Global landscape of hepatic organoid research: A bibliometric and visual study

Abstract

BACKGROUND

Hepatic organoid-based modelling, through the elucidation of a range of in vivo biological processes and the recreation of the intricate liver microenvironment, is yielding groundbreaking insights into the pathophysiology and personalized medicine approaches for liver diseases.

AIM

This study was designed to analyse the global scientific output of hepatic organoid research and assess current achievements and future trends through bibliometric analysis.

METHODS

Articles were retrieved from the Web of Science Core Collection, and CiteSpace 6.3.R1 was employed to analyse the literature, including outputs, journals, and countries, among others.

RESULTS

Between 2010 and 2024, a total of 991 articles pertaining to hepatic organoid research were published. The journal Hepatology published the greatest number of papers, and journals with an impact factor greater than 10 constituted 60% of the top 10 journals. The United States and Utrecht University were identified as the most prolific country and institution, respectively. Clevers H emerged as the most prolific author, whereas Huch M had the highest number of cocitations, suggesting that both are ideal candidates for academic collaboration. Research on hepatic organoids has exhibited a progressive shift in focus, evolving from initial investigations into model building, differentiation research in stem cells, bile ducts, and progenitor cells, to a broader spectrum encompassing lipid metabolism, single-cell RNA sequencing, and therapeutic applications. The phrases exhibiting citation bursts from 2022 to 2024 include “drug resistance”, “disease model”, and “patient-derived tumor organoids”.

CONCLUSION

Research on hepatic organoids has increased over the past decade and is expected to continue to grow. Key research areas include applications for liver diseases and drug development. Future trends likely to gain focus include patient-derived tumour organoids, disease modelling, and personalized medicine.

Key Words: Hepatic organoid; Bibliometric analysis; CiteSpace; Web of Science Core Collection; Three-dimensional culture

Core Tip: We systematically analyzed the global scientific contributions in the field of hepatic organoids research through a meticulous bibliometric assessment. We constructed a mapping knowledge domain to visualize the achievements of hepatic organoid research, including global scientific output, active journals, prolific countries, institutions, and authors, as well as the historical progression of the research field.

INTRODUCTION

Hepatic organoids, which serve as three-dimensional (3D) in vitro models for human liver development and disease, are typically derived from primary tissue, embryonic stem cells, or induced pluripotent stem cells (iPSCs). These organoids exhibit both structural and functional similarities to the liver[1-3]. Unlike traditional 2D cell cultures, hepatic organoids encompass multiple organ-specific cell types arranged in a spatial architecture that recapitulates several key functions of the source organ[4]. These organoids exhibit various in vivo biological properties, including self-organization and self-renewal. Consequently, hepatic organoids have emerged as a promising tool in a range of basic biological research and clinical applications, such as liver disease modelling, drug screening, and personalized medicine (Figure 1 presents a schematic diagram illustrating the development and applications of hepatic progenitor organoids and hepatocyte organoids)[5-7].

Figure 1 Diagram of hepatic organoid establishment and potential applications. Hepatic organoid spheroids can be generated from induced pluripotent stem cells, embryonic stem cells, or primary liver tissues that undergo dissociation, differentiation, and reaggregation. Hepatic organoids have been used extensively for basic biology research, disease modelling, drug screening, and personalized medicine. ESCs: Embryonic stem cells; IPSCs: Induced pluripotent stem cells.

Over the past decade, substantial advancements have been made in the development and optimization of hepatic organoid culture methodologies. Initial research efforts focused on the differentiation of pluripotent stem cells and hepatic progenitor cells into functional hepatocytes[8,9]. Subsequent investigations have examined the application of diverse biomaterials and scaffolds to develop more intricate and functional hepatic organoids[10,11]. Researchers have successfully generated hepatic organoids that replicate the genetic and metabolic features of particular liver diseases via patient-derived iPSCs. These disease-specific hepatic organoids have proven invaluable for elucidating the pathophysiology of liver disorders and evaluating prospective therapeutic interventions[12-14]. To date, hepatic organoids have not been extensively utilized in clinical settings; however, they present significant potential for advancing liver disease research and treatment[15-17]. Ongoing research endeavors are focused on enhancing the functionality and scalability of hepatic organoids, as well as addressing challenges associated with their long-term culture, vascularization, and integration with host tissue[18-20]. Our research group has long been committed to the cultivation and application of digestive system organoids. We have utilized these organoids to investigate pathological mechanisms and develop therapeutic drugs for digestive system diseases, resulting in a series of significant advancements[21,22]. We have successfully established mouse-derived hepatic progenitor organoids and hepatocyte organoids. Hepatic progenitor organoids are 3D structures featuring cavities, originating from hepatic progenitor cells or stem cells. These organoids have the potential to differentiate into hepatocytes and cholangiocytes but do not express hepatocyte-specific markers[23]. The hepatocyte organoid was differentiated from the hepatic progenitor organoid under specific differentiation conditions and subsequently stained positively for the hepatocyte marker albumin.

Bibliometric analysis integrates mathematical and statistical methodologies and is extensively utilized to construct knowledge frameworks and investigate developmental trends within various research domains. This approach aids researchers in comprehending the characteristics of advancements and informs subsequent investigative efforts[24]. In this study, we constructed a mapping knowledge domain to analyse achievements of hepatic organoid research, including global scientific output, active journals, prolific countries, institutions, and authors, as well as historical development of the research field through bibliometric analysis. We also assessed current research topics from the past decade and predicted the potential frontiers in future hepatic organoid research.

MATERIALS AND METHODS

Data source and search strategy

A literature search pertaining to hepatic organoids was performed utilizing the Science Citation Index-Expanded within the Web of Science Core Collection (WoSCC) on March 31^st, 2024. The search terms used were as follows: (TS = organoid) AND (TS = (liver or hepatic or hepatocyte or hepatology)) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article) and the time span was set as 2010-2024. All searches were completed within the same day to avoid bias when obtaining articles.

Data extraction

A total of 991 published articles were obtained during hepatic organoid-related literature retrieval. All the data were downloaded from a public database and imported into CiteSpace 6.3.R1 (Drexel University, Philadelphia, United States). There were no ethical concerns regarding the data.

Statistical analysis

The WoSCC was used to analyse the characteristics of the publication outputs and journals. The numbers of publication articles were presented via GraphPad Prism 8. Several bibliometric methods have been used to assess the collaborations between countries, institutions, and authors as well as analyse cocitations between authors, references, and term bursts. The mapping knowledge domains mentioned above were constructed via CiteSpace 6.3.R1. The articles in a three-year slice with a g-index (k = 25) were selected for further analysis.

RESULTS

Publication outputs

According to the established literature retrieval criteria, a total of 991 articles were selected for bibliometric analysis (Figure 2A). Annual publications are presented in Figure 2B. From 2010 to 2014, there was no significant change in the rate of publication of hepatic organoid-related research articles. After 2015, the annual number of publications on hepatic organoid-related research increased dramatically. The overall trend of publication output consistently increased.

Figure 2 Article screening process and publication outputs in hepatic organoid research. A: The systematic article screening process; B: The publication outputs in hepatic organoid research spanning from 2010 to 2024, along with the fitted curve representing the annual publication volume trends.

Journal and cocited journal analysis

A total of 200 academic journals published papers in hepatic organoid research. The top 10 journals contributing to hepatic organoid research are shown in Table 1, among which the journal Hepatology [2023 impact factor (IF) = 13.5] published the most papers (29 publications, 2.93%), followed by Scientific Reports (2023 IF = 4.6, 28 publications, 2.83%) and Nature Communications (2023 IF = 16.6, 27 publications, 2.72%). In addition, our analysis of cocited journals revealed that the five most frequently cocited journals are Nature (705 cocitations), Cell (625 cocitations), Proceedings of the National Academy of Sciences of the United States of America (525 cocitations), Gastroenterology (508 cocitations), and Science (488 cocitations).

Table 1 Top 10 journals contributing to publications in hepatic organoid research.

Rank	Journal title	Country	Count	Percent	Impact factor 2023
1	Hepatology	United States	29	2.93%	13.5
2	Scientific Reports	England	28	2.83%	4.6
3	Nature Communications	England	27	2.73%	16.6
4	Biomaterials	Netherlands	26	2.62%	14.0
5	International Journal of Molecular Sciences	United States	21	2.12%	5.6
6	Journal of Hepatology	Netherlands	21	2.12%	25.7
7	Gastroenterology	United States	20	2.02%	29.4
8	Cells	Switzerland	17	1.72%	6.0
9	Plos One	United States	15	1.51%	3.7
10	Advanced Science	United State	14	1.41%	15.1

Distribution of countries and institutes

The world map depicting the contribution of each country on the basis of publication count is shown in Figure 3A. The international collaboration network in hepatic organoid research is shown in Figure 3B. Each node represents a country or institute, and each link reflects a collaboration. The colours of different nodes are based on the average year countries and institutes published their articles. A total of 57 countries and regions have contributed to hepatic organoid research, with the United States leading the way with 363 publications, closely followed by China (243), the Netherlands (156), Germany (140), and Japan (124). The United States and Japan have been active in recent decades. Furthermore, England and South Korea have become increasingly active in recent years. Figure 3C shows the institutional collaboration network in liver organoid-related research. Utrecht University (82, 8.27%) ranked first, followed by the Erasmus MC (65, 6.56% ), Hubrecht Institute (57, 5.75% ), Royal Netherlands Academy of Arts and Sciences (57, 5.75%), and Chinese Academy of Sciences (41, 4.14%). The top 10 most contributive countries and institutes are shown in Table 2.

Figure 3 The distribution of countries and institutes involved in hepatic organoid research. A: The world map depicting the contribution of each country on the basis of publication count; B: The international collaboration network in hepatic organoid research; C: The institutional collaboration network in hepatic organoid research. Each node represents a country or institute, and each link reflects a collaboration. The colours of different nodes are based on the average year countries and institutes published their articles.

Table 2 Top 10 countries and institutes contributing to publications in hepatic organoid research.

Rank	Country/region	Count	Institute	Count
1	United States	363	Utrecht University	82
2	China	243	Erasmus MC	65
3	Netherlands	156	Hubrecht Institute (KNAW)	57
4	Germany	140	Royal Netherlands Academy of Arts and Sciences	57
5	Japan	124	Chinese Academy of Sciences	41
6	England	74	University of California System	36
7	South Korea	60	University System of Ohio	34
8	Italy	59	Harvard University	32
9	Spain	39	Helmholtz Association	31
10	France	39	Cincinnati Children's Hospital Medical Center	30

Author and cocited author analysis

Figure 4A shows the author collaboration network. Each node represents an author, and each link reflects a collaboration. The colours of different nodes are based on the average year the authors published their articles. In terms of frequency and centrality, Clevers H (47 publications), Van der laan LJW (44 publications), Verstegen MMA (36 publications), Huch M (24 publications), and Spee B (24 publications) were the five most prolific authors. Figure 4B shows the cocited author collaboration network. Huch M (275 cocitations) was ranked first, followed by Sato T (239 cocitations), Broutier L (200 cocitations), Takebe T (171 cocitations), and Lancaster MA (125 cocitations). Table 3 shows the top 10 most cited scholars in the liver organoid field.

Figure 4 Author and cocited author collaboration network in hepatic organoid research. A: Author collaboration network in hepatic organoid research; B: Cocited author collaboration network in hepatic organoid research. Each node represents an author, and each link reflects a collaboration. The colours of different nodes are based on the average year the authors published their articles.

Table 3 Top 10 most cited scholars in the hepatic organoid field.

Rank	Author	Citations	Country	Institute	Centrality
1	Huch M	275	England	University of Cambridge	0.12
2	Sato T	239	Japan	Keio University	0.10
3	Broutier L	200	England	University of Cambridge	0.07
4	Takebe T	171	United States	Cincinnati Children's Hospital Medical Center	0.09
5	Lancaster MA	125	Austria	Austrian Academy of Sciences	0.05
6	Clevers H	96	Netherlands	Utrecht University	0.02
7	Barker N	93	England	The University of Edinburgh	0.08
8	Hu HL	88	China	Shandong University	0.02
9	Fotios S	86	England	University of Cambridge	0.06
10	Van de wetering M	70	Netherlands	Princess Maxima Center for Pediatric Oncology	0.07

Analysis of co-cited references

A cocited reference network was constructed to analyse the historical development trends of key clusters of research fields. As shown in Figure 5, the minimum visible cluster size was set to 25, and the cocited reference network was subsequently divided into 9 clusters, including “liver organoid”, “liver transplantation”, “regenerative medicine”, “intrahepatic cholangiocyte organoid”, “intestinal organoid”, “treatment”, “patient-derived organoid”, “organ-on-a-chip”, and “preclinical cancer models”. The modularity Q was 0.8213, and the mean silhouette S was 0.9262, which means that the clusters were reasonable and credible. Each coloured outline represents a cluster. Liver organoid research has been the largest cluster, and with the development of organoid technologies, patient-derived organoids, regenerative medicine, and intrahepatic cholangiocyte organoids have become the latest clusters. Table 4 shows the top 10 cocited references in hepatic organoid research and their main findings[4,23,25-32]. Huch M’s publication (2015) was the most cocited reference.

Figure 5 Cluster analysis of the cocited reference network in hepatic organoid research. Each coloured outline represents a cluster. The colours of different clusters are based on the average year in which similar articles were cited.

Table 4 Top 10 cocited references and main findings in hepatic organoid research.

Rank	Ref.	Count	Main findings
1	Huch M et al[25], 2015, Cell, volume 160	100	Established a long-term and stable human liver organoid culture condition, in which liver organoid can differentiate to functional hepatocytes and model liver disease
2	Hu HL et al[26], 2018, Cell, volume 175	82	Establishment of a long-term 3D organoid culture system for mouse and human primary hepatocytes from single hepatocytes, while retaining key morphological, functional and gene expression features
3	Broutier L et al[27], 2017, Nature Medicine, volume 23	79	Extend the culture system to the propagation of primary liver cancer organoids from three of the most common primary liver cancer subtypes
4	Broutier L et al[23], 2016, Nature Protocols, volume 11	78	Developed culture conditions for self-renewing 3D organoids that allow the long-term expansion of adult primary tissues from human and mouse adult liver and pancreas
5	Ouchi R et al[28], 2019, Cell Metabolism, volume 30	55	Developed a reproducible method to derive multi-cellular human liver organoids composed of hepatocyte-, stellate-, and Kupffer-like cells that exhibit transcriptomic resemblance to in vivo-derived tissues
6	Clevers H[4], 2016, Cell, volume 165	47	Reviewed the organoid applications in modeling human organ development and pathologies as well as personalized medicine
7	Huch M et al[29], 2013, Nature, volume 494	44	Lgr5+ stem cells in actively self-renewing tissues can also be extended to damage-induced stem cells in a tissue with a low rate of spontaneous
8	Van de Wetering M et al[30], 2015, Cell, volume 161	42	Established the tumor organoid cultures from 20 consecutive colorectal carcinoma patients
9	Takebe T et al[31], 2013, Nature, volume 499	42	This is the first report demonstrating the generation of a functional human liver organ from pluripotent stem cells
10	Boj SF et al[32], 2015, Cell, volume 160	39	Generated the pancreatic cancer-derived organoids and revealed that they are suitable for ductal pancreatic cancer research

3D: Three-dimensional.

Time zone visualization of co-occurring terms and burst terms in hepatic organoid research

Analysis of co-occurring terms under different years reveals the changes and trends in research topics over various timespans. Figure 6 shows the time zone of the co-occurring terms network map. Each node represents a term, and each link reflects co-occurrence. The 5 most frequently co-occurring terms were “liver organoid”, “hepatocellular carcinoma”, “stem cell”, “mouse model”, and “extracellular matrix”. Twenty terms with strong citation bursts beginning from 2010 to 2024 were identified. As shown in Figure 7, the blue line represents the time interval, and the red line represents the period of citation bursts. The top 5 terms with the strongest citation bursts were “liver-specific function”, “stem cell”, “tissue engineering”, “intestinal organoids”, and “tumour heterogeneity”. The terms with the strongest citation bursts beginning from 2022 to 2024 were “drug resistance”, “disease model”, and “patient-derived tumour organoids”, which suggests potential future trends in hepatic organoid research.

Figure 6 Time zone visualization of co-occurring term networks in hepatic organoid research. Each node represents a term, and each link reflects a term shift over time. 3D: Three-dimensional.

Figure 7 The top 20 terms with the strongest citation bursts in hepatic organoid research. The green line represents the time interval and the red line represents the period of citation bursts.

DISCUSSION

Along with the deepening understanding of the stem cell microenvironment and improvements in culture systems, especially the establishment of intestinal crypt–villus units from single stem cells in the absence of a nonepithelial cellular niche in 2009, the number of organoid studies has increased explosively[33,34]. The identification of Lgr+ stem cells has led to significant advancements in research and development within the fields of regenerative medicine and organoid technology. This has led to the successful establishment of a variety of liver organoid models, such as hepatic progenitor organoids, hepatocyte organoids, and patient-derived hepatocellular carcinoma (HCC) organoids, which are now available for in-depth research purposes[12,23,35].

General information

Mapping the global trajectory of hepatic organoid research from 2010 to 2024 reveals an expansive and evolving canvas of studies and innovations that continue to shape the horizon of this field. The number of published hepatic organoid studies published between 2010 and 2014 was relatively small, and the trend was stable. However, great achievements in hepatic organoid culture technology have been made since the generation of a functional human liver organ from pluripotent stem cells and the establishment of long-term and stable human liver organoid culture conditions[29,31]. The overall number of publications increased dramatically over the following ten years (2015–2024). Currently, organoid technology has become a useful tool for studies of liver diseases. Hepatic organoid-related research has sprung up in all fields of medicine, including basic biology, disease modelling, and drug discovery, and will likely increase further in the next few years[36-38].

Journal analysis revealed that, among the top 10 journals, the 6 journals Hepatology, Nature Communications, Biomaterials, Journal of Hepatology, Gastroenterology, and Advanced Science each had IFs greater than 10. Journals with IFs greater than 5 accounted for 90% of the top 10 journals, indicating that most of the hepatic organoid-related research articles were accepted by authoritative journals in the field. In terms of country and institution collaboration and contribution, the United States ranked first and contributed more than one-third of the total number of papers (36.63%). China followed closely, accounting for 24.12% of the total publications. The top 10 most productive institutions collectively contributed 46.92% of the total publications.

Authors and citation information

The articles published by the network of authors and cocited authors represent the academic authority in the field of hepatic organoid research, and deserve the long-term attention of researchers. Clevers H from Utrecht University is the most active author, and Huch M at the University of Cambridge is the most active cocited author. Clevers H and Huch M are two scientists who have made significant contributions to the fields of stem cell biology and organoid development. Clevers H is a professor at Utrecht University in the Netherlands and also the director of the Hubrecht Institute. He has pioneering work in the field of stem cell research, particularly in the study of Lgr5-positive intestinal stem cells[39]. His research has provided an important foundation for organoid technology development. In 2008, Huch M was a postdoctoral researcher in Clevers’ laboratory. They collaborated on several important research projects and together developed the first 3D hepatic organoid[29].

Huch M’s publication (2015) ranked first in the analysis of cocited references. She developed robust and sustainable culture conditions for human hepatic organoids, facilitating their differentiation into functional hepatocytes and enabling the modeling of liver diseases[25]. In addition, Hu HL (2018), also from Clevers’ laboratory, developed a long-term 3D organoid culture system for mouse and human primary hepatocytes from single hepatocyte, while retaining key morphological, functional and gene expression features[26]. Their collaborative efforts have yielded pivotal methodologies that have not only facilitated the exploration of fundamental research questions, such as the pathogenesis of liver diseases, but, also paved the way for advancements in autologous liver transplantation and the pursuit of personalized medical treatments.

Research hotspots and frontiers

The term analysis revealed that hepatic organoids are used in five main types of disease research, including HCC, liver fibrosis, hepatitis, regenerative medicine, and colorectal cancer. The time zone and burst analysis of terms represent past research hotspots and possible future research trends. Research into hepatic organoids has seen a progressive shift in focus from the initial exploration of model building, induction research in stem cells, bile ducts, and progenitor cells, towards a broader spectrum that includes lipid metabolism, single-cell RNA sequencing, and therapeutic applications such as drug discovery, drug resistance, and the use of patient-derived tumour organoids. Burst terms were considered prospective for future research frontiers. The terms “drug resistance”, “patient-derived tumor organoids” and “disease model” represented burst periods between 2022 and 2024.

Drug resistance: Compared with traditional 2D cell cultures, 3D organoids more accurately recapitulate primary tissue heterogeneity and maintain the stability of the genome[40]. Multidisciplinary bioengineering techniques related to organoid modelling are being implemented to construct more optimized and drug sensitive research patterns[41,42].

Patient-derived tumour organoids: With great advances in stem cell differentiation and gene editing techniques, an increasing number of studies have focused on the cultivation and induction of organoids from different primary tissues. Organoid technology can be utilized in patient-derived cancer organoid generation to study liver cancer biology, drug sensitivity screening, and personalized therapy[27,43].

Disease model: The current establishment and continuous advancements in hepatic organoids provide unique and valuable platforms for understanding the fundamental features of liver development and related disorders. These results indicate that organoid systems, as in vitro 3D culture models, are among the most promising and essential tools for studying diseases, including hepatitis C virus infection and nonalcoholic fatty liver disease[44], liver fibrosis[45], steatohepatitis[28], liver cancer[46], and cholangiocarcinoma[47].

Strengths and limitations

Although hepatic organoid models present many unique advantages in applications related to development and disease, many of these have just begun to be explored by scientists. Moreover, this bibliometric study has several limitations. First, our study specifically focused on English-language articles from the WoSCC database, which may have resulted in the exclusion of relevant studies published in other languages and other databases. Second, many affiliated research institutes that contributed to hepatic organoid-related studies were analysed independently, which affected the statistical results concerning the research institutes and the consistency of the acknowledged national contributions. Despite these limitations, bibliometric analysis remains a crucial tool for offering a comprehensive overview of the literature and global landscape of a certain discipline or field. Our study is the first bibliometric analysis and visualization of hepatic organoid research and can track research trends and the latest hotspots of hepatic organoid research.

CONCLUSION

In this study, we performed the first bibliometric and visual analysis of hepatic organoid research. We demonstrated that the overall number of publications related to hepatic organoid research increased dramatically over the past decade and will likely continue to rise over the next few years. The most prolific country was the United States, and the most active institute was Utrecht University. Clevers H and Huch M may be ideal candidates for academic cooperation. The major research topics pertained to applications of hepatic organoid technology in different liver diseases and the development of therapeutic drugs. Recent research on hepatic organoids has evolved from its initial emphasis on model construction and differentiation studies involving stem cells, bile ducts, and progenitor cells, towards a more comprehensive scope encompassing lipid metabolism, single-cell RNA sequencing, and therapeutic applications. Furthermore, patient-derived tumour organoids, disease models, and personalized medicine represent potential trends in future hepatic organoid research and should receive more attention.