Stem cell therapy is considered a new treatment for a cluster of diseases. Mesenchymal stem cells (MSCs), which do not display associated hematological markers, have been proven safe and effective in clinical practice for over ten years (1). MSCs are notable for lacking the expression of CD40, CD40 ligand (CD40L), CD80, CD86, and major histocompatibility class II (MHC- II), all of which are required to activate effector T cells (2). As its low immunogenicity and immunoregulatory effects, MSCs can educate immune cells and ultimately regulate the disease-specific microenvironment through direct or indirect cell-to-cell communication, such as various surface molecules and extracellular vesicles (3). MSCs have important research value and broad application prospects based on these unique properties.

Liver disease is a leading cause of global death and morbidity (4–6). Many inflammatory liver diseases do not respond to treatment, and these individuals frequently progress to end-stage liver diseases, necessitating liver transplantation. MSCs have made great progress in liver basic and clinical research in recent years. MSCs have been reported to be capable of causing the differentiation of hepatocyte-like cells, which may hold promise in augmenting liver regeneration (7). Aurich H found that under conditions favoring hepatocyte differentiation, human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) obtained functions of hepatocyte differentiation, including urea production, glycogen synthesis, cytochrome P450 enzyme activity, and hepatocyte-specific transcription expression-carbamoyl phosphate synthase, albumin, and cytochrome P45 type 3A4 (CYP3A4) (8). MSCs have a hepatoprotective impact in mice with hepatic ischemia/reperfusion (I/R) damage, reducing hepatocellular apoptosis and mtROS accumulation through upregulating the PINK1-dependent mitophagy pathway (9). MSCs release the major soluble mediator milk fat globule-EGF factor 8 (MFGE8), which lowers extracellular matrix (ECM) proteins and liver fibrosis in mice by inhibiting transforming growth factor beta 1 (TGFB1)-mediated activation of hepatic stellate cells (HSCs) (10). In addition, He Y found that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) can inhibit inflammatory cell infiltration and hepatocyte apoptosis, most likely via inhibiting of Notch, IFN-γ/Stat1, and IL-6/Stat3 signaling in liver tissues of ACLF rats (11). These promising preclinical findings have sparked a slew of clinical investigations on MSCs. There is, however, no complete and impartial assessment on the trend of publishing outputs, influential countries/regions, institutions, or authors, and their collaboration, knowledge base, hotspots, and frontiers in MSCs and liver disease research.

The bibliometric analysis focuses on the system and features of research literature and has been widely used in qualitative and quantitative analysis of scientific literature to comprehend the knowledge structure and the relationships and clustering of studies (12, 13). Contributions from different nations, organizations, experts, and publications can be compared to describe and project future advancements in a certain study topic (14). Many scholars have used bibliometrics analysis in various fields of medicine, such as psychological disorders (15), cardiovascular disease (16), endocrine disease (17), digestive system neoplasms (18), ferroptosis (13), and biological signaling molecule (19). It is becoming increasingly important in assessing hotspots frontiers and formulating guidelines between MSCs and liver disease research.

Thus, this research explores the hotspots and frontiers trends of MSC research in liver disease over the past 20 years and forms a corresponding knowledge map with CiteSpace and VOSviewer. This study provides the latest progress, evolution path, frontier research hotspots, and future research trends in MSCs in liver diseases for basic research and clinical prevention and treatment.

This study is the first bibliometric analysis of the structural and temporal dynamics of MSCs in liver diseases. According to the WoSCC database, as of October 2, 2021, a total of 18167 authors from 3251 institutions in 113 countries have published 3404 papers on MSCs and hepatopathy in 926 academic journals. We used CiteSpace and VOSviewer to evaluate the spatial and temporal distribution, authors’ contributions, and journals of 3404 retrieved articles. We used literature co-citation and keyword co-occurrence analysis to identify the research knowledge base, hotspots, and frontiers in each period and define the theme’s core evolutionary route. Then, we identified the current research frontiers of MSCs in the field of liver diseases.

The absence of research on MSCs in liver disorders before 2001 implies a dearth of relevant data. A tiny number of studies began to appear between 2001 and 2006, and research was still in its infancy at that time. During this period, Jiang Y found that MSCs could differentiate into visceral mesoderm, including liver cells in vitro (47), which resulted in developing a novel technique for the long-term investigation of liver regenerative medicine. More and more researchers began to pay attention to the role of MSC therapy in liver diseases (47). Research publications on MSCs have exploded in the last ten years. Clinical data showed that autologous MSC infusion was utilized to treat end-stage liver disease with good tolerance (48). Hundreds of clinical trials are already underway, and thousands of individuals have received MSC treatment (49–52), indicating that MSC research in the field of liver disease science is expected to become a hot spot and research direction in the future.

Concerning the spatial distribution map of countries/regions and institutions, Table 2 and Figures 3 , 4 showed that China, the USA, and Japan were the top 3 high-yield nations. Furthermore, the United States and Germany were the earliest countries to take up the MSC study, followed by the Netherlands, Japan, France, England, and Sweden; these four countries are among the ten most productive. Professor Freeman (Freeman, L, 1978/1979), an American sociologist, proposed betweenness centrality as an index that measures the extent to which a point lies in the “middle” of other “point pairs” in the graph (53). It is mainly used to measure the bridge function value of nodes in the whole network structure (54). Of the top 10 countries in Table 2 , the United States has the highest betweenness centrality (0.54), which plays a key bridge role in national cooperation networks worldwide. Interestingly, the number of publications in China is substantially more than that in the United States, but the betweenness centrality of the former was lower than that of the latter. This result might be explained because China alone publishes a huge quantity of papers, resulting in low betweenness centrality. The top 10 institutions were from three countries. It is worth noting that, despite its late start (2008), Zhejiang University was able to become the center of the highest number of publications (107) and influence (0.2) in a short time. Furthermore, we discovered extensive collaboration between the University of Pittsburgh, Harvard University, the Chinese Academy of Medical Sciences, and other institutions, signifying significant contributions to MSCs in liver illnesses.

To identify the most productive authors, we rank authors based on the total number of articles they published on MSCs related to liver diseases and evaluate them in combination with other indexes to offer a more comprehensive view of the most prolific author (55, 56). Li L (50 papers) is the author with the highest number of publications, followed by Shi X (31 papers), Li J (19 papers), and Ding Y (16 papers). It is noteworthy that the betweenness centrality is relatively low (≤ 0.01), implying a lack of communication and collaboration among authors in this work. It can be seen from Figure 5A that the distribution of researchers is relatively scattered, and the main researchers, such as Lanjuan Li, Yitao Ding, and Li Li, do not form a network, indicating a lack of academic exchanges between researchers. Therefore, it is strongly advised that academics from the United States, China, and other countries break down academic boundaries, collaborate, and communicate to advance MSC research and development in liver illnesses. Three writers were co-cited more than 300 times among the total cited authors, with Pittenger MF receiving the most co-citations (384 citations), followed by Dominici M (384 citations) Le Blanc K (305 citations).Furthermore, we can see that Pittenger MF (0.17) and Parekkadan B (0.10) have high centralities. In 1999, Pittenger MF and his colleagues identified the multilineage potential of MSCs in vitro (45). This finding reveals that hMSCs can proliferate widely and maintain the ability to differentiate multiple various cell types in vitro, establishing their stem cell properties, and their cultivation and selective differentiation should provide a further understanding of the important precursors of this diverse type of tissue. This research will confirm that MSCs have the potential to provide innovative therapies for injured or diseased tissue, as well as the theoretical underpinning for MSCs to differentiate into liver cells. Moreover, Parkkadan B and his colleagues further found that systemic infusion of MSC conditioned medium (MSC-CM) induces liver protection in acute liver injury by inhibiting cell death and stimulating repair procedures (38, 57). This discovery aided in the paradigm change from basic MSCs to extracellular vesicles (EVs). These prominent academic pioneers and emerging young researchers can attract a large number of talented researchers to join MSCs in the clinical transformation of liver diseases.

Journal and co-cited journal analysis can provide considerable information, which helps researchers choose appropriate journals to submit papers (58). Our study found that nearly one-fifth (19.01%) of the total papers published in the top ten most active journals related to MSCs in the field of hepatopathy, suggesting that the literature distribution is relatively concentrated. Table 4 showed that Stem Cell Research & Therapy (126 publications, IF: 6.832) published the most articles, while Hepatology attracted the largest number of co-citations. Both of these are journals on medicine research, experimental medicine, cell biology, cell & tissue engineering, which is consistent with the dual-map analysis ( Figure 6 ). The dual-map overlay of journals represents a subject distribution of academic journals (59, 60). Figure 6 showed two main citation paths from Molecular/Biology/Genetics co-cited journals to Medicine/Medical/Clinical journals and from Molecular/Biology/Genetics and Healthy/Nursing/Medicine co-cited journals to Molecular/Biology/Immunology journals, implying that MSCs related studies in liver disease have developed from cell biology to clinical medicine (61). Meanwhile, journals with IF>5 accounted for most of the top 10 journals (60%) and co-cited journals (80%), suggesting that these journals have interests and play significant roles in this field, which reminds scholars interested in this topic should pay more attention to these journals.

Marrow-derived stem cells could differentiate into nonhematopoietic cells of multiple tissues, including epithelial cells of the liver, gastrointestinal (GI) tract, and myocytes of heart and skeletal muscle (62). It can be seen from Figure 7B that it is the earliest Cluster # 3 (marrow-derived stem cell), which was the first report that bone marrow-derived stem cells had hepatic differentiation potential (63–65). Subsequently, Schwartz, R.E and his colleagues found that postpartum bone marrow-derived MSCs combined with a variety of growth factors, cytokines, and compounds (i.e., HGF, epidermal growth factor [EGF], fibroblast growth factor [FGF]-2/-4, etc.) could increase the expression of hepatocyte markers such as HNF-3b, GATA4, transthyretin, albumin, a-fetoprotein, CK18, and CK19 (66). In addition, Cluster # 2 (functional hepatocyte) further studied the hepatogenic differentiation capacity of MSCs in many independent studies on BM-MSC (37, 40, 67), hAT-MSCs (8), UCB-MSC (68) and human placenta-MSCs (hPMSCs) (69). In this cluster, MSCs can effectively rescue experimental liver failure, promote liver regeneration, and provide a potential alternative therapy for liver transplantation (35). The aforementioned two clusters aided the advancement of liver tissue engineering (Cluster # 8) and provided a theoretical foundation for using MSCs in the treatment of a variety of liver illnesses (41). Due to the low retention rate and low survival rate, MSCs need to be combined with a variety of biologically active tissue structures to effectively integrate into the target tissue, such as polyethene glycol hydrogels (70), alginate (71), collagen (72, 73) and chitosan (74). MSCs could be transformed in vitro into functional hepatocyte-like cells through induction using a specific biomatrix scaffold-decellularized liver matrix (75). The natural ECM framework allows for specified differentiation of stem cells into mature cell types in space, making this an appealing 3D bioscaffold for cell biology and tissue regeneration investigations.

In addition to the properties of hepatic differentiation, Cluster # 6 (mesenchymal stem cell) demonstrates that MSCs have low immunogenicity and an extensive immunoregulatory role via cell contact-dependent mechanisms and soluble factors (76). MSCs regulate many types of innate immune cells in inflammatory sites, including macrophages, dendritic cells, and natural killer (NK) cells (77–79). One of the main adaptive immunomodulation for MSCs is the regulation of T cells. MSCs not only inhibit the proliferation of T cells (80) but also inhibit the reaction of naive T cells and memory antigen-specific T cells (81). MSCs also inhibit the activation of cytotoxic CD8⁺ T cells and the differentiation of Th1 and Th17 cells (82) while promoting the Treg differentiation and activity (83, 84). In addition, the role of MSCs on the activation, proliferation, and antibody production of B cells has received less attention in liver diseases, which poses new requirements and challenges for researchers (85).

Their immunoregulatory capabilities and differentiation capacity give them Cluster#7 (therapeutic potential) for clinical treatment of pathological liver disorders in which inflammation and immunological, pathological responses play a key role. These liver diseases mainly include Cluster#0 (liver cirrhosis) and Cluster#5 (graft-versus-host disease). In Cluster#7 and Cluster#5, we found that MSCs were the clinical, theoretical basis for treating liver diseases. Cluster#0 (liver cirrhosis) is the largest cluster from Figure 7 . The main focus of this cluster is to explore the role of MSCs in the randomized controlled trials (RCT) studies of liver cirrhosis from the perspective of clinical application (39, 42, 51, 86).

In basic studies, the mechanism of MSCs in treating liver cirrhosis has been evaluated from multiple perspectives. Chronic injury factors such as hepatitis virus and alcohol can gradually destroy the endothelial barrier and liver cells, causing inflammatory cell infiltration and activating hepatic stellate cells (HSCs) (87). Activation of HSCs (aHSCs) obtains a phenotype of myofibroblasts characterized by increased expression of α-smooth muscle actin (α-SMA) and increased production of ECM components, growth factors and cytokines, which is the main determinant during liver fibrosis (88). In the progression of liver fibrosis caused by different chronic injury factors, MSCs migrate to the liver fibrosis microenvironment to participate in liver injury repair. MSCs have a direct anti-fibrosis effect on HSCs by MSC-secreted cytokines/growth factors or cell-cell contact, which can inhibit the activation of HSCs and the potential of producing ECM and induce apoptosis of HSCs. MSCs have an anti-fibrotic impact on HSCs through a paracrine mechanism, such as matrix metalloproteinases-13(MMP-13), MMP-9 (89), MFGE8 (10, 90), tumour necrosis factor-inducible gene 6 protein (TSG-6) (91, 92) and hepatocyte growth factor (HGF) (93). Transplantation of MSCs enhanced the activity of MMP-9 and MMP-13 and attenuated activation of tissue inhibitors of metalloproteinase1 (TIMP-1), resulting in increased degradation of ECM proteins in the fibrotic liver (89, 94). MFGE8 secreted by MSCs downregulates the expression of TGFβ1 receptor by binding to α_vβ₃ integrin on HSCs and interferes with the activation of TGFβ1 mediated HSCs, thereby promoting fibrosis regression (10). TSG-6 induces HSCs transformation into stem cell-like cells in vitro, and TSG-6-treated HSC-derived organoids can repair fibrotic liver (92). HGF derived from MSCs can also accelerate HSCs apoptosis, and MSCs cultured with HGF can improve serum albumin level, reducing liver fibrosis (93). In addition, MSCs inhibit HSCs activation and proliferation through direct cell-cell contact mode. Chen et al. found that MSCs induced arrest of HSCs in G0 cells via Notch-dependent pathway and significantly inhibited the proliferation and α-SMA expression of HSCs (95). MSCs also have an indirect anti-fibrosis impact by regulating immune cells, such as macrophages, and decreasing the activity of HSCs (96). In addition, MSCs conditioned medium and extracellular vesicles have been shown to reduce liver fibrosis (97) greatly. Although some literature suggests that the potential contribution of bone marrow-derived cells, such as fibrocytes and MSCs, to fibrogenic myofibroblasts has not been excluded (98, 99), some clinical trials using autologous and allogeneic MSCs transplantation have been carried out in patients with fibrosis, with a slight improvement of clinical parameters (such as albumin, creatinine) without serious adverse reactions, which indicates that MSCs have potential therapeutic effects on liver diseases (50, 100). However, few clinical trials involving MSCs improving liver failure and survival rates following liver transplantation, posing new challenges for researchers.

Actually, several classes of pharmacological agents are being used for the treatment of liver fibrosis, dependent on the aetiology, staging and progress of liver fibrosis (101, 102). Although the role of MSCs in mitigating fibrosis is encouraging, concomitant pharmacological agents remain a challenge for the treatment of liver fibrosis. Melatonin (MT) is the product of the pineal gland and has a variety of physiological functions. This hormone is an effective targeted therapy for liver fibrosis. Excitedly, Mias C. et al. found high expression of MT receptors (MT1and MT2) in MSCs, and it could enhance survival (103) and homing (104) of MSCs through a receptor-mediated mechanism. Preconditioning of MSCs with MT showed lower expressions of TGF-β1 and Bax and lowered ALT content but higher expressions of MMPs and Bcl2 with the MSCs group in the treatment of liver fibrosis (105). Similarly, vitamin E (Vit E) is widely considered one of the strongest antioxidants in nature, Vit E pretreated MSCs reduced the Timps/Mmps and promoted the degradation of ECM protein by inhibiting TGF-β1 signaling pathway during liver fibrosis (106). Most medications for liver fibrosis promote MSCs, but some may limit their viability or function. For example, rapamycin inhibits hepatic fibrogenesis by regulating the balance of Th17/Treg cells (107), but the beneficial role of MSCs will be antagonized by rapamycin via decreasing cell viability, differentiation, and proliferation (108). Therefore, more consideration should be given when selecting the combination therapy with MSCs.

Although Cluster#5 (mesenchymal stem cell therapy) has been reported to treat liver diseases in laboratory, preclinical and clinical trials, some issues still need attention. Long-term liver fibrosis can promote the abnormal proliferation, regeneration and repair of hepatocytes, making hepatocytes prone to spontaneous mutations, thus developing into hepatocellular carcinoma (HCC). In this process, MSCs, as a part of the fibrosis inflammatory microenvironment matrix, may be involved in the initiation and progression of HCC (109, 110). In the initial stage of HCC (Is), MSCs showed protective effects against drug damage by reducing DNA damage and ROS accumulation. In addition, MSCs in Is also have anti-inflammatory and anti-liver fibrosis effects. However, in the progressive stage of HCC (Ps), MSCs promote HCC formation not only by promoting cancer cell proliferation but also by promoting stem cell-like characteristics and epithelial-mesenchymal transition (EMT) of hepatoma carcinoma cell (111). Furthermore, when MSCs differentiated into hepatocytes after malignant transformation, the abnormal expression or localization of some genes may be related to tumour phenotype, such as β-catenin (112). Gleeson, B. M. et al. demonstrated that tissue factor (TF) is expressed on the surface of MSCs, which is the key promoter of the soluble coagulation cascade. This expression profile in vitro leads to the prethrombotic phenotype of MSCs and aggravates the complications of acute myocardial infarction (AMI), including microvascular obstruction (113). The potential tumorigenicity and microvascular obstruction of MSCs in vivo inhibit the clinical application of MSCs in the current regenerative medicine. Moreover, the short life span, easy agglomeration, and low transplantation rate of MSCs also limit the clinical application (114). With the further evolution of clusters, MSC-derived Cluster#1 (extracellular vesicles) in liver diseases gradually emerge.

With the further evolution of clusters, MSC-derived Cluster#1 (extracellular vesicles) in liver diseases gradually emerge. Recently, evidence has suggested that MSCs exerted their therapeutic effects in a paracrine manner Parekkadan B found that MSCs-CM derived from MSCs can reverse fulminant hepatic failure (57). MSCs conditioned medium (MSCs-CM) includes free soluble factors and EVs, which are divided into three categories, including exosomes (30–100 nm in diameter), microvesicles (100–1000 nm in diameter), and apoptotic bodies (500–2000 nm in diameter), may promote tissue regeneration, immune regulation, and angiogenesis by mediating intercellular micro-communication and transporting paracrine factors (115–117). Exosomes contain various lipids, proteins, and nucleic acids, such as lncRNAs and miRNAs, which play an important role in regulating homeostasis (118). MSCs-derived exosomes without self-replication have a lower risk of ectopic differentiation, tumorigenesis, immune rejection, and genetic instability (119). Meanwhile, Tamura et al. demonstrated that MSCs-derived exosomes pass through microvascular and are broadly distributed in damaged liver tissues (120). MSCs-derived exosomes improve liver function and hepatocyte proliferation and reduce apoptosis and liver necrosis in multiple liver disease models (97, 121, 122). Exosomes derived from MSCs have attracted much attention in regenerative medicine and tissue engineering. There is a scarcity of large-scale clinical evidence to back this up, and future research is needed to overcome these constraints.

Co-citation determines the topic’s knowledge base and clustering evolution, and keyword co-occurrence analysis can be the research hotspot and frontier of the topic. Excitedly, keyword co-occurrence analysis is a further extension and expansion of hot spots, some new terms, such as “machine perfusion”, “liver transplantation”, and “microRNAs”, which also may become research hotspots in the future. The term “machine perfusion” refers primarily to the continuous perfusion of transplants to mimic the body’s physiological state. Transplants can recover metabolism and even function during perfusion, especially at room temperature with matrix and oxygen supply in the machine perfusion system (123). As is well known, liver transplantation is still the definitive treatment for patients with end-stage liver failure, but the number of acceptable donor organs limits this definitive treatment. The emergence and application of (donation after circulatory death) DCD provide the possibility to solve the shortage of clinical liver supply (124). However, the long-term hepatic ischemia-reperfusion injury (IRI) and intracellular reactive oxygen species (ROS) injury lead to the damage of DCD donor liver structure and function, which may lead to complications such as primary non-function after liver transplantation (125). Machine perfusion has become a novel strategy for liver graft preservation, and the treatment with MSCs has unique advantages in the clinical application during perfusion in recent years (126, 127). Yang et al. confirmed that MSCs could inhibit macrophages activation, reduce ICAM expression, improve epithelial cell injury, and improve liver microcirculation of DCD during normothermic machine perfusion (128, 129). In addition, several new organ preservation technologies such as ischemic pre-conditioning (IPC), ischemic post-conditioning (IPostC) and remote ischemic conditioning (RIC) can also improve the availability of transplanted liver (130). The clinical application of new technologies combined with MSCs in liver transplantation will undoubtedly be another research hotspot.

MicroRNAs, as a unique class of non-coding RNAs, regulate the expression of their target genes at post-transcriptional level (131). Many studies have shown that microRNAs derived from exosomes of MSCs hepatocytes play a crucial role in the pathological and physiological processes of the liver, including hepatocyte differentiation, diseases and HCC. Cui, L. et al. found that miR-1246, miR-1290, miR-30a, miR-148a, miR-424 and miR-542-5p were highly expressed in MSCs during liver differentiation (132). Ectopic overexpression of the seven microRNAs can stimulate MSCs to transform into functional hepatocytes, improving liver injury induced by CCL4. Inhibition of let-7b caused upregulation of liver-enriched transcription factors, an increase in the expression of miR-122, and accumulation of MSCs in the G0/G1 phase of the cell cycle, activating hepatic differentiation (133). In the pathological and physiological processes of the liver, MSCs decreased TNFRSF21 (DR6) expression and hepatocyte apoptosis and improved ACLF by inducing miR-20a-5p expression in exosomes and hepatocytes (134). Exosomal miRNA-299-3p inhibited the inflammatory response and NLRP3 activation in the transplantation models to repair liver tissue (135). Interestingly, a variety of microRNAs in the extracellular vesicles of MSCs show anti-hepatoma effects, such as miR−199a−3p, miR-199a, miR-15a and miR-375 (136–139). In addition, long non-coding RNAs (lncRNA) and circular RNAs (circRNA), as components of non-coding RNAs, also play an irreplaceable role in the underlying mechanism of MSCs in the treatment of liver diseases (140, 141).

Through the analysis and visualization of bibliometrics, this field’s structural and temporal dynamics can be understood to some extent. The research has some certain limitations inherent in bibliometrics. First, the data is retrieved only from the WoSCC database, and some important findings published in other databases may be missed. However, WoSCC is an authoritative and comprehensive database in the medical field. WoSCC data represent most of the information to some degree (142–144). Secondly, data are included only in research articles and reviews. Nevertheless, the amount of data we analyze is large enough to reflect MSCs research in liver diseases. Lastly, VOSviewer and CtieSpace may miss some information because they cannot analyze the full text of publications, leading to bias as reported in other bibliometric studies.

MSCs are generally considered a safe and potentially relevant treatment strategy for liver diseases. The bibliometric analysis provides an objective and quantitative method for evaluating trends and frontiers of MSCs in liver diseases. With the help of CiteSpace and VOSviewer, we have a deeper understanding of the research status, evolution path, frontier hotspots, and future trends of MSCs in liver diseases in recent 20 years. The leading countries are China and the US; however, it is necessary to strengthen cooperation and exchanges among countries, institutions, and authors. Increasing numbers of articles published in international core journals show a significant impact. Tissue engineering, translational medicine, and extracellular vesicle of MSCs in liver diseases will focus on future research. This study can provide important clues for researchers to understand this field’s structural and temporal dynamics.

BS, conception and design, data analysis and interpretation, and manuscript writing. Y-FQ, S-HR and Q-FP, collection and assembly of data, data analysis, and interpretation. HQ, Z-BW, H-DW, G-ML, Y-LZ, C-LS, J-YZ, and XL, collection of data and data analysis. HW, conception and design, financial support, administrative support, manuscript writing, and final approval of the manuscript. All the authors have read and approved the final content of this manuscript.

This work was supported by grants to HW from the National Natural Science Foundation of China (No. 82071802), Science and Technology Project of Tianjin Health Commission (No. TJWJ2021MS004), Tianjin Key Medical Discipline (Specialty) Construction Project and to Z-BW from the National Training Program of Innovation and Entrepreneurship for Undergraduates (No. BK11020220).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.