical model development. Notably, the therapeutic potential of hUCMSC-Exos reveals particular promise in SCI repair, ischemic diseases intervention, and immune disorder management. This analysis provides a structured framework for navigating academic research in the hUCMSC-Exos field, clarifying intellectual frameworks. Furthermore, this study identifies key areas for mechanistic exploration and therapeutic innovation.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Abbreviations
Exos:
Exosomes
hUC:
Human umbilical cord
hUCMSC-Exos:
Human umbilical cord mesenchymal stem cell-derived exosomes
MSC:
Mesenchymal stem cell
SCI:
Spinal cord injury
WoSCC:
Web of science core collection
MAPK:
Mitogen-activated protein kinase
Wnt:
Wingless-related integration site
JAK/STAT:
Janus kinase/signal transducer and activator of transcription
IL:
Interleukin
miR:
microRNA
KLF5:
Krüppel-like factor 5
EFNA3:
Ephrin-A3
Traf6:
Tumor necrosis factor receptor-associated factor 6
Irak1:
Interleukin-1 receptor-associated kinase 1
NF-κB:
Nuclear factor kappa-B
TCs:
Total citations
AACs:
Average article citations
IF:
Impact factor
NCT:
National clinical trial
IRCT:
Iranian registry of clinical trials
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Acknowledgements
The authors would like to extend their sincere appreciation to Dr. Win Topatana for his polishing of the manuscript.
Funding
This research was supported by the National Key Research and Development Program of China (Grant No. 2024YFA1107200), the National Natural Science Foundation of China (Grant Nos. 82103448, 81972286), the Natural Science Foundation of Guangdong Province (Grant No. 2023A1515010322), and the Guangzhou Science and Technology Basic and Applied Basic Research Project (2023A04J1802).
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Author notes
Desheng Chen, Zeping Chen, Jiabin Yuan and Guanzi Chen contributions are equal.
Authors and Affiliations
Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Desheng Chen, Yutao Chen, Kaiming He, Yongwei Hu, Linsen Ye & Yang Yang
Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Desheng Chen, Yutao Chen, Kaiming He, Yongwei Hu, Linsen Ye & Yang Yang
Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Zeping Chen
Department of Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, China
Jiabin Yuan
Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
Guanzi Chen
Contributions
Data analysis, data interpretation, and manuscript drafting were conducted by D.C., Z.C., J.Y., and G.C. Investigation and visualization were performed by Y.C. and K.H. The conception, design, revision of the manuscript, and acquisition of funding were led by Y.Y., L.Y., and Y.H.
Corresponding authors
Correspondence to Yongwei Hu, Linsen Ye or Yang Yang.
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