Trends and Frontiers in Stem Cell Research for Sepsis: A Bibliometric Analysis (1990–2025)

Abstract

Purpose

To systematically map the 35-year intellectual evolution of stem cell research in sepsis and identify emerging frontiers for clinical translation.

Methods

We retrieved 3890 publications (1990–2025) from the Web of Science Core Collection. Multi-dimensional bibliometric analyses, including co-citation networks, keyword bursts, and alluvial flow mapping, were performed using CiteSpace, HistCite, and R to delineate the field’s trajectory.

Results

Annual publications increased significantly, peaking in 2024, with the USA and China as primary contributors. The research focus has undergone a major paradigm shift: from early “bone marrow transplantation” and hematopoietic reconstitution (1990s–2000s) to the immunomodulatory mechanisms of “mesenchymal stem cells” (2010s). Currently, the field has entered a “cell-free” era, characterized by intense research into “extracellular vesicles” and “exosomes” (2021–2025). Alluvial analysis identified “cancer”, “immunotherapy”, and “COVID-19” as dominant integrated modules. Notably, the emergence of “guidelines” and “precision care” highlights a growing emphasis on clinical standardization and targeted treatment for sepsis-induced organ failure.

Conclusion

This study demonstrates that the frontier of sepsis therapy is moving toward refined, secretome-based biologics. Our findings provide a strategic roadmap for researchers to prioritize high-potential therapeutic targets and for clinicians to design more focused trials, ultimately accelerating the integration of stem cell-derived products into mainstream sepsis management.

Introduction

Sepsis, defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, represents a formidable global health crisis.^1,2 It stands as a leading cause of morbidity, mortality, and critical illness worldwide, placing an immense burden on healthcare systems.³ The Global Burden of Disease Study estimated that in 2017 alone, there were 48.9 million incident cases of sepsis and 11.0 million sepsis-related deaths, accounting for nearly 20% of all global deaths.⁴ Despite significant advances in antimicrobial therapy, fluid resuscitation, and organ support, the mortality rate for sepsis and septic shock remains unacceptably high.⁵ Furthermore, a growing number of survivors experience long-term sequelae, including profound physical, cognitive, and psychological impairments, collectively known as post-sepsis syndrome, which severely diminishes their quality of life.^6,7 In recognition of its staggering impact, the World Health Organization (WHO) has designated sepsis a global health priority, underscoring the urgent need for novel and effective therapeutic strategies.⁸

The pathophysiology of sepsis is characterized by a complex and dynamic interplay of pro-inflammatory and anti-inflammatory responses that fail to return to homeostasis.⁹ The initial phase is often dominated by a hyper-inflammatory response, a “cytokine storm”, triggered by the recognition of pathogen-associated molecular patterns (PAMPs). This leads to the systemic release of a cascade of inflammatory mediators intended to eradicate the invading pathogens.¹⁰ However, an excessive and uncontrolled inflammatory surge can inflict collateral damage on host tissues and organs, precipitating endothelial dysfunction, microvascular thrombosis, and ultimately, multiple organ dysfunction syndrome (MODS), a hallmark of severe sepsis.^11,12 Paradoxically, this pro-inflammatory state is often followed by, or coexists with, a protracted state of profound immunosuppression, termed “immunoparalysis”.¹³ This phase is characterized by the apoptosis of key immune cells (such as lymphocytes), the functional exhaustion of surviving cells, and the expansion of regulatory cell populations, rendering the host highly susceptible to secondary nosocomial infections, which are a major cause of late mortality in sepsis patients.^14,15 The profound heterogeneity of this immune response, both between patients and over the course of the illness within a single patient, is believed to be a primary reason for the consistent failure of numerous clinical trials targeting single cytokines or specific inflammatory pathways.^16,17

The clinical management of sepsis is currently navigating a diverse landscape of emerging therapeutic modalities beyond traditional protocols. These include novel biological agents designed to neutralize specific inflammatory mediators or modulate immune checkpoints,¹⁸ as well as extracorporeal blood purification techniques, such as hemoperfusion, which aim to non-selectively remove circulating endotoxins and cytokines to mitigate the “cytokine storm”.¹⁹ While these single-target or physical-removal strategies have shown potential in specific patient subsets, the systemic and dynamic nature of sepsis-induced dysregulation often limits their overall efficacy. In this context, MSCs are investigated not as a replacement, but as a complementary, biologically “intelligent” intervention. Unlike static biologics, MSCs can dynamically sense the inflammatory microenvironment and exert pleiotropic effects—ranging from immunomodulation to enhanced bacterial clearance and tissue repair—offering a multifaceted response that aligns with the complex pathophysiology of sepsis.

In the face of these challenges, regenerative medicine, and particularly stem cell-based therapy, has emerged as a highly promising paradigm that moves beyond targeting single molecules to holistically modulating the dysregulated host response.²⁰ Among various stem cell types, mesenchymal stem/stromal cells (MSCs) have garnered the most significant attention due to their unique biological properties and established safety profile in clinical settings.²¹ Initially recognized for their multilineage differentiation capacity, the therapeutic potential of MSCs is now largely attributed to their powerful paracrine and immunomodulatory functions.²² A vast body of preclinical evidence demonstrates that MSCs exert multifaceted protective effects in sepsis models. They can sense the inflammatory microenvironment and orchestrate a sophisticated, context-dependent immunomodulatory response: suppressing the hyper-inflammatory cascade during the early phase while simultaneously enhancing macrophage phagocytic activity and bacterial clearance during the immunosuppressive phase, thereby helping to restore immune balance.^23–25 Moreover, MSCs secrete a broad array of trophic factors, anti-apoptotic molecules, and pro-angiogenic proteins that protect endothelial and epithelial barriers, mitigate organ injury, and promote tissue repair.^26,27 Some studies even suggest MSCs possess direct antimicrobial properties through the secretion of antimicrobial peptides.²⁸ This pleiotropic mechanism of action makes MSCs an ideal therapeutic candidate to counteract the complex pathophysiology of sepsis. Encouragingly, early-phase clinical trials have confirmed the safety and suggested the potential efficacy of MSC administration in patients with sepsis and its most common complication, acute respiratory distress syndrome (ARDS).^29,30

More recently, the field has evolved with the discovery that many of the therapeutic benefits of MSCs are mediated by their secreted extracellular vesicles (EVs), particularly exosomes.³¹ These nano-sized, lipid bilayer vesicles act as intercellular messengers, transporting a rich cargo of proteins, lipids, and nucleic acids (eg, microRNAs, lncRNAs) from the parent MSC to recipient cells, thereby modulating their function.^32,33 As a “cell-free” therapy, MSC-derived EVs (MSC-EVs) offer several distinct advantages over their parent cells, including lower immunogenicity, no risk of cellular replication or ectopic differentiation, ease of standardization and storage, and the ability to cross biological barriers.^34,35 Compelling evidence from sepsis models has shown that MSC-EVs can recapitulate, and in some cases exceed, the therapeutic effects of MSCs by attenuating systemic inflammation, protecting against organ damage, and improving survival.^36,37 As our bibliometric analysis reveals, “extracellular vesicles” has been one of the most prominent bursting keywords from 2021 to 2025, signaling a major paradigm shift in the field towards more refined, safer, and potentially more potent cell-free therapeutic agents.

Over the past three and a half decades (1990–2025), research at the intersection of stem cells and sepsis has grown exponentially, transitioning from early explorations of “bone marrow transplantation” to the current focus on “mesenchymal stem cells” and their “extracellular vesicles”. This explosion of knowledge has produced a vast and complex body of literature. While this rapid accumulation of data is a testament to the vibrancy of the field, it also presents a significant challenge for researchers. Navigating thousands of publications to systematically understand the field’s historical trajectory, identify foundational intellectual milestones, track the dynamic evolution of research hotspots, and accurately forecast future trends has become an increasingly daunting task for both seasoned investigators and newcomers. A macroscopic, data-driven “academic map” is needed to provide clear guidance.

Bibliometrics, the quantitative analysis of academic literature using mathematical and statistical methods, offers a powerful set of tools to construct such a map. By analyzing the metadata of publications—including countries, institutions, authors, keywords, and citations—bibliometrics can objectively visualize the knowledge structure, evolutionary pathways, and emerging frontiers of a research domain. For instance, co-occurrence network analysis can delineate influential research communities and collaborative patterns, keyword burst detection can pinpoint topics that have garnered intense interest over specific periods, and reference co-citation analysis can reveal the intellectual base and landmark papers that have shaped the field’s direction. Although bibliometric studies have been applied to the broader fields of sepsis or stem cells individually, to our knowledge, there has been no comprehensive, long-term bibliometric analysis specifically focused on the intersection of stem cells and sepsis over a 35-year span. The selection of a 35-year longitudinal window (1990–2025) is not merely a quantitative choice but a strategic one, designed to capture the complete lifecycle of therapeutic paradigms. This expansive timeframe allows us to move beyond the limitations of single-topic bibliometric studies—which often focus either on the clinical epidemiology of sepsis or the biological properties of stem cells in isolation—to provide a unique theoretical insight: the “evolutionary co-adaptation” of these two fields. By analyzing three and a half decades of data, we can systematically map how stem cell research has dynamically restructured itself in response to major clinical milestones, such as the shifting consensus definitions of sepsis. This long-term perspective is essential to distinguish between transient academic hotspots and the fundamental paradigm shift from early hematopoietic reconstitution to contemporary paracrine-mediated immunomodulation, thereby providing a robust theoretical framework for forecasting the next generation of cell-free precision therapies.

Previous bibliometric studies have predominantly focused on isolated domains, such as the general global trends in sepsis research^38–40 or the broad regenerative applications of mesenchymal stem cells across various diseases.^41,42 While valuable, these analyses often overlook the nuanced, co-evolutionary dynamics at the specific intersection of stem cell biology and sepsis pathology. This study fills this critical gap by providing a targeted, cross-disciplinary synthesis that maps how fundamental stem cell discoveries have been progressively “recruited” to address the shifting clinical definitions and failure of traditional anti-inflammatory therapies in sepsis.

Beyond academic curiosity, the data-driven “academic map” constructed herein provides actionable insights for multiple stakeholders. For clinical researchers, it identifies high-impact biomarkers and paracrine mechanisms that can be prioritized as primary endpoints in Phase II/III trials. For trial designers, the collaboration and keyword evolution maps highlight the necessity of shifting from “one-size-fits-all” cell injections toward stratified patient selection based on immune endotypes. Furthermore, for regulatory bodies and industry, the emergence of clusters like “guidelines” and “cell-free therapy” offers a temporal framework to evaluate the maturity of these technologies, aiding in the development of standardized protocols and manufacturing requirements. By delineating the lineage from bench to bedside, this study serves as a strategic compass for accelerating the clinical translation of stem cell-derived products into the standard of care for sepsis.

This study, therefore, aims to fill this critical gap by conducting a large-scale bibliometric analysis of 3890 publications on stem cells in sepsis retrieved from the Web of Science Core Collection from 1990 to 2025. Using a suite of bibliometric tools, including CiteSpace and HistCite, we seek to: (1) delineate the historical evolution of publication output; (2) identify the most productive and influential countries, institutions, authors, and journals, and map their collaborative networks; (3) uncover the intellectual foundation and landmark publications of the field through co-citation analysis; and (4) systematically track the evolution of research hotspots and identify current research frontiers and future trends through keyword burst detection, clustering, and timeline visualization, with a particular focus on emerging themes such as “extracellular vesicles”, “immunotherapy”, and “COVID-19”. By providing this panoramic, data-driven overview, we intend to offer a valuable reference and comprehensive knowledge map for the global research community, facilitating a deeper understanding of the field’s past, present, and future, and ultimately helping to accelerate the translation of promising stem cell-based therapies from the laboratory to the bedside for patients suffering from sepsis.

Methods

Data Acquisition and Statistical Processing

To ensure a comprehensive and high-quality assessment of the field, bibliometric data were retrieved from the Thomson Reuters Web of Science Core Collection (WoSCC), a database widely recognized for indexing over 12,000 influential academic journals. We constructed a rigorous search strategy employing Boolean logic to capture the intersection of stem cell biology and sepsis pathology. The literature retrieval strategy is shown in Table 1. The search timeframe spanned from 1990 to 2025. All identified literature records were exported as plain text files in the “Full Record and Cited References” format to preserve complete metadata and citation linkages. This process yielded a final dataset of 3890 bibliographic records (designated as DATA). Primary metadata—including publication country/region, contributing institutions, journals, authors, and article types—were extracted and subjected to descriptive statistical analysis using WPS Office Excel (Version 2019).

Table 1.

Literature Retrieval Strategy

Number	The Specific Retrieval Query
#1	TS=(“Stem Cells” OR “Cell, Stem” OR “Cells, Stem” OR “Stem Cell” OR “Progenitor Cells” OR “Cell, Progenitor” OR “Cells, Progenitor” OR “Progenitor Cell” OR “Mother Cells” OR “Cell, Mother” OR “Cells, Mother” OR “Mother Cell” OR “Colony-Forming Unit” OR “Colony Forming Unit” OR “Colony-Forming Units” OR “Colony Forming Units”)
#2	TS=(Sepsis OR “Bloodstream Infection” OR “Bloodstream Infections” OR “Infection, Bloodstream” OR Septicemia OR Septicemias OR “Blood Poisoning” OR “Blood Poisonings” OR “Poisonings, Blood” OR “Poisoning, Blood” OR “Severe Sepsis” OR “Sepsis, Severe” OR Pyemia OR Pyemias OR Pyaemia OR Pyaemias OR Pyohemia)) OR Pyohemias)
#3	#2 AND #1

Co-Occurrence Network and Visualization Analysis via CiteSpace

We employed CiteSpace (Version 6.2.R4) to visualize the structural and temporal dynamics of the scientific landscape through co-occurrence network analysis. In this context, scientific partnership is operationally defined as the simultaneous appearance of multiple authors, institutions, or countries within a single publication. The software visualizes these relationships using color-coded nodes and edges, where the edge color corresponds to the year a co-occurrence link was first established, and node size (represented by “tree rings”) reflects citation or occurrence volume. We incorporated Betweenness Centrality analysis to identify pivotal nodes (marked by purple rings) that bridge distinct clusters, and Kleinberg’s Burst Detection algorithm to highlight citation bursts (marked by red rings), which serve as indicators of emerging active topics or intense scientific attention. For the analysis of the DATA set, the time slicing was configured to the interval of 1990–2025 with a slice length of 1 year. Terms were sourced from Titles, Abstracts, Author Keywords, and Keywords Plus. We generated collaboration networks for countries, institutions, and authors, manually adjusting the visualizations for clarity. For keyword analysis, the timeline was segmented into four distinct periods (1990–1998, 1999–2007, 2008–2016, and 2017–2025) to map the evolution of research themes. Furthermore, clustering analysis was performed using the Timeline View to illustrate the rise and decline of specific conceptual clusters, while burst maps were generated for keywords, categories, and references to pinpoint transient yet high-impact research fronts.

Historiographic and Temporal Flow Analysis

To complement the network analysis and elucidate the chronological evolution of the domain, we utilized HistCite Pro 2.1 and alluvial flow mapping. HistCite was employed to identify seminal works by calculating the Local Citation Score (LCS)—the frequency with which a paper is cited within the analyzed collection—and the Global Citation Score (GCS) within the WoSCC database. By importing the 3890 records and setting the limit parameter to 30, we generated a citation historiography that visualizes the “citation backbone” of stem cell research in sepsis, enabling the rapid identification of high-impact studies. Additionally, to capture the fluidity of research themes over time, we constructed alluvial diagrams using the Alluvial Generator. Individual co-occurrence networks for keywords were exported from CiteSpace and processed to visualize how scientific modules split, merge, and intersect across different time slices. Quantitative visualizations, specifically the donut chart presented in Figure 10, were rendered using the R statistical computing environment (Version 4.2.2), utilizing the geom_bar function within the ggplot2 package (Version 3.4.4) to ensure precise graphical representation.

Figure 10.

Keyword clusters of the top six emerging research modules in Stem Cell Research for Sepsis. The modules represent the most active and distinct thematic sub-fields identified through clustering analysis. Different colors represent different keywords, and the proportion of color within each circle indicates the keyword’s relative weight within that module. (A) Cancer, (B) Pre-engraftment, (C) Adipose Tissue, (D) Extracelluar Vesicles, (E) Care, (F) Delivery.

Results

Historical Features of the Literature on Stem Cells in Sepsis

Historical Trends and Bibliometric Characteristics of the Literature

The temporal evolution of scientific output serves as a critical metric for quantifying the accumulation of knowledge and gauging the developmental trajectory of a specific domain. In this study, a comprehensive search strategy identified a total of 3890 publications related to stem cell research in the context of sepsis. This corpus involves contributions from 22,239 authors affiliated with 4029 institutions, spanning 110 scientific categories and published across 1168 distinct journals (Table 2). The annual distribution of research output is presented in Figure 1. The initial phase (1990) saw the publication of 10 relevant papers, followed by 17 in 1991. The period from 1990 to 1992 represented a nascent stage with relatively low output. However, a substantial inflection point occurred subsequently, with publication volume increasing rapidly from 1993 to 2013. This upward trajectory persisted beyond 2014, culminating in a peak in publication volume in 2024. In terms of publication venues, Bone Marrow Transplantation ranked first with 103 articles, followed by Critical Care Medicine (89 articles) and Shock (75 articles). Figure 2 delineates the top 20 most prolific journals, providing a strategic reference for researchers selecting venues for future dissemination.

Table 2.

Basic Information on the Distribution of the Publications

Categories	Publication	Articles	Review	Authors	Institutions	Journals	Subject Categories
Amount	3375	2901	474	22,239	4029	1168	110

Figure 1.

The annual distribution of publications.

Figure 2.

Key journals in Stem Cell Research for Sepsis. The top 20 most productive academic journals publishing on Stem Cell Research for Sepsis.

Citation Network Architecture and Intellectual Evolution

To elucidate the intellectual structure of the field over the past three decades, we constructed a reference co-citation network (Figure 3), comprising 1657 nodes and 5952 links. This high degree of connectivity indicates a robust and deeply intertwined research landscape. The temporal evolution of this network reveals distinct developmental phases: the early period (1990–2010), represented by gray-coded nodes, exhibits high density and extensive interconnectivity, serving as the foundational “root system” that supported subsequent disciplinary growth. The middle period (2011–2018), marked by blue nodes, indicates a transitional phase where research themes began to diversify and branch out. In the most recent period (2019–2025), the network architecture evolved into distinct, tighter clusters, signaling a simultaneous trend toward specialization and differentiation within the field.

Figure 3.

Citation co-citation network of Stem Cell Research in Sepsis. The network illustrates the relationships between key publications, with node colors representing their publication year from 1990 (white) to 2025 (red). The structure reveals the foundational core of the field and the subsequent emergence and evolution of distinct research fronts over time.

Analysis of specific high-impact contributions reveals that ten pivotal papers have dominated the citation landscape: Singer M (2016), Rudd KE (2020), Nemeth K (2009), Mei SHJ (2010), Krasnodembskaya A (2012), Wilson JG (2015), Matthay MA (2019), McIntyre LA (2018), Song YX (2017), and Lee JW (2009). These studies achieved co-citation frequencies of 121, 82, 61, 56, 50, 46, 45, 40, 37, and 35, respectively, underscoring their status as foundational works in the domain of stem cells and sepsis. This structural evolution is further corroborated by the reference timeline view. Complementing the co-citation analysis, we employed HistCite Pro 2.1 to map the historiography of the field (Table 3). The analysis identified three seminal papers with the highest impact: “Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production”, “Mesenchymal Stem Cells Reduce Inflammation while Enhancing Bacterial Clearance and Improving Survival in Sepsis”, and “Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes”. In these visualizations, node size correlates with citation importance, while the density of linkages reflects high betweenness centrality. By integrating these methodologies, we not only visualized the citation lineage but also pinpointed the high-contribution literature that has defined the field’s trajectory.

Table 3.

The Information of the Top 30 Literature Sorted by LCS and GCS Score

No	Article Information	Journal	LCS	GCS
1	Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production23	Nat Med	261	1910
2	Mesenchymal Stem Cells Reduce Inflammation while Enhancing Bacterial Clearance and Improving Survival in Sepsis43	Am J Resp Crit Care	202	566
3	Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes25	Am J Physiol-Lung C	122	266
4	Antibacterial Effect of Human Mesenchymal Stem Cells Is Mediated in Part from Secretion of the Antimicrobial Peptide LL-3744	Stem Cells	100	607
5	Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung45	P Natl Acad Sci USA	87	574
6	Mesenchymal stem (stromal) cells for treatment of ARDS: a Phase 1 clinical trial46	Lancet Resp Med	71	583
7	Exosomal miR-146a Contributes to the Enhanced Therapeutic Efficacy of Interleukin-1-Primed Mesenchymal Stem Cells Against Sepsis47	Stem Cells	68	387
8	Mesenchymal Stromal Cells Improve Survival During Sepsis in the Absence of Heme Oxygenase-1: The Importance of Neutrophils48	Stem Cells	67	139
9	Pre- and post-engraftment bloodstream infection rates and associated mortality in allogeneic hematopoietic stem cell transplant recipients49	Transpl Infect Dis	61	136
10	Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia50	Thorax	60	266
11	Blood Stream Infections in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Reemergence of Gram-Negative Rods and Increasing Antibiotic Resistance51	Biol Blood Marrow Tr	54	180
12	Therapeutic Effects of Human Mesenchymal Stem Cell-derived Microvesicles in Severe Pneumonia in Mice27	Am J Resp Crit Care	52	371
13	Mesenchymal stem cells ameliorate sepsis-associated acute kidney injury in mice52	Shock	51	91
14	Human Mesenchymal Stem Cell Microvesicles for Treatment of Escherichia coli Endotoxin- Induced Acute Lung Injury in Mice53	Stem Cells	49	1184
15	Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury54	Nat Med	49	767
16	Intestinal Domination and the Risk of Bacteremia in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation55	Clin Infect Dis	49	536
17	Human mesenchymal stromal cells decrease the severity of acute lung injury induced by E. coli in the rat56	Thorax	48	227
18	Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis57	Lancet Resp Med	48	169
19	Increased circulating endothelial progenitor cells in septic patients: Correlation with survival58	Crit Care Med	46	105
20	Cellular Immunotherapy for Septic Shock A Phase I Clinical Trial29	Am J Resp Crit Care	46	115
21	Treatment With Human Wharton’s Jelly-Derived Mesenchymal Stem Cells Attenuates Sepsis-Induced Kidney Injury, Liver Injury, and Endothelial Dysfunction59	Stem Cell Transl Med	43	80
22	Incidence, risk factors, and outcome of bloodstream infections during the pre-engraftment phase in 521 allogeneic hematopoietic stem cell transplantations60	Transpl Infect Dis	41	105
23	Concise Review: Mesenchymal Stromal/Stem Cells: A New Treatment for Sepsis and Septic Shock?61	Stem Cells	40	78
24	Mesenchymal stem cells as a therapeutic tool to treat sepsis62	World J Stem Cells	39	83
25	Mortality after bloodstream infections in allogeneic haematopoietic stem cell transplant (HSCT) recipients63	Infection	35	90
26	Exosomes from Endothelial Progenitor Cells Improve the Outcome of a Murine Model of Sepsis64	Mol Ther	35	168
27	Intravenous infusion of mesenchymal stem cells is associated with improved myocardial function during endotoxemia65	Shock	34	47
28	The acute respiratory distress syndrome66	J Clin Invest	33	1431
29	The Toll-like Receptor 3 Ligand, Poly(I:C), Improves Immunosuppressive Function and Therapeutic Effect of Mesenchymal Stem Cells on Sepsis via Inhibiting MiR-14367	Stem Cells	33	125
30	Adipose-derived mesenchymal stromal cells induce immunomodulatory macrophages which protect from experimental colitis and sepsis68	Gut	31	228

Abbreviations: GCS, global citation score; LCS, local citation score.

Global Patterns of Scientific Collaboration

The analysis of collaboration networks reveals extensive synergistic relationships across three dimensions: countries, institutions, and individual authors, as illustrated by the dense nodal linkages in Figure 4. The geographic network (Figure 4A and Supplementary Table S1) consists of 96 nodes and 745 links, with the United States, China, Germany, and Italy emerging as the dominant epicenters of research activity based on node size. The institutional collaboration network (Figure 4B) comprises 647 nodes and 1096 links; notably, Harvard University, the University of Texas System, the University of California System, and the University of Toronto represent the most central nodes, indicating their leading roles in driving research output. At the individual level (Figure 4C), the network highlights key opinion leaders with the highest publication volumes, including Matthay, Michael A; Yip, Hon-Kan; Laffey, John G; and Cairo, MS. The high density of connecting lines between these authors signifies a strong tradition of collaborative research within the community.

Figure 4.

Scientific cooperation networks in Stem Cell Research for Sepsis. (A) Network of country-level collaborations, with node size representing the volume of publications. (B) Network of institutional collaborations, showing both international and domestic partnerships. (C) Network of author collaborations, highlighting major research teams.

Spatiotemporal Dynamics of Research Frontiers

Evolution of Disciplinary Focus

The temporal migration of research attention across scientific categories provides a macroscopic view of the field’s evolution. Between 1990 and 2025, distinct citation bursts were identified in 105 out of 110 relevant subject categories, indicating a highly dynamic research landscape. Figure 5 visualizes the top 50 categories with the highest burst strength; blue lines delineate the observational timeline, while red segments mark the duration of heightened citation activity. Notably, the category Pharmacology and Pharmacy exhibited the most intense burst (Strength = 17.23) between 2022 and 2025, signaling a recent paradigm shift toward therapeutic interventions and drug development.

Figure 5.

The top 50 subject categories with the strongest citation bursts in Stem Cell Research for Sepsis from 1990 to 2025. The red segments on the timeline indicate the duration of the subject categories’ burst period, reflecting intervals when it attracted significant scholarly attention. The “Strength” value quantifies the intensity of each burst.

The chronological progression of these bursts reveals the multidisciplinary trajectory of stem cell applications in sepsis. Early research was anchored in diagnostic and clinical frameworks, exemplified by bursts in Radiology, Nuclear Medicine and Medical Imaging (2004–2007) and Critical Care Medicine (2007–2009). Subsequently, the focus expanded to broader health impacts (Public, Environmental and Occupational Health, 2012–2013) and cross-disciplinary applications (Agriculture, Multidisciplinary, 2017–2019). The most recent phase (2020–2025) is characterized by a deep dive into molecular mechanisms, dominated by Chemistry, Multidisciplinary and Biochemistry and Molecular Biology. Currently, as we approach 2025, 20 categories remain in an active burst state (Supplementary Table S2), with Pharmacology and Pharmacy, Chemistry, and Biochemistry leading the field, underscoring the current emphasis on molecular characterization and pharmaceutical translation.

Shifting Conceptual Hotspots

At a granular level, keyword burst detection elucidates the specific topics driving the field from 1990 to 2025. Among the 777 keywords exhibiting bursts, the top 50 are presented in Figure 6. The historical data highlights the foundational role of “bone marrow transplantation”, which commanded the highest burst strength (55.24) from 1996 to 2010, followed by “stem cell transplantation” (Strength = 15.7; 2006–2011). This indicates that the field’s origins were deeply rooted in hematopoietic reconstitution and cellular engraftment.

Figure 6.

Timeline of the top 50 keywords with the strongest citation bursts in Stem Cell Research for Sepsis (1990–2025). The red segments indicate the duration of a keyword’s burst period, representing intervals of intense scholarly interest. The “Strength” value quantifies the intensity of each burst.

However, a significant conceptual transition is evident in the recent data. The emergence of “extracellular vesicles” as a high-intensity burst (Strength = 20.24; 2021–2025) suggests a pivot away from whole-cell therapies toward cell-free, paracrine-mediated mechanisms. We identified 20 keywords that remain in an active burst state through 2025, representing the current research frontiers. These include “mesenchymal stem cells” (Strength = 8.2; 2023–2025) and “microvesicles” (Strength = 6.16; 2019–2025), alongside clinical standardization terms such as “guidelines” (Strength = 6.26; 2022–2025). This pattern indicates that future investigations will likely focus on the therapeutic efficacy of stem cell-derived secretomes and the standardization of clinical protocols (Supplemetary Table S2).

Identification of Seminal Literature

Citation burst analysis identified 1606 articles that garnered intense scholarly attention. Figure 7 lists the top 30 references with the highest citation bursts between 1990 and 2025. An analysis of the three most significant bursts reveals the pivotal studies that have shaped the intellectual structure of this domain.

Figure 7.

The references with citation bursts at different period. The colored horizontal lines represent the citation burst periods of each reference. Light blue line: The entire time span of citation activity (1990–2025). Red line: The specific interval when the reference experienced a strong citation burst.

Figure 7.

Continued.

Figure 7.

Continued.

The most prominent burst is associated with “The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)”, which maintained a citation burst from 2017 to 2021. This consensus paper fundamentally recalibrated the clinical landscape. A task force of 19 experts in pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Through a synthesis of evidence, Delphi processes, and electronic health record analysis, the task force concluded that previous definitions (focusing on SIRS) lacked specificity and sensitivity. They redefined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, operationalized by an increase in the Sequential Organ Failure Assessment (SOFA) score of 2 points or more (associated with >10% in-hospital mortality). Furthermore, they defined septic shock as a subset of sepsis involving profound circulatory and metabolic abnormalities (vasopressor requirement to maintain MAP ≥65 mm Hg and serum lactate >2 mmol/L), associated with mortality rates exceeding 40%. The introduction of the qSOFA (quickSOFA) score for rapid bedside assessment—identifying patients with altered mentation, systolic blood pressure ≤100 mm Hg, or respiratory rate ≥22/min—provided a standardized framework for early recognition and intervention.

The second key foundational work, “Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production” (Burst: 2009–2014), elucidated the immunomodulatory mechanism of Mesenchymal Stem Cells (MSCs). Addressing the high mortality of sepsis (>200,000 annual deaths in the US), this study demonstrated that infusing bone marrow stromal cells (BMSCs) into mice with polymicrobial sepsis (induced by cecal ligation and puncture) significantly reduced mortality and improved organ function. Crucially, the study identified that this protective effect was dependent on the reprogramming of host macrophages to secrete Interleukin-10 (IL-10). The mechanism involved LPS- or TNF-α-activated BMSCs releasing Prostaglandin E2 (PGE2), which acted on macrophage EP2 and EP4 receptors. This study established the therapeutic potential of culture-expanded, “off-the-shelf” human BMSCs for sepsis without the need for HLA matching.

The third landmark paper, “Mesenchymal Stem Cells Reduce Inflammation while Enhancing Bacterial Clearance and Improving Survival in Sepsis” (Burst: 2013–2017), further expanded the mechanistic understanding of MSCs. Using a C57Bl/6J mouse model of sepsis (CLP), researchers demonstrated that intravenous administration of MSCs six hours post-injury significantly reduced systemic and pulmonary cytokine levels, preventing acute lung injury and organ dysfunction. Microarray analysis revealed a global downregulation of inflammatory genes (eg, IL-6) and an upregulation of genes promoting phagocytosis and bacterial killing. Notably, MSC-treated mice exhibited enhanced bacterial clearance, attributed to increased phagocytic activity of host immune cells. This study provided robust evidence that MSCs exert beneficial effects through paracrine modulation of the host immune response, reinforcing their potential as an adjuvant therapy to reduce sepsis-associated morbidity and mortality.

Looking ahead to the 2025 horizon, we identified 104 references currently experiencing citation bursts. Table 4 details the top 20 active articles by burst strength, comprising 14 original research articles and 6 reviews. A notable characteristic of these publications is their immediate recognition; they entered the burst phase within one year of publication. The high prevalence of review articles suggests a need for synthesis in a rapidly expanding field, while the immediate impact of original articles highlights the urgency and clinical relevance of current findings in stem cell applications for sepsis.

Table 4.

The References with Citation Bursts from Beginning to 2025

Begin	End	Strength	Year	Type	Title
2022	2025	11.44	2020	Article	Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Attenuate LPS-Induced ARDS by Modulating Macrophage Polarization Through Inhibiting Glycolysis in Macrophages76
2022	2025	11.44	2021	Article	Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 20212
2022	2025	11.43	2020	Article	Human umbilical cord mesenchymal stem cell exosomes alleviate sepsis-associated acute kidney injury via regulating microRNA-146b expression77
2022	2025	11	2021	Article	Exosomal miR-21 secreted by IL-1β-primed-mesenchymal stem cells induces macrophage M2 polarization and ameliorates sepsis78
2022	2025	11	2020	Review	The biology, function, and biomedical applications of exosomes32
2023	2025	10.63	2022	Review	Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options79
2023	2025	9.1	2021	Article	Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury80
2022	2025	8.79	2021	Review	Immunomodulatory and Therapeutic Effects of Mesenchymal Stem Cells on Organ Dysfunction in Sepsis81
2021	2025	8.31	2020	Review	Efficacy of mesenchymal stem cell therapy for sepsis: a meta-analysis of preclinical studies82
2023	2025	8.13	2021	Article	microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway83
2022	2025	7.91	2020	Article	Protective function of exosomes from adipose tissue-derived mesenchymal stem cells in acute kidney injury through SIRT1 pathway84
2022	2025	7.61	2019	Review	The Pathogenesis of Sepsis and Potential Therapeutic Targets85
2023	2025	7.08	2022	Article	Differential Lung Protective Capacity of Exosomes Derived from Human Adipose Tissue, Bone Marrow, and Umbilical Cord Mesenchymal Stem Cells in Sepsis-Induced Acute Lung Injury86
2023	2025	7.08	2022	Article	Exosomes from adipose-derived mesenchymal stem cells alleviate sepsis-induced lung injury in mice by inhibiting the secretion of IL-27 in macrophages87
2023	2025	7.04	2021	Article	Human mesenchymal stromal cells small extracellular vesicles attenuate sepsis-induced acute lung injury in a mouse model: the role of oxidative stress and the mitogen-activated protein kinase/nuclear factor kappa B pathway88
2023	2025	6.91	2019	Review	Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs89
2023	2025	6.57	2021	Article	Bone marrow-mesenchymal stem cell-derived exosomal microRNA-141 targets PTEN and activates β-catenin to alleviate myocardial injury in septic mice90
2023	2025	6.5	2020	Article	Incidence, Risk Factors, and Outcomes of Patients Who Develop Mucosal Barrier Injury-Laboratory Confirmed Bloodstream Infections in the First 100 Days After Allogeneic Hematopoietic Stem Cell Transplant91
2023	2025	6.06	2022	Article	Circular RNA mmu_circ_0001295 from hypoxia pretreated adipose-derived mesenchymal stem cells (ADSCs) exosomes improves outcomes and inhibits sepsis-induced renal injury in a mouse model of sepsis92
2023	2025	6.06	2022	Article	Bloodstream Infections and Outcomes Following Allogeneic Hematopoietic Cell Transplantation: A Single-Center Study93

Emerging Trends and New Developments

The Temporal Variation of Keyword Clusters

The intrinsic semantic cohesion among keywords serves as a powerful lens for delineating the shifting “hotspots” and evolutionary trajectory within the domain of stem cell applications in sepsis. By stratifying the bibliometric data from the past three decades into four distinct six-year phases, we identified a clear conceptual metamorphosis through cluster analysis (Figure 8). In the initial phase (1990–1998), the research landscape was dominated by foundational concepts, yielding eight clusters such as #0 factor alpha, #1 colonization, and #2 bone marrow transplantation, which established the biological basis for subsequent inquiries (Figure 8A). The second phase (1999–2007) witnessed a transition toward mechanistic and therapeutic exploration, evidenced by the emergence of clusters like #0 nitric oxide and #1 chemotherapy, while #2 stem cell transplantation remained central (Figure 8B). As the field matured into the third phase (2008–2016), the focus expanded to specific clinical syndromes, highlighted by clusters such as #0 acute lung injury and #2 bloodstream infection (Figure 8C). However, the most significant paradigm shift occurred in the fourth and current phase (2017–2025), where the analysis of 1802 publications revealed a diversification into highly specialized niches (Figure 8D); while classic themes persist, six novel clusters emerged, including #1 hematopoietic stem cell transplantation, #2 identification (focusing on diagnostics and neonatal sepsis), #3 disease (exploring sepsis across diverse pathologies), #4 critical illness, and #5 heart failure. This distinct evolution from broad cellular therapies to targeted interventions for specific comorbidities—detailed in Supplementary Table S3 indicates that the contemporary frontier is defined by a granular understanding of how stem cells interact with complex, multi-organ failure syndromes.

Figure 8.

Evolution of keyword clusters in Stem Cell Research for Sepsis across four time periods Snapshots of thematic clusters derived from keyword co-occurrence analysis are shown for (A) 1990–1998, (B) 1999–2007, (C) 2008–2016, and (D) 2017–2025.

The Keyword Alluvial Flow Visualization

To elucidate the dynamic continuity, divergence, and convergence of research themes over time, we employed an alluvial flow visualization, which models scientific topics as fluid modules that evolve analogous to a river system (Figure 9). An analysis of the data spanning thirty years reveals that Module 1 (highlighted in red) represents the most robust and enduring tributary, consistently aggregating high-traffic keywords to form the central backbone of the field. Projecting into the 2025 horizon (Figure 10), the landscape crystallizes into six distinct, high-impact modules that forecast the immediate future of scientific inquiry: Module 1 (“Cancer”) stands as the largest assembly, integrating 116 keywords such as neutropenia, cancer patients, and leukemia, thereby underscoring the persistent critical challenge of sepsis in immunocompromised oncological populations (Figure 10A); Module 2 (“Pre-engraftment”) focuses on the epidemiological and clinical complexities of transplantation (Figure 10B); Module 3 (“Adipose Tissue”) highlights alternative stem cell sources and immune clearance mechanisms (Figure 10C); Module 4 (“Extracellular Vesicles”) marks a pivotal technological shift toward cell-free therapeutics, characterized by keywords like exosomes and mesenchymal stem cells (Figure 10D); Module 5 (“Care”) addresses the management of critically ill patients (Figure 10E); and Module 6 (“Delivery”) explores targeted interventions for acute lung injury (Figure 10F). As detailed in Supplementary Table S4, the persistence and reconfiguration of these modules suggest that the next quinquennium will be defined by the intersection of cancer immunology, cell-free exosomal therapies, and precision critical care management.

Figure 9.

Alluvial flow map of keyword evolution in Stem Cell Research for Sepsis (1990–2025). The map visualizes the rise, fall, and merging of thematic research modules over time. The X-axis represents the timeline divided into slices, and the Y-axis represents different thematic modules. The width of the streams corresponds to the number of keywords within a module, illustrating how research focus has shifted from general immunology to specific cellular pathways and clinical phenotypes over the 25-year period.

The Timeline Visualization of References

The timeline visualization, plotted according to the temporal span of citations, can predict which topics are emerging, which are classic, and which are relatively outdated. The timeline map for stem cell research in sepsis consists of 15 clusters arranged from top to bottom by size (Figure 11A).

Figure 11.

Recent citation trends of influential publications. (A) The citation timeline visualization, (B) The burst citation in #0, #2,#3,#5 and #10, (C) Citation frequency distribution of the burst citation, X-axis: Year, Y-axis: Cited frequency.

Among these, clusters #1 “cell-based therapy”, #4 “graft-versus-host disease”, #7 “procalcitonin”, #9 “colony-forming units”, #13 “immunosuppressed”, and #14 “mannan-binding lectin” represent classic topics. While they may not be the newest areas of inquiry, they maintain intricate connections with other clusters. In contrast, clusters #6 “granulocyte”, #8 “growth factors”, #11 “myeloablative therapy”, #12 “systems biology”, #15 “candida albicans”, and #16 “animal models” are relatively outdated topics. They show few connections to other clusters and lack subsequent development along their own timelines. Clusters #0 “sepsis syndrome”, #2 “covid-19”, #3 “extracellular vesicles”, #5 “hematopoietic stem cell transplantation”, and #10 “immunotherapy” are emerging topics. Their continuous activity on the timeline from their inception to the present suggests they will become future research hotspots. Supplementary Table S5 provides a more detailed overview of these emerging clusters. Furthermore, several classic papers (represented by large nodes with red circles) have played a pivotal role in driving the development of these subfields (Figure 11B). Cluster #0: The paper by Singer M (2016), “The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)”, has a co-citation frequency of 121. It provided updated definitions and clinical criteria for sepsis and septic shock, defining sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection and introducing the qSOFA score for rapid patient assessment. Cluster #2: The article by Matthay MA et al, “Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial”, has a co-citation frequency of 45. This study established the safety of a single intravenous infusion of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS, finding no predefined MSC-related adverse events and concluding that larger trials are needed to evaluate efficacy. Cluster #3: “Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Attenuate LPS-Induced ARDS by Modulating Macrophage Polarization Through Inhibiting Glycolysis in Macrophages”, with a co-citation frequency of 26, demonstrated that BMSC-derived exosomes mitigate LPS-induced lung injury by suppressing M1 macrophage polarization and promoting M2 polarization. This effect was mediated by inhibiting glycolysis in macrophages, suggesting a novel therapeutic strategy for ARDS. Cluster #5: The paper “Antimicrobial Resistance in Gram-Negative Rods Causing Bacteremia in Hematopoietic Stem Cell Transplant Recipients: Intercontinental Prospective Study” investigated antimicrobial resistance in GNR causing bacteremia in HSCT recipients. It found high rates of resistance to fluoroquinolones, carbapenems, and multidrug resistance, identifying risk factors and highlighting that inappropriate empirical therapy was associated with significantly higher mortality, questioning the utility of fluoroquinolone prophylaxis. Cluster #10: The review “Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options” discusses immunosuppression as a key contributor to sepsis mortality. It details the mechanisms, including the release of anti-inflammatory cytokines, apoptosis of immune cells, expansion of immunosuppressive cells, and activation of immune checkpoints, highlighting the potential of therapies targeting these pathways, such as immune checkpoint inhibitors.

We further analyzed the annual citation distribution of these five articles (Figure 11C). The trends predict that these foundational works will likely continue to be highly cited in the coming years.

Discussion

This bibliometric analysis, spanning thirty-five years of scientific literature, provides a comprehensive, data-driven cartography of the intellectual landscape of stem cell research in sepsis. Our study charts a clear and compelling evolutionary narrative: the field has progressively matured from early investigations into broad cell-replacement strategies, exemplified by “bone marrow transplantation”, towards a sophisticated focus on the precise immunomodulatory functions of “mesenchymal stem cells” (MSCs). Now, it stands at the cusp of a new frontier, rapidly advancing towards more refined, safer, and translatable “cell-free” therapeutics, namely “extracellular vesicles” (EVs). This trajectory not only mirrors our deepening understanding of the complex pathophysiology of sepsis but also aligns with a broader paradigm shift within regenerative medicine, moving from the complexities of living cell products to the pursuit of well-characterized, off-the-shelf biologics.^94,95

The theoretical value of this long-term analysis lies in its ability to delineate the “intellectual lineage” that shorter-term studies might overlook. A narrow analysis (eg, the last 5–10 years) might perceive the rise of EVs as a spontaneous technological trend. However, our 35-year trajectory reveals that EVs are the logical maturation of the MSC-secretome hypothesis, which was itself a response to the clinical failures of direct cell-engraftment models identified in the late 1990s. This longitudinal view provides a critical insight into the “translational inertia” of the field, showing that while biological concepts evolve rapidly, their integration into clinical “Guidelines” requires a decades-long accumulation of evidence. Consequently, this study provides a “macro-map” that helps researchers understand not just what the current trends are, but why they have emerged as the dominant solutions to historical bottlenecks in sepsis treatment.

One of the most striking findings of our analysis is the powerful citation burst of the keyword “extracellular vesicles”, which has dominated the research landscape in the last five years (2021–2025). This explosive interest is not a spontaneous event but is built upon more than a decade of research into the paracrine mechanisms of MSCs.⁹⁶ It was initially hypothesized that the therapeutic efficacy of MSCs relied on their engraftment and differentiation at sites of injury. However, accumulating evidence has decisively shown that in vivo survival and differentiation of MSCs are typically poor and transient, and their benefits are overwhelmingly mediated by their secretome.^97,98 As the key functional component of this secretome, EVs (particularly exosomes) serve as natural nanocarriers, transferring a rich cargo of bioactive molecules—including immunomodulatory microRNAs (eg, miR-146a, miR-223), proteins, and lipids—to recipient cells, thereby reprogramming their function.^99,100 Mechanistically, MSC-EVs have been shown to mitigate sepsis-induced acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) by inhibiting macrophage pyroptosis and hyperinflammation, promoting the polarization of macrophages towards an anti-inflammatory M2 phenotype, and preserving endothelial barrier integrity.^101,102 This cell-free approach retains most of the therapeutic benefits of the parent cells while elegantly circumventing many of the inherent challenges of cell-based therapies, such as immunogenicity, tumorigenic risk, and pulmonary vascular embolism, while offering significant advantages in manufacturing, quality control, dosing, and storage.^103,104 The ascent of EVs, therefore, signifies the field’s entry into a new era of precision medicine centered on advanced biologics.

Corroborating the rise of EVs, our timeline and keyword cluster analyses prominently identified “immunotherapy” as a critical emerging frontier. This reflects a pivotal conceptual shift in the field: sepsis is now understood not merely as an uncontrolled inflammatory event but as a profound disorder of immune homeostasis, characterized by an early cytokine storm and a subsequent, often debilitating, phase of immunoparalysis.^105,106 Whereas early stem cell research primarily viewed MSCs as a global anti-inflammatory agent, contemporary studies increasingly appreciate their role as bidirectional immunomodulators.¹⁰⁷ MSCs and their EVs can sense the local microenvironment and mount a tailored response, suppressing exuberant neutrophil and T-cell activation during hyper-inflammation, while enhancing monocyte/macrophage phagocytosis and antigen presentation to restore effective anti-pathogen immunity during the immunosuppressive phase.^94,108 This intelligent, context-dependent modulation is crucial for treating a disease as dynamically heterogeneous as sepsis. The emergence of the “immunotherapy” cluster also suggests a future where stem cell-based products are used in combination with other immunomodulatory strategies, such as immune checkpoint inhibitors (eg, anti-PD-1/PD-L1), to synergistically reverse sepsis-induced T-cell exhaustion—a highly promising avenue for future investigation.^109,110

Another salient finding from our analysis is the rapid formation of a distinct “COVID-19” cluster. The pathophysiology of severe Coronavirus Disease 2019, particularly the associated cytokine storm and ARDS, shares remarkable similarities with that of classical bacterial sepsis. Consequently, the global pandemic catalyzed an unprecedented “repurposing” of MSC therapies, which had already shown promise in preclinical sepsis and ARDS models, for the treatment of critically ill COVID-19 patients.¹¹¹ This resulted in the rapid initiation of hundreds of clinical trials worldwide to evaluate the safety and efficacy of MSCs for COVID-19-related ARDS.^112,113 While the definitive results of these trials are still being aggregated and analyzed, this global health crisis has undoubtedly acted as a powerful accelerator for the clinical translation of MSCs and their derivatives. It has spurred advancements in manufacturing processes, forged new regulatory pathways, and deepened our understanding of the mechanisms of cell therapy in the context of viral sepsis.¹¹⁴ The wealth of data and experience generated during the pandemic will have a lasting and profound impact on the future development of stem cell therapies for sepsis and ARDS from all causes.

Beyond therapeutic applications, our analysis of bursting categories—specifically the surge in “Pharmacology and Pharmacy” (Strength = 17.23) and “Biochemistry and Molecular Biology”—reflects a fundamental shift in how sepsis is modeled preclinically. Historically, the field relied heavily on animal models like cecal ligation and puncture (CLP). However, the persistent failure of translation from murine studies to human trials has led to the rise of stem cell-derived organoids and “Organs-on-a-Chip” (OoC) as high-fidelity human-centric platforms. By utilizing induced pluripotent stem cells (iPSCs) or adult stem cells to generate gut, liver, or lung organoids, researchers can now simulate sepsis-induced organ dysfunction and barrier breakdown in a controlled human environment. This methodological evolution is further catalyzed by the FDA Modernization Act 2.0 (2022), which formally recognizes non-animal testing methods, including microphysiological systems and organoids, as viable alternatives to traditional animal studies for drug development and safety assessment. We posit that the integration of MSC-derived EVs with these human-on-a-chip models will define the next generation of precision pharmacology in sepsis, facilitating more accurate screening of therapeutic candidates and reducing the ethical and biological limitations of animal-based research.

Furthermore, our alluvial flow analysis revealed the persistence and evolution of several key research modules, with those centered on “cancer” and “care” being particularly significant. This accurately reflects the two primary clinical arenas for the application of stem cell therapies in sepsis. Patients with hematological malignancies undergoing “hematopoietic stem cell transplantation” (HSCT) are among the most vulnerable to sepsis, owing to profound myelosuppression and immunodeficiency induced by conditioning regimens.^115,116 Sepsis remains a leading cause of transplant-related mortality in this population. Consequently, strategies to prevent or treat infectious complications in these patients, including the use of granulocyte transfusions or MSCs, have been an enduring research theme.¹¹⁷ The “care” module, on the other hand, represents the primary battleground for sepsis treatment: the intensive care unit (ICU). Keywords such as “critically ill patients”, “bloodstream infections”, and “multiple organ failure” within this module underscore the strong clinical orientation of the field, which is focused on translating these therapies into tangible benefits for ICU patients.¹¹⁸ The concurrent burst of the keyword “guidelines” further supports this, indicating a growing need within the community to establish standardized protocols for patient selection, treatment administration, and efficacy assessment as more clinical trial data become available.⁸²

While this study offers a panoramic and insightful overview of the field’s 35-year evolution, its inherent limitations must be acknowledged. First, our analysis was restricted to the Web of Science Core Collection. Although this database covers the vast majority of high-impact journals, it may exclude some regional journals or conference proceedings, potentially introducing a selection bias. Second, bibliometric analysis is, by its nature, a quantitative assessment of publication metadata and citation metrics. It can effectively identify trends and influential works but cannot appraise the scientific quality, rigor, or ultimate clinical value of individual studies. A highly cited paper may be influential for its novelty or controversy, which does not necessarily equate to its conclusions being correct. Third, our keyword analysis relies on the terms provided by authors and indexed by the database, which may not always capture the full conceptual scope of a publication. Finally, as our analysis concludes in early 2025, it cannot account for disruptive technologies or unforeseen research directions that may emerge thereafter.

While our bibliometric data identifies EVs and “immunotherapy” as high-intensity research frontiers, it is imperative to interpret these “hotspots” with caution to avoid overestimating their clinical maturity. Bibliometric bursts reflect intense academic interest and a surge in primary discovery, but they do not inherently equate to clinical readiness. Despite the exponential growth in publications, the transition of MSC-EVs from laboratory success to standardized clinical therapy faces formidable “real-world” bottlenecks. A primary challenge lies in the scalable manufacturing and standardization of EV products. Unlike synthetic pharmaceuticals, the molecular cargo of EVs is highly sensitive to the parent cell source, culture conditions, and isolation techniques, leading to significant batch-to-batch heterogeneity. This lack of reproducibility poses a major hurdle for establishing a universal dosing regimen and quality control metrics. Furthermore, the regulatory landscape for cell-free biologics remains in its infancy. Current frameworks, while evolving, have yet to provide specific CMC guidelines tailored for the complex, multi-component nature of secretome-based products. Addressing issues of long-term storage stability, biodistribution tracking, and the potential for off-target effects is essential before these therapies can move beyond early-phase safety trials. Therefore, while our map highlights the “paracrine shift” as the future direction, the field must now pivot from quantitative accumulation to qualitative refinement, prioritizing the resolution of these pharmacological and regulatory barriers to ensure that the promise of stem cell research translates into safe and effective treatments for sepsis.

Conclusion

This study systematically charts the 35-year evolutionary trajectory of stem cell research in sepsis, revealing a profound paradigm shift from early cellular replacement models toward paracrine-mediated immunomodulation. Our analysis provides a clear scientific insight: the future of the field is defined by the transition from “living cell” therapies to “cell-free” precision biologics, with MSCs remaining the indispensable biological foundation of this progress.

The identification of EVs as a primary research frontier is a logical response to the inherent limitations of whole-cell MSC therapy, such as pulmonary sequestration and manufacturing variability. EVs represent a more stable, measurable, and scalable pharmacological platform that retains the pleiotropic protective effects of MSCs while minimizing safety risks. Furthermore, the focus on immunotherapy reflects the field’s shift toward addressing the dynamic immune phases of sepsis—specifically, using the MSC secretome to “reprogram” host macrophages and reverse sepsis-induced immunoparalysis, a capability that distinguishes stem cell-based products from traditional single-target biologics. Within this framework, COVID-19 acted not as a separate research direction, but as a critical clinical “accelerator” that validated the efficacy of MSC-derived interventions against hyper-inflammatory cytokine storms under global scrutiny.

In summary, the integration of MSC-derived secretomes into the management of sepsis represents a promising frontier for regenerative critical care. To move forward, the global research community must prioritize the clinical stratification of patients based on immune phenotypes and the standardization of secretome manufacturing. By bridging the gap between biological potency and clinical precision, the immense potential of stem cell research can finally be translated into a life-saving reality for patients suffering from sepsis and its multi-organ complications.

Funding Statement

This work was supported by Science and Technology Project of Changzhou Health Commission (Grant No.QN202521). Joint Funds for the innovation of science and Technology, Fujian province (Grant No.2024Y9408). Traditional Chinese Medicine Science and Technology Project,Fujian province (Grant No.2025QNGGA004). Fujian Provincial Natural Science Foundation of China (Grant No.2026J001689).

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author, Rongsheng Han (E-mail: 531092324@qq.com), upon reasonable request.

Ethics Approval and Consent to Participate

Only publicly available data were used and no additional ethical approval was required.

Author Contributions

Kaiming Han: Conceptualization, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review and editing.

Hui Ding: Conceptualization, Data curation, Formal analysis, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.

Haiying Ma: Formal analysis, Investigation, Methodology, Software, Supervision, Writing – original draft.

Junbin Li: Data curation, Formal analysis, Investigation, Supervision, Validation, Writing – original draft.

Yizheng Zu: Funding acquisition, Project administration, Resources, Visualization, Writing – original draft, Writing – review and editing.

Rongsheng Han: Conceptualization, Project administration, Resources, Supervision, Visualization, Writing – review and editing.

All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that there are no conflicts of interest.