Harnessing stem cell therapeutics in LPS-induced animal models: mechanisms, efficacies, and future directions

Abstract

The severity and threat posed by inflammation are well documented, and lipopolysaccharides (LPS), as important inducers of inflammatory responses, are widely recognized for studying host immunity and the resulting tissue and organ damage. The LPS-induced disease model, triggers a remarkable release of inflammatory factors, immune and coagulation dysfunction, and damage to vital organs such as the brain, lungs, heart, liver, and kidneys. Recently, the role of mesenchymal stem cells (MSCs) in various clinical diseases has garnered significant attention due to their immunomodulatory, anti-inflammatory, tissue healing, anti-apoptotic, and antibacterial properties. Despite the common use of LPS models to induce disease models and simulate acute inflammation, the integration of stem cell therapy within these models remains underexplored. This article integrates the LPS induced animal model and reviews the current evidence regarding the therapeutic mechanisms of stem cells in LPS-induced disease models across various human body systems. Furthermore, this review predicts and hypothesizes the feasibility and potential of using stem cells in disease models that have not yet been extensively studied, based on existing animal inflammation models.

Graphic abstract

Introduction

Inflammation is a local pathological process characterized by a defensive response to damage caused by inflammatory factors. Owing to their high mortality rates, inflammation-related diseases have become a global medical challenge [1]. Lipopolysaccharide (LPS), known as an inflammatory inducer, can trigger responses in monocytes, macrophages, endothelial cells, and epithelial cells, activating cellular signaling pathways that result in a surge of cytokines and other inflammatory mediators [2]. Injection of bacterial LPS into the human body results in increased plasma pro-inflammatory cytokines and disease onset. Therefore, inflammation-related animal models are usually induced by administering LPS to study the mechanisms of diseases associated with inflammation and to assess the efficacy of pharmaceutical interventions. However, no effective treatment methods currently exist to improve inflammation-related diseases such as sepsis and multi-organ dysfunction.

Mesenchymal stem cells (MSCs) are multipotent stem cells, having the potential for multidirectional differentiation and migration. MSCs originate from various organs and tissues, such as the muscle, umbilical cord, fat, bone marrow, and placental tissue [3, 4], and are widely used in the field of tissue regeneration. Recently, numerous studies have shown that MSCs can enhance survival by regulating the immune status, balancing inflammatory responses [5–7], reducing bacterial load [8, 9], improving organ function [10–12], repairing tissue damage, and promoting tissue regeneration. MSCs hold promise as a new therapeutic strategy in clinical trials for cardiovascular, neurological, lung, and cerebrovascular diseases, making them a focus of interest for researchers in life sciences and medicine.

Therefore, understanding the research progress in the field related to LPS can help deepen the comprehension and exploration of the pathogenesis and therapeutic approaches of inflammation. This article provides a review of the achievements and advancements in LPS-based inflammation model construction in recent years and comprehensively discusses the potential of stem cell therapy in LPS-induced disease models. We attempt to make reasonable predictions about the potential therapeutic effects of stem cells in disease models that have not yet been extensively studied using existing animal models, with the goal of providing new perspectives and ideas for future research.

LPS-induced animal models

Overview of LPS

The inflammatory response is an interaction between the immune system and damaged tissues in the body. Various stimuli, such as infections or injuries, can cause tissue damage and trigger an inflammatory response. Gram-negative bacteria such as Escherichia coli cause infections in humans and animals. The main component responsible for the infectivity of gram-negative bacteria is LPS, which is a key component of their cell wall and can cause significant pathological damage, making it an important inflammation inducer.

The two most common methods for creating inflammatory models in animal models are the CLP- and LPS-induced methods. The CLP-induced method, also known as the cecal ligation and puncture method, involves surgically exposing the animal’s cecum, allowing intestinal contents containing multiple bacteria to flow into the abdominal cavity through a puncture hole [13]. The experimental animals developed polymicrobial peritonitis because of surgical trauma, necrosis of the ligated intestine, and the presence of feces containing multiple bacteria, subsequently showing the classical clinical symptoms of sepsis. The CLP model can simulate the disease process caused by endogenous bacterial translocation and infection, which is similar to clinical disease progression. In contrast, LPS or bacterial suspensions induce more reproducible sepsis with a single bacterial etiology. The LPS-induced method involves injecting endotoxins into the body of an animal, which is a simple and sterile method for inducing disease. This model is reproducible, and its systemic effects are easy to recognize and measure. Compared to CLP, LPS can be qualitatively and quantitatively standardized, with induced signaling pathways depending on Toll-like receptors (TLRs) and cytokines and hemodynamic changes occurring much more rapidly than in human disease processes [14]. As LPS-induced in vivo experimental models closely resemble clinical diseases, LPS is commonly used to induce sepsis and the associated organ failure. LPS can also induce rare diseases, such as intrauterine infection, preterm birth [15], preeclampsia [16], and mouse nasal polyp models [17]. Therefore, LPS is considered the gold standard for establishing acute inflammation models and can induce nearly all inflammation-related diseases. Figure 1 illustrates the application of LPS in constructing animal injury models.

Fig. 1

Application of LPS in constructing animal injury models. LPS is an extract from the cell wall of Gram-negative bacteria, capable of effectively stimulating cells and the body to trigger corresponding inflammatory responses. As a potent inflammation inducer, LPS is widely used to establish models of acute inflammation and various diseases. Currently, commonly studied disease models are typically induced through intravenous or intraperitoneal injection, allowing for the induction of inflammatory disease such as preterm labour [111, 112], hemophagocytic lymphohistiocytosis [113], orchitis [114, 115], nasal polyp [17], rheumatoid arthritis [93, 94], periodontitis [105], diabetes [90], liver failure [66], acute pancreatitis [68], intestinal barrier dysfunction [70], lung injury [60, 62], uveitis [102], cataract, myocardial injury [83], renal failure [75], cystitis [71], neurological disease [80, 81]. LPS, Lipopolysaccharide. ALI, Acute Lung Injury; ARDS, Acute Respiratory Distress Syndrom; HLH, Hemophagocytic Lymphohistiocytosis. The image was created using BioRender (https://biorender.com/) with publication and licensing rights (Agreement number: DO27WBND6R)

Molecular and cellular mechanisms of LPS action

When bacteria invade the human body, they release LPS, which first binds to LPS-binding protein (LBP). LBP then transports LPS to the membrane surface of immune cells such as monocytes/macrophages and neutrophils, where it binds to the membrane protein CD14. CD14 subsequently transfers LPS to Toll-like receptor 4 (TLR4) and medullary differentiation protein 2 (MD2) to form a protein complex [18, 19]. This complex activates signaling molecules such as myeloid differentiation factor 88 (MyD88), IL-1R-associated kinase (IRAK) and IRAK2, and TNF receptor-associated factor 6 (TRAF6). Through a series of biochemical processes, these molecules phosphorylate the IκB kinase complex (IKK), leading to IκB degradation and the eventual activation of the transcription factor nuclear factor kappa B (NF-κB). NF-κB can bind to specific regions on the chromosome by crossing the nuclear membrane, enabling the expression of certain latent genes that produce various cytokines and other soluble mediators. Additionally, downstream of TRAF6 and TAK1, mitogen-activated protein kinase is phosphorylated to activate the transcription factors AP-1 and CREB [20]. Overall, the MyD88-dependent signaling pathway induces the expression of genes that can encode pro-inflammatory mediators, such as tumor necrosis factor (TNF-α), IL-1β, IL-6, IL-8, high mobility group protein B1 (HMGB1), macrophage inflammatory protein-1β (MIP-1β), and anti-inflammatory cytokines such as IL-10. Pro-inflammatory cytokines such as TNF-α and IL-1 can further upregulate the expression of pro-inflammatory mediators through their respective receptors and downstream signaling pathways. Moreover, TLR4 stimulation activates TRIF, which, along with non-classical TBK1 and IKKi, activates Interferon Regulatory Factor 3 (IRF3) to induce inflammatory cytokines [21, 22], leading to IFN-α/β expression. Figure 2 illustrates the LPS signaling pathway. These activated transcription factors upregulate pro-inflammatory cytokines, leukocyte chemokines, adhesion molecules involved in leukocyte homing and migration, prostaglandins, and inducible nitric oxide synthase (iNOS). Early pro-inflammatory factors are in dynamic balance with anti-inflammatory factors. However, once the body’s immune-inflammatory response becomes uncontrolled, a cascade of cytokine and inflammatory mediator activation occurs, along with simultaneous activation of the complement system. These substances collectively lead to an inflammatory cytokine storm, causing endothelial cell damage and resulting in clinical syndromes, such as fever, disseminated intravascular coagulation, multiple organ dysfunction, and shock, eventually leading to organ failure.

Fig. 2

LPS proinflammatory signaling pathway. LPS binds to host cell surface receptors, and TLR4 is activated and triggers two signaling cascades: The first signaling cascade involving the TIRAP and MyD88 adaptor proteins is induced in the plasma membrane, while the second signaling cascade involving the adaptor proteins TRAM and TRIF begins in the early endocytosis after eyhndocytosis. The transcription and expression of inflammatory cytokine genes are activated through many signal transduction pathways such as NF-κB and AP-1, and inflammatory response is induced to initiate the pathogenic process of bacterial infection. See the text for details. LPS, Lipopolysaccharide; LBP, LPS-binding Protein; TLR4, Toll-like Receptor 4; CD14, Cluster of Differentiation 14; MD2, Medullary Differentiation Protein 2; TRAF6, TNF Receptor-associated Factor 6; TAK,Transforming Growth Factor-β-Activated Kinase 1; IRAK, IL-1R-associated Kinase; TIRAP, TIR-domain-containing Adaptor Protein; MyD88, Myeloid Differentiation Factor 88; MAPK, mitogen-activated protein kinase; TRAM, TRIF-related Adaptor Molecule; TRIF, TIR-domain-containing Adaptor Inducing IFN-β; NF-κB, Nuclear Factor Kappa B; AP-1, Activator Protein 1. IKKi, IKK-related Kinase; IRF3, Interferon Regulatory Factor 3; IL, Interleukin (e.g., IL-1β, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17); TRAF3: TNF Receptor-Associated Factor 3; TBK: TANK-Binding Kinase; MKK3/6: Mitogen-Activated Protein Kinase Kinase 3/6; MEK1/2: MAPK/ERK Kinase 1/2; MKK4/7: Mitogen-Activated Protein Kinase Kinase 4/7; ERK1/2: Extracellular Signal-Regulated Kinase 1/2; JNK: c-Jun N-terminal Kinase; IκB: Inhibitor of NF-κB; NEMO: NF-κB Essential Modulator; CCL2: C–C Motif Chemokine Ligand 2; CXCL8: C-X-C Motif Chemokine Ligand 8. The image was created using BioRender (https://biorender.com/) with publication and licensing rights (Agreement number: TH27WBVDQD)

Stem cells: types, sources, and therapeutic potential

Stem cells have the ability to self-renew and undergo pluripotent differentiation. Based on their differentiation potential, they can be classified as pluripotent, totipotent, and unipotent stem cells. Among them, adult stem cells, embryonic stem cells, and induced pluripotent stem cells (iPSCs) are the main categories. However, embryonic stem cells pose risks of immune rejection and ethical concerns, while iPSCs may exhibit genetic instability. Additionally, although adult stem cells have promising applications, their natural abundance in tissues is often low, making extraction more challenging.

Mesenchymal stem cells (MSCs), a type of adult stem cell, were first discovered by Friedenstein et al. in the 1970s [23]. Due to their diverse tissue sources, including bone marrow, umbilical cord blood, placenta, adipose tissue, olfactory mucosa, dental pulp, and synovial membrane [24–30], MSCs have become a research hotspot. MSCs not only possess multipotent differentiation potential, allowing them to develop into neurons, cardiomyocytes, bone, cartilage, and pancreatic cells under specific conditions [31], but they also exhibit low immunogenicity, making them relatively easy to isolate, culture, and expand [32]. They can be transplanted between individuals without triggering immune rejection. Furthermore, MSCs have strong anti-inflammatory and immunomodulatory properties, promoting tissue repair and regeneration, inhibiting inflammation progression, and enhancing the body’s natural healing abilities. Therefore, stem cell therapy has garnered widespread attention as a novel treatment method and has become a popular topic in both basic research and clinical applications. This has brought hope to the treatment of various diseases. Numerous clinical trials have reported no adverse events following MSC infusion, indicating that these cells are safe for clinical use [33–36]. Stem cells can help repair the structure and function of damaged tissues, promote cell regeneration, regulate immune responses, and inhibit the progression of inflammation [37–39], showing beneficial effects in various conditions, particularly sepsis and septic shock.

Mechanisms and efficacy of stem cell therapy in LPS-induced animal models

MSCs can adapt their therapeutic effects depending on their local microenvironment. Increasing evidence suggests that the primary mechanism of MSC-based therapy is their paracrine function, where they secrete various soluble factors such as cytokines, chemokines, and growth factors, which exert anti-fibrotic, angiogenic, anti-apoptotic, and antioxidant effects [40, 41]. Stem cells exert immunosuppressive effects through cell–cell contact, for example, by reducing the toxicity of natural killer cells and modulating their immunosuppressive effects. They release IL-6, TSG-6, IGF1, and prostaglandin E2 to regulate immune responses, reduce excessive inflammation, and prevent immunosuppression to help restore immune balance and promote cell survival. MSCs can transfer mitochondria to damaged cells via tunneling nanotubes [42, 43]. Additionally, during tissue repair, MSCs reduce inflammation and promote cell proliferation by releasing extracellular vesicles that contain proteins, mRNA, and microRNA [44, 45]. These extracellular vesicles include exosomes and micro-vesicles. MSCs can differentiate into various cell lineages to replace damaged tissues, and they also possess antibacterial capabilities, acting on bacteria by secreting antimicrobial peptides such as lipocalin-2 [46], IL-37 [40, 47], and β-defensin-2 [48]. They can also be indirectly mediated by an increase in the phagocytic activity of macrophages and neutrophils. Therefore, LPS plays a significant role in the pathogenesis of host inflammatory diseases, and the application of stem cells in LPS-induced disease models has broad potential. Table 1 lists the preclinical trials of mesenchymal stem cell therapy in animal models of LPS-induced inflammatory diseases. Elucidating the specific mechanisms of stem cell therapy in the treatment of inflammatory diseases is crucial.

Table 1 Preclinical trials of mesenchymal stem cell therapy in animal models of LPS-induced inflammatory diseases

Sepsis model

Sepsis is a systemic inflammatory response syndrome. This severe and life-threatening syndrome can lead to shock and multiple organ dysfunction, and is a leading cause of morbidity and mortality in hospitalized patients. Sepsis models are widely used because of their importance. At the cellular and molecular levels, the pathogenesis of sepsis is relatively complex and involves various pathophysiological processes, such as imbalanced inflammatory responses, immune dysfunction [49], mitochondrial damage, coagulopathy, abnormalities in the neuroendocrine-immune network, endoplasmic reticulum (ER) stress, and autophagy, ultimately leading to organ dysfunction. Despite several years of research on the mechanisms of sepsis, clinical treatment remains primarily focused on symptomatic and supportive care. As a novel therapeutic strategy aimed at improving the prognosis of patients with sepsis, stem cells are intended to reduce inflammatory responses, enhance immune function, and improve tissue repair capabilities, demonstrating efficacy in LPS-induced sepsis models [50, 51]. Several preclinical studies have shown the beneficial effects of MSCs in sepsis models, including those using endotoxins or live bacteria. Systemic administration of MSCs may exert beneficial effects by inhibiting SIRS and organ damage caused by sepsis, reducing apoptosis and multiple organ failure rates through various mechanisms. MSCs can reduce anti-inflammatory factors such as IL-10 and IL-2 while reducing the production of inflammatory factors such as TNF-α and IL-6 [52]. Co-injection of endothelial progenitor cells (EPCs) and MSCs can modulate the TLR4/MyD88 signaling pathway, thereby reducing the inflammatory response in sepsis [53]. Recent studies have shown that exosomal KCNQ1OT1 inhibits sepsis by regulating miR-154-3p/RNF19A, thus providing a potential target for sepsis treatment [54]. In another study, mice injected with a lethal dose of LPS showed an increased phagocytic function of monocytes after MSC treatment, thereby exerting an antibacterial effect [55].

Respiratory disease model

Acute lung injury (ALI) is a common respiratory disease that can progress to lung fibrosis, and acute respiratory distress syndrome (ARDS) is its severe form. LPS is considered the most common cause of death in patients with lung injury [56]. ALI and ARDS are common in patients with severe sepsis who experience diffuse damage to alveolar and pulmonary capillary endothelial cells, which can lead to increased alveolar-capillary permeability, causing pulmonary edema [57, 58]. Clinically, it manifests as refractory hypoxemia and fatal respiratory failure [59]. Numerous studies have demonstrated that stem cells can alleviate lung injury through various pathways, and as novel biological treatments, stem cells have shown promising efficacy in animal models of LPS-induced lung injury. Researchers exploring the mechanisms by which MSCs reverse lung injury and fibrosis revealed that MSC-derived exosomes deliver miR-23a-3p and miR-182-5p, which inhibit Ikbkb and destabilize IKKβ, thereby inhibiting the NF-κB and Hedgehog pathways and reversing the progression of LPS-induced lung injury and fibrosis [60]. Moreover, MSC-derived exosomes delivered miR-130b-3p to alleviate LPS-induced ALI in mice [61]. Adipose-derived MSC exosomes can also alleviate ALI by transferring mitochondrial components to restore the homeostasis of alveolar macrophages [62]. MSCs release cytokines such as TNF-α, IL-1, and IL-6, which protect lung cells from damage and regulate inflammatory cell function, contributing to their therapeutic effects. RNA sequencing also shows that human umbilical cord MSCs (hUC-MSCs) activate the IL-17, JAK-STAT, NF-κB, and TNF-α signaling pathways. These activations enhance oxygen delivery, diminish extracellular matrix tissue, and alleviate ALI by reducing inflammation, suppressing pulmonary fibrosis, and improving respiratory function [63].

Digestive system disease models

The primary pathophysiological features of liver failure are inflammation and immune disorders in both the liver and entire body. LPS stimulates the immune cells to release inflammatory factors, leading to hepatocyte apoptosis and necrosis [64]. MSC transplantation has emerged as a new therapeutic strategy for treating acute liver failure (ALF). Numerous experimental studies on the stem cell treatment of LPS-induced ALI have provided valuable insights for clinical applications. Some researchers have explored the therapeutic effects of adipose-derived human adult stem cells in a rat model of endotoxemia, showing that MSCs can reduce the levels of liver injury biomarkers (such as ALT and AST), indicating less organ damage [65]. The paracrine effects of MSCs play an important role in liver injury. However, the low survival rate and poor homing ability of MSCs in damaged tissues limit their clinical application. Researchers have evaluated the effect of hypoxia-preconditioned human amniotic mesenchymal stem cell (hA-MSC) transplantation on the homing and repair of d-galactosamine/LPS-induced ALF. Hypoxic preconditioning promotes hA-MSC proliferation, migration, anti-apoptotic effects, and homing, thereby improving ALF repair, which is potentially mediated by the HGF/c-Met signaling axis [66].

Acute pancreatitis (AP) refers to a condition in which abnormal activation of pancreatic enzymes leads to digestion of the pancreas and surrounding organs. It is characterized by a localized inflammatory response, which may even cause organ dysfunction. Macrophage infiltration and activation are key steps in AP, and L-arginine, caerulein, and LPS induce pancreatic damage and systemic inflammation in mice [67]. Adipose-derived MSCs secrete TSG-6 to protect pancreatic acinar cells in a caerulein and LPS co-induced severe acute pancreatitis (SAP) model by inhibiting ER stress and the NF-κB signaling pathways, revealing new avenues for targeting ER stress in patients with SAP [68]. Injection of hcMSCs also reduced malondialdehyde levels and increased glutathione peroxidase and superoxide dismutase levels, effectively mitigating pancreatitis damage and making it a promising treatment for SAP, although further research is required [69].

Intestinal barrier dysfunction occurs when various factors cause damage and atrophy of the intestinal mucosa, leading to increased intestinal permeability and dysbiosis. This allows bacterial and endotoxin translocation, which induces or exacerbates systemic inflammation and multiple organ dysfunction. Intestinal barrier dysfunction is common in critically ill patients. However, there are currently no objective clinical diagnostic criteria or unified treatment protocols available. Zani et al. were the first to demonstrate that injecting amniotic fluid stem cells into a mouse model of LPS-induced necrotizing enterocolitis enhanced intestinal repair and improved survival, clinical status, intestinal structure, and function through a COX-2-dependent mechanism [70].

Urinary system disease models

Interstitial cystitis (IC) is a chronic inflammatory disease that mainly affects the submucosal and muscle layers of the bladder. Since the cause of IC remains unknown, no effective treatment is available. To date, few experimental studies have been conducted on stem cell therapy for LPS-induced cystitis. Arifin et al. demonstrated that in a rat model of LPS-induced IC, multipotent MSCs and N-acetylcysteine-based therapies improved urinary dysfunction, regenerated urothelial cells, and alleviated tissue inflammation [71]. Li et al. showed that urine-derived stem cells restored bladder function and histological structure in PS/LPS-induced IC rodent models by inhibiting oxidative stress, inflammatory responses, and apoptosis, thus offering potential treatment options for patients with IC [72].

Acute kidney injury (AKI) is a common clinical syndrome. It is characterized by a sharp decline in kidney function, with a diagnosis based on increased serum creatinine levels and reduced urine output. Currently, there is no effective treatment for AKI, and renal replacement therapy is required in severe cases. In a mouse model of LPS-induced AKI, intraperitoneal administration of MSC secretions resulted in lower inflammation, necrosis, hemorrhage, and degeneration scores in the treatment group than in the AKI group [73]. In an animal model of sepsis-induced AKI, MSC therapy improved kidney function, reduced renal fibrosis, and decreased tubular cell apoptosis [74]. Exosomes derived from adipose-derived stem cells target miR-16-5p via circVMA21, alleviating LPS-induced AKI by inhibiting apoptosis, inflammation, and aerobic glycolysis, thus potentially offering a molecular target for treating sepsis-associated AKI [75]. Injecting LPS-induced AKI mice with EPCs improved kidney function. Co-encapsulation of EPCs and MSCs enhanced medullary blood flow in the kidneys, increased stress resistance, promoted M1 to M2 macrophage polarization, and improved kidney and vascular function when MSCs were preconditioned with hypoxia [76].

Neurological disease models

Neuroinflammation is primarily caused by chronic activation of glial cells (astrocytes and microglia) in the brain. It is a recognized feature of various neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple sclerosis, autism spectrum disorders, cerebral palsy, and amyotrophic lateral sclerosis. LPS, an inflammatory inducer, triggers both peripheral inflammatory processes and responses in the central nervous system (CNS). This is manifested by the activation of microglia in the brain, which then produces more pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. These peripheral inflammatory signals reach the CNS through the blood–brain barrier via endothelial cells or secondary messengers, causing neuroinflammation. Hence, administering LPS peripherally or centrally can trigger microglial activation, inducing a series of inflammatory reactions that may lead to neurological and psychiatric disorders.

Such as depression, cognitive decline, anxiety, and post-traumatic stress disorder. MSCs regulate the inflammatory and immune responses by releasing various bioactive molecules, thereby protecting the CNS. Studies using in vitro LPS-induced BV2 microglial activation models have demonstrated the anti-inflammatory effects of MSCs, indicating that MSCs significantly suppress the expression of pro-inflammatory mediators in activated microglia. MSCs are ideal therapeutic agents for treating neurotraumatic injuries and neuroinflammatory diseases associated with microglial activation [77, 78].

Depression can be induced by LPS, which triggers strong immune activation and severe depression-like behaviors, as measured by increased immobility time in forced swim and tail suspension tests. Research has shown that the administration of HUCPVC reduces the surge in pro-inflammatory cytokines in the brain and significantly improves LPS-induced depression-like behaviors [79]. In another study, bone marrow-derived MSCs genetically engineered to overexpress glial cell line-derived neurotrophic factor (GDNF) were used to treat inflammation in LPS-induced Parkinson’s disease models, emphasizing the neurotrophic role of GDNF in LPS-induced neuroinflammation and neurodegenerative diseases [80]. Additionally, the role of miR-155 in an LPS-induced Alzheimer’s disease rat model was assessed. Researchers have studied the effects of MSC-derived microvesicles and H2S, either separately or in combination, on the regulation of proinflammatory signaling and improvement of neuroinflammation and cognitive function in LPS-induced Alzheimer’s disease [81].

Cardiovascular disease models

Myocardial injury is a common LPD-induced cardiovascular disease. LPS stimulates TLRs on macrophages and monocytes, leading to the secretion of various pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-8. These cytokines can cause fever, hypotension, and, ultimately, myocardial dysfunction, potentially resulting in heart failure [82]. Evidence suggests that MSCs regulate systemic and local cytokine production (TNF-α, IL-1β, and IL-6) by reducing the expression of macrophage receptors (TLRs) and inhibiting NF-kB signaling in macrophages.

Since the release of pro-inflammatory cytokines is associated with calcium imbalance, increased iNOS, and the generation of excessive toxic oxygen species, which in turn reduces contractile function, regulating pro-inflammatory cytokine secretion through MSCs may be a potent strategy to alleviate cardiac suppression and improve heart function [83, 84].

Bone marrow-derived MSCs regulate the expression of inflammatory cytokines and mitigate LPS-induced myocardial injury by activating the mTORC2-Akt signaling pathway and blocking the mTORC1-p70S6K signaling pathway [85]. Exosomes derived from MSCs can alleviate myocardial injury in mouse models of sepsis, and non-coding RNAs, including miRNAs and lncRNAs secreted by exosomes, play a crucial role in this process [86]. MSC-derived exosomes promoted macrophage polarization to the M2 phenotype via miR-21-5p, thereby reducing inflammation and promoting cardiac repair [87]. Calcium is an important secondary messenger that plays a key role in myocardial contractility. In addition to regulating miRNAs, MSC-derived exosomes may reduce mitochondrial damage by alleviating calcium overload, thereby protecting cardiac function during sepsis.

Metabolic disease models

One key feature of type 2 diabetes (T2D) is insulin resistance. Increasing evidence suggests that insulin resistance is associated with chronic systemic inflammation, which plays a central role in the pathogenesis of T2D [88, 89]. Cani et al. investigated the effects of long-term, low-grade inflammatory stimulation on blood glucose levels in rats by inducing chronic inflammation through a single subcutaneous injection of low-dose LPS [90]. Blood glucose levels in the model group were significantly higher than those in the control group, thus meeting the criteria for the T2D model. MSCs alleviate insulin resistance [91, 92]. In an in vitro model, researchers explored the anti-inflammatory mechanisms of hUC-MSCs under insulin resistance induced by palmitic acid and LPS and identified the anti-inflammatory mechanisms of MSCs in improving insulin sensitivity [91]. However, no relevant studies on stem cell therapy using in vivo models of LPS-induced diabetes are currently available. The LPS-induced model mainly simulates insulin resistance and β-cell dysfunction caused by inflammation; however, it does not cover all the pathological mechanisms of diabetes, and further research is needed. Therefore, it can be hypothesized that in addition to directly differentiating into pancreatic β-cells, stem cells can secrete various insulin-promoting factors to enhance insulin secretion, inhibit autoimmune responses to reduce pancreatic cell damage and promote metabolism to increase insulin sensitivity, thereby improving T2D.

Other disease models

In addition to the aforementioned disease models, LPS also plays a role in the occurrence and development of autoimmune diseases. Rheumatoid arthritis (RA) is a systemic autoimmune disorder. Collagen-induced arthritis and complete Freund’s adjuvant-induced arthritis are the most widely studied autoimmune RA models. The collagen antibody-induced arthritis model involves the administration of a mixture of endotoxins (LPS) and monoclonal antibodies, which can induce severe, persistent arthritis within a few days, suggesting that LPS-induced local inflammatory responses may play a role in RA pathogenesis [93, 94]. However, there are currently no studies on stem cell treatment for LPS-induced RA, and further research is needed. One study using LPS-stimulated HIG-82 synovial cells in vitro has shown that artificial cell-derived vesicles combined Exos derived from MSCs with Curc can significantly reduce the expression levels of anti-apoptotic proteins IAP1 and IAP2, as well as inflammatory mediators such as IL-6, TNF-α, matrix metalloproteinase 1, and prostaglandin E2 [95].

Ankylosing spondylitis (AS) is a chronic, progressive inflammatory arthritis that predominantly affects the spine, sacroiliac joints, and peripheral joints. Some studies have suggested that bacterial infections, particularly those caused by Gram-negative bacteria, may play an important role in the onset and progression of AS [96]. LPS-induced enthesitis is a key example of an inflammation-induced AS animal model, where mice, under certain conditions, spontaneously develop pathologies such as enthesitis and joint ankylosis, which resemble human spondyloarthritis in many aspects. Following LPS induction, mice may develop enthesitis in their hind paws [97]. However, reports on stem cell treatment in LPS-induced AS models are currently not available, and further research is warranted.

Uveitis refers to a range of conditions characterized by eye inflammation. It is a common, recurrent ophthalmic disease that can lead to secondary conditions, such as cataracts, glaucoma, or blindness [98]. Endotoxin-induced uveitis (EIU) is the most widely accepted uveitis animal model. The injection of LPS into an animal footpad induces an inflammatory response as early as the 6th hour, primarily manifesting as iridocyclitis and retinitis. Compared with melanin-induced uveitis models, the EIU model is relatively easy to induce and has no side effects [99, 100]. Corticosteroids are the first-line treatment for uveitis. However, their side effects highlight the need for new therapeutic approaches Existing studies have suggested that intraperitoneal administration of hMSCs can improve autoimmune uveitis by inhibiting the Th1/Th17 immune response [101]. Human cervical stem cells (CM-hUCESCs) reduce pro-inflammatory cytokines in human retinal pigment epithelial cell lines (ARPE-19) and significantly reduce ocular inflammation in an EIU model. This suggests that MSCs may serve as potential therapeutic agents for patients with ocular inflammation [102].

Since uveitis can lead to secondary cataracts and LPS promotes the proliferation of human lens epithelial cells by upregulating epidermal growth factor receptor expression, contributing to the formation of posterior capsular opacification, it can be hypothesized that LPS may also induce cataract models. D-galactosamine combined with LPS can induce liver and heart failure [103, 104]. Recent studies have used this combination to induce cataracts in rats; however, reports of stem cell treatment in LPS-induced cataract models are not available, warranting further research.

LPS also stimulates human periodontal ligament cells to release matrix metalloproteinase 2 and activate NF-κB, leading to the production of various inflammation-related factors that play important roles in promoting the progression of periodontitis. Researchers have treated periodontal ligament stem cells (PDLSCs) in vitro with Pg-LPS from Porphyromonas gingivalis to study the immunoregulatory effects of exosomes derived from gingival MSCs (GMSC-Exos) on periodontal bone regeneration in the periodontitis inflammatory microenvironment, as well as their regulation of the NF-κB and Wnt/β-catenin pathways. GMSC-Exos can regulate the osteogenic differentiation of PDLSCs by activating the Wnt/β-catenin signaling pathway [105]. Stem cell-conditioned medium inhibited the activation of the NLRP3 inflammasome and expression of LPS-induced pro-inflammatory, thereby protecting human gingival epithelial cells [106].

Challenges and future directions

Over 50 years have passed since MSCs were first discovered, and significant progress has been made in MSC-based tissue engineering, with promising broad prospects in the field of regenerative medicine. Table 2 lists the disease models that can be induced by LPS. However, stem cell therapy has not yet been employed. Despite these challenges, MSC-based tissue engineering is a promising clinical approach for regenerative medicine. However, the malignant transformation potential of MSCs limits their clinical applications, and the oncogenic potential of uncontrolled MSC differentiation requires further investigation [107]. In addition, the low viability of cryopreserved MSCs may have affected their use. Donor age can also affect the proliferation and differentiation potential of MSCs, with MSCs from younger donors exhibiting less damage and better proliferation [108]. The differentiation potential, surface markers, and transcriptional levels of MSCs from various tissue sources vary, presenting a challenge for their clinical translation.

Table 2 Disease models induced by LPS but not treated with stem cells to date

Numerous studies have proposed various strategies to enhance the efficacy of stem cell therapies from different perspectives. Among them, the method of modifying stem cell genes using genetic engineering has received significant attention, as it can overcome some of the limitations of using stem cells or genes alone. Genetically modified MSCs have greatly expanded their clinical applications. During tissue repair, modified MSCs promote healing and recovery by expressing neurotrophic factors, anti-inflammatory cytokines, and angiogenic factors. MSCs can also be combined with other therapies, such as gene therapy or drug treatment, to improve their efficacy [31].

Future research should focus on optimizing the therapeutic applications of novel stem cell therapies, including their mechanisms of action, delivery strategies, and potential for personalized treatment approaches. In recent years, olfactory mucosa-mesenchymal stem cells (OM-MSCs) have attracted significant attention due to their immunomodulatory and neuroregenerative properties. A recent study by Wang et al. demonstrated that OM-MSC-derived exosomes inhibit microglial pyroptosis through the lncRNA RMRP/EIF4A3/SIRT1 pathway, thereby reducing neuroinflammation and promoting spinal cord injury recovery [29]. These findings highlight the potential of OM-MSCs in developing novel therapies for neuroinflammatory and neurodegenerative diseases.Understanding how different stem cell-based therapies interact with the inflammatory microenvironment will be crucial for developing more effective treatments for inflammation-associated diseases.

With the development of precision medicine, MSC therapies may become more personalized and tailored to meet the specific needs of individual patients [109]. Given the significant variations in individual inflammatory responses, designing tailored stem cell treatments based on specific inflammatory profiles may enhance efficacy and reduce side effects. For instance, by analyzing a patient’s cytokine profile, gene expression levels, and immune microenvironment, the type, dosage, and delivery method of stem cells can be optimized to more precisely regulate inflammation. This approach not only improves the effectiveness of stem cell therapies but also advances precision medicine in inflammation-related diseases. Therefore, future research should further explore how personalized stem cell treatments can be tailored to individual inflammatory profiles to achieve more accurate and efficient disease management.

Conclusion

As a potent inflammation inducer, LPS is widely used to establish models of acute inflammation and various diseases, playing a significant role in medical research. At the same time, inflammation models continue to facilitate studies on the pathogenesis and treatment of inflammation and other diseases. In future inflammation research, LPS will remain a key tool, and we hope that LPS-based models will continue to contribute greater value to scientific experiments, further advancing medical research.

Stem cells show great potential in these models, demonstrating promising prospects for treating human diseases. Through paracrine, mitochondrial transfer and extracellular vesicles, mesenchymal stem cells secrete proteins to the damaged tissues or transfer mitochondria, exosomes and microvesicles to the damaged cells, and secrete antimicrobial peptides and immunomodulatory effects to exert antibacterial abilities, reduce excessive inflammation and prevent immunosuppression to help restore immune response balance and promote cell survival. Future research is needed to explore ways to overcome current challenges and fully unlock the therapeutic potential of stem cells.