Strategies for Preventing Esophageal Stenosis After Endoscopic Submucosal Dissection and Progress in Stem Cell-Based Therapies

Abstract

Endoscopic submucosal dissection (ESD) has been widely used in the early neoplasia of the esophagus. However, postoperative esophageal stenosis is a big problem, particularly when a large circumferential proportion of esophageal mucosa is resected. Currently, there are several methods available to prevent esophageal stenosis after ESD, including steroid administration, esophageal stent implantation, and endoscopic balloon dilation (EBD). However, the therapeutic effects of these are not yet satisfactory. Stem cell-based therapies has shown promising potential in reconstructing tissue structure and restoring tissue function. In this study, we discussed the current strategies for preventing esophageal stenosis after ESD and perspectives of stem cell-based therapies for the prevention of esophageal stenosis.

Impact statement

Currently, there are no satisfactory means of treating esophageal stenosis after endoscopic submucosal dissection (ESD), but stem cell-based treatment methods and regenerative medicine show great potential in this regard. They may be the future solution for treating esophageal stenosis after ESD. Therefore, we have reviewed recent research literature on stem cells and regenerative medicine in the prevention of esophageal stenosis after ESD, summarized the applications of stem cell therapy and regenerative medicine in this field, and presented future prospects.

Introduction

Esophageal cancer is globally ranked as the seventh most prevalent tumor and the sixth leading cause of tumor-related mortality.^1,2 Esophageal cancer is highly malignant, with a 5-year survival rate of 20%. However, patients with early-stage esophageal tumor that can receive a complete removal of neoplasms by endoscopic submucosal dissection (ESD), thus can achieve a better prognosis.³

ESD is a minimally invasive treatment for early esophageal cancer worldwide for the past decade.^4,5 However, if the postoperative mucosal defect encompasses more than three-fourths of the esophageal circumference, there is a 90% likelihood of postoperative stenosis during the healing process. Esophageal stenosis is a severe complication after ESD, significantly impacting patients' quality of life and posing challenges for clinicians.^6,7

Patients with esophageal stenosis experience varying degrees of dysphagia, nausea, and vomiting, which necessitate the use of proton pump inhibitors for treatment, leading to increased economic burden. Traditional treatment approaches for esophageal stenosis after ESD, such as dilation and stenting, have limitations in terms of efficacy and long-term outcomes.⁸ In recent years, stem cell-based therapies have emerged as a promising field to overcome these limitations.^9,10 This review provides an overview of the advances in stem cell-based therapies and its potential role in preventing esophageal stenosis after ESD. Furthermore, it discusses the challenges and future directions in this field.

Risk Factors of Esophageal Stenosis After ESD

After ESD, an inflammatory response is triggered by the injury to the esophageal mucosa. This leads to the release of pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha. The inflammatory process contributes to tissue damage and subsequent scarring.¹¹ Moreover, the activation of fibroblasts is stimulated by the inflammatory response, which is responsible for collagen deposition and scar formation. Excessive collagen production and abnormal deposition result in the formation of fibrotic tissue in the esophageal wall, replacing the normal esophageal mucosa and submucosa, ultimately leading to stenosis.¹²

Previous studies have suggested that ESD should be confined to ∼75% of the esophageal circumference to minimize the occurrence of esophageal stenosis. In addition, tumors with a circumferential size exceeding half of the esophageal circumference may also contribute to the development of stenosis.¹³ Another study suggests that tumor location, particularly in the neck of the esophagus, may also be a risk factor for post-ESD stenosis.¹⁴

Traditional Approaches in the Prevention of Esophageal Stenosis After ESD

The traditional methods for preventing post-ESD esophageal stenosis include endoscopic balloon dilation (EBD), local injection of steroids, oral administration of steroids, placement of esophageal stents, anti-allergic drug tranilast, anti-inflammatory and antifibrotic drugs such as mitomycin C (MMC), and type A botulinum toxin (BTX-A).

EBD is the preferred method for treating mechanical stenosis, although its effectiveness is uncertain.^15–17 Repeated stenosis may occur, necessitating multiple EBD. However, multiple expansions can worsen scar stenosis and increase the risk of EBD complications, including perforation, massive bleeding, and bacteremia.^18,19

Steroids, renowned for their anti-inflammatory and antifibrotic properties, are a mainstay in clinical settings to prevent esophageal stenosis post-ESD. Approaches vary from local injections and systemic administration to a combined strategy with polyglycolic acid (PGA) shielding. Although long-term oral steroids appear more effective against refractory stenosis than local injections,^20,21 their systemic use raises concerns due to risks such as gastrointestinal mucosal injury, osteoporosis, immunosuppression, and other steroid-related diseases, necessitating further research for safer more effective alternatives.

Comparatively, local triamcinolone injections are linked with fewer systemic effects. Studies suggest that endoscopic local injections of triamcinolone reduce the incidence of esophageal stenosis post-ESD compared with untreated cases.^22,23 However, potential complications such as perforation and bleeding^24–26 highlight the need for cautious application.

Recent evidence suggests that combining steroid injections with PGA films effectively counters refractory stenosis,²⁷ but this innovative approach requires validation through more extensive research. Steroid efficacy is well-recognized for mucosal defects under three-quarters of the esophageal circumference, yet its benefit in larger defects remains debated. Some studies support steroid use for near-complete esophageal involvement,^25,28 whereas others question its utility in such extensive cases.^29,30

Esophageal stent implantation encompasses self-expanding esophageal stents and biodegradable stents; however, the use of stents is a topic of debate within the academic community. Common adverse reactions associated with stent implantation include bleeding, perforation, stent migration, and recurrence of stenosis.^31–33 Although the self-expanding esophageal stent is relatively easy to remove, it is important to note that esophageal stenosis is prone to relapse after removal, and the efficacy of this procedure is not entirely satisfactory.^34,35

Recent research on biomaterials stents has been flourishing, and acellular dermal matrix (ADM) has shown significant potential. Several animal experiments indicate that ADM grafts may serve as a promising treatment strategy for preventing esophageal post-ESD stenosis.^36,37 Biodegradable stents offer the advantage of not requiring removal and providing adequate dilatation of the esophagus compared with metallic or plastic stents. However, the long-term efficacy of biodegradable stents still needs to be thoroughly evaluated.^38–40

MMC shows promise in inhibiting fibroblast proliferation and reducing collagen fiber formation, potentially decreasing esophageal stenosis post-ESD.^41,42 Although MMC shows promise in reducing esophageal stenosis as supported by prospective and animal studies, its potential side effects, including delayed mucosal healing and risk of severe infections,^43,44 underscore the need for larger-scale studies to thoroughly assess its safety and therapeutic efficacy. Tranilast, an anti-allergy agent, suppresses mediators such as TGF-β1, PGE2, and IL-1, contributing significantly to reduced collagen synthesis and fibrosis.⁴⁵

Kaname Uno's preliminary study underscores the effectiveness and safety of oral tranilast in preventing post-ESD stenosis.⁴⁶ Notably, tranilast's adverse effects, such as liver dysfunction and allergic cystitis, are less pronounced compared with MMC and steroids, yet warrant further investigation through extensive randomized trials to establish definitive safety and efficacy profiles.⁴⁷

BTX-A is a neurotoxin that acts on cholinergic nerve endings at the neuromuscular junction. Some studies have indicated that BTX-A also helps prevent scar formation after tissue injury.⁴⁸ In a study conducted by Zhou et al., it was demonstrated that BTX-A injection was particularly effective in patients with entire circumference mucosal defects, which holds significant clinical relevance for esophageal stenosis patients after ESD.⁴⁹ The efficacy of BTX-A remains unsupported by convincing evidence from evidence-based medicine and has not gained widespread clinical acceptance.

Stem Cell-Based Therapies in the Prevention of Esophageal Stenosis After ESD

Stem cell-based therapy is an interdisciplinary field that aims to restore, replace, or regenerate damaged or diseased tissues and organs. It encompasses a range of approaches and techniques that leverage the body's natural healing processes to promote tissue repair and regeneration.⁵⁰ Stem cells have the unique ability to differentiate into various cell types, making them promising for tissue regeneration. Researchers are exploring their potential in treating various conditions, including heart disease, gastrointestinal disease, neurodegenerative disorders, and musculoskeletal injuries.^51,52 At present, the utilization of regenerative medicine techniques to prevent post-ESD esophageal stenosis is predominantly confined to laboratory environments, with minimal clinical application.

Stem cells therapies

Recent studies have shown that stem cells can prevent esophageal post-ESD stenosis, opening new therapeutic possibilities. For instance, Tsuda et al. conducted an experiment on pigs, where they performed full-circumferential ESD on the rectum and administered mesenchymal stem cell (MSC) culture supernatant intracolonically for 4 days after the procedure. The results indicated that MSC culture supernatant had a preventive effect on luminal stenosis.⁵³

Similarly, Takeshi Mizushima and colleagues designed an experiment in which they performed semi-circumferential ESD on the esophagus of pigs and applied conditioned medium derived from MSC culture to the postoperative wound. These findings suggest that orally administered conditioned medium derived from MSC culture might be a potential solution for preventing esophageal stenosis in humans after ESD.⁵⁴

Currently, endoscopic direct injection of cell suspensions is used for preventing post-ESD stenosis, including autologous oral mucosal epithelial cell (OMEC) suspension, skin epidermal cell suspension, and adipose tissue-derived stem cell (ADSC) suspension. Endoscopic injection of cell suspensions has demonstrated a positive impact on stenosis prevention, which has been confirmed in several animal experiments.

Honda et al. conducted an experiment in which they injected ADSC suspension into the esophagus of five dogs that had undergone esophageal endoscopic mucosal resection (EMR). Another group of five dogs served as the control group and only underwent esophageal EMR without the ADSC injection. After 2 months, the control group exhibited severe esophageal stenosis, whereas the injection group showed only mild esophageal stenosis. Pathological examination results indicated that in the control group, the mucosal layer was significantly damaged, the submucosa exhibited notable fibrosis, and there were fewer microvessels.

In contrast, the injection group displayed good mucosal regeneration, and there were more newly formed blood vessels in the submucosa.^55–57 The method of injecting cell suspension is simple and cost-effective, requiring minimal time and resources. However, it has limitations in terms of the number of separated cells and overall efficiency. Furthermore, there is currently no research addressing the relationship between ADSCs and residual cancer cells. As a result, there is an ongoing debate regarding whether the intra-wound injection of cell suspension might increase the risk of tumor recurrence, especially in wounds where residual tumor cells are present.

Another approach is ADSC sheets that have gained significant attention in research. A prospective study was conducted to investigate their potential in preventing esophageal stenosis. The results revealed that all pigs in the control group developed esophageal stenosis, whereas only one pig in the ADSC group experienced a milder degree of esophageal stenosis compared with the control group. This finding confirmed the effectiveness of allogeneic transplantation of ADSC sheets in reducing the severity of stenosis and delaying fibrosis development.

ADSCs possess various beneficial properties, including anti-inflammatory effects, local immunomodulation, neovascularization induction, and the ability to differentiate into both stromal and non-stromal cells. These characteristics likely contribute to the mechanism underlying the prevention of esophageal stenosis.^58,59

Although there have been notable achievements in stem cell therapies, the unresolved challenges lie in directing their differentiation toward specific target tissues and maintaining their stability and activity within the body.

Stem cell combined with biomaterial therapies

Researchers have been continuously exploring and implementing various stem cell-based approaches in addition to the studies mentioned earlier. These approaches include self-crosslinkable hydrogel approach, extracellular vesicles (EVs) derived from ADSCs approach.

Chung et al. injected self-crosslinkable hydrogel-mediated stem cells into the site of esophageal mucosal injury after ESD in pigs and compared it with a control group. They discovered that this method effectively prevented esophageal stenosis after ESD, providing a novel approach for preventing such stenosis.⁶⁰

Coffin et al. demonstrated innovation by transplanting EVs derived from ADSCs and a thermoresponsive hydrogel onto the postoperative wounds of pigs that had undergone extensive esophageal ESD. They established an EV + gel group (pigs with postoperative wounds treated with EV and thermoresponsive hydrogel), a gel group (pigs with postoperative wounds treated only with thermoresponsive hydrogel), and a control group (pigs that only underwent esophageal ESD).

After 21 days, endoscopic, radiological, and histological examinations confirmed a significant reduction in the rate of esophageal stenosis in the EV + gel group. The EV + gel group exhibited a decrease in the average fibrotic area and an increase in the regenerated muscle layer and mucosal area.⁶¹ These findings suggest that this nanotherapeutic approach may potentially address unmet medical needs in the future.

Other Regenerative Medicine Approaches

Cell sheets transplantation

Currently, there are several cell sheets used for the prevention of esophageal stenosis after ESD, including the use of autologous OMEC sheets, autologous skin epidermal cell sheets, and ADSC sheets.

In 2006, Ohki et al. first transplanted OMEC to the mucosal injury site in the esophagus of dogs after ESD. The results showed that the transplanted cultured autologous OMEC sheets promoted wound healing and achieved complete re-epithelialization after 4 weeks post-ESD. Since the size of the canine esophagus is similar to that of humans, this suggests that cell sheet transplantation may inhibit post-ESD stenosis formation, as well as prevent postoperative bleeding and perforation.⁶² Another study by Takagi et al. involved the transplantation of OMEC sheets from seven volunteers onto the wounds in the esophagus of three dogs after ESD.

This study demonstrated that the transplantation of human OMEC sheets can effectively prevent the occurrence of esophageal stenosis in dogs, providing evidence for xenogeneic transplantation.⁶³ The stability and safety of OMEC sheets prepared in vitro have also been validated in subsequent research. The transplantation of in vitro-prepared OMEC sheets has proven effective in preventing post-ESD esophageal stenosis.

Moreover, there is evidence to support the feasibility of centralized cell sheet preparation, overcoming technical and geographic barriers to cell sheet transplantation. This paves the way for the possibility of cell sheet transplantation in all hospitals in the future.^64–66 Previous research on humans has mainly focused on autologous OMEC transplantation, which has shown promising results but comes with high costs.

If ready-made allogeneic cell transplantation could be produced and transported to hospitals in need of this technology, it could significantly reduce treatment costs. Therefore, addressing the issue of allogeneic cell transplantation is crucial for the future.

Epidermal cell transplants are another type of cell transplant. In 2012, a group of Japanese researchers successfully prepared autologous epidermal cell transplants and implanted them into pig esophageal mucosal defects after full-circumferential ESD. The transplant group exhibited early re-epithelialization and mild fibrosis in the muscle layer, in contrast to the control group. These findings indicate that self-made autologous epidermal cell transplants could be utilized to prevent severe esophageal stenosis after full-circumferential ESD.⁶⁷

Subsequent research has confirmed this conclusion. Building upon these studies, Shinichiro Kobayashi and colleagues conducted a new study in 2022, exploring the possibility of allogeneic epidermal cell sheet transplantation. The transplantation of allogeneic epidermal cell sheets demonstrated evidence of promoting ulcer mucosal healing and vascular regeneration after esophageal ESD, thereby preventing excessive inflammation and granulation tissue formation.^68,69 This study provides evidence and insights for further research on allogeneic transplantation.

In a study conducted by Chinese researchers, the potential of autologous esophageal mucosal transplantation in preventing esophageal stenosis after ESD was explored. Nine patients with esophageal cancer underwent esophageal ESD and received autologous esophageal mucosal transplantation fixed with metal clips. Epithelialization occurred within a median of 7.1 days, and the survival rate of the transplants was 96.5%. The preliminary results indicate that autologous esophageal mucosal transplantation is a safe and effective method for reducing the severity of esophageal stenosis after ESD.⁷⁰ These studies had a limited sample size, and although they indicated a potential role in preventing post-ESD esophageal stenosis, further verification is required to ascertain its true effectiveness and safety.

Novel strategies

These approaches include self-assembling peptide hydrogels (PeptiGelDesign), PGA sheets, high-density collagen patch, carboxymethyl cellulose (CMC) sheets, ammonolysis-based tetra-armed poly(ethylene glycol) (Tetra-PEG) hydrogel, and more.

Kumar et al. utilized self-assembling peptide hydrogels to establish a three-dimensional coculture model showcasing the multilayered and multicellular nature of the esophageal submucosa. The study emphasized the significance of synthesizing peptide hydrogels to enhance the cell compatibility of esophageal cells and provided a research direction for the treatment of esophageal stenosis after ESD.⁷¹ Subsequently, two studies in pigs applied this biomaterial to prevent post-ESD esophageal stenosis, and both showed that self-assembling peptide hydrogels have a preventive effect on it.^72,73

Aoki et al. developed a high-density collagen patch and transplanted it onto the mucosal defects of the esophagus in pigs that underwent esophageal full-circumferential ESD. After treatment with the collagen patch, the rate of mucosal epithelialization at the wound site significantly increased, whereas the degree of mucosal inflammation and fibrosis significantly decreased. This study suggests that this high-density collagen protein device can reduce esophageal stenosis caused by extensive ESD.⁷⁴

The role of CMC sheets in preventing esophageal stenosis after ESD was evaluated by researchers. Fourteen porcine models were randomly divided into a control group and a CMC group. All pigs underwent full-circumferential ESD of the esophagus. In the CMC group, CMC sheets were immediately placed over the mucosal defects after ESD, whereas the control group underwent conventional ESD only.

The results showed a significantly lower incidence of esophageal stenosis in the CMC group compared with the control group. Histological examination revealed less fibrosis in the submucosa, less damage to the muscularis propria, and enhanced re-epithelialization in the CMC group. This study suggests that CMC sheets hold promise as a method for preventing esophageal stenosis after ESD.⁷⁵

Wei et al. (2023) prepared a novel tetra-PEG based hydrogel, which demonstrated biocompatibility, effective water retention, strong tissue adhesion, and high mechanical strength. To evaluate its potential, a study was conducted on six female pigs The findings revealed that PEG promoted early healing of esophageal ulcers, facilitated epithelial regeneration, reduced inflammation, and alleviated fibrosis. These results suggest that the tetra-PEG hydrogel holds promise as an attractive candidate for preventing fibrotic stenosis formation during the repair process of ESD-induced esophageal ulcers.⁷⁶

Discussion

Since the introduction of ESD, postoperative esophageal stenosis has emerged as a significant concern, affecting patients' health, quality of life, and imposing a burden on the national economy. Although there are several strategies available to prevent stenosis formation, each strategy has its own limitations. Therefore, further comprehensive research is necessary to effectively tackle this clinical challenge.

To address post-ESD esophageal stenosis, understanding the mechanisms underlying stenosis formation is crucial. The development of esophageal post-ESD stenosis involves inflammatory cell migration and aggregation, proliferation of spindle-shaped myofibroblasts, and increased deposition of fibrotic tissue beneath the epithelium. By targeting these steps, it is possible to prevent stenosis formation and guide the repair of esophageal mucosal injury toward regenerative healing.

Steroids have been clinically used to prevent esophageal post-ESD stenosis by reducing prolyl hydroxylase and enhancing collagenase activity, thereby modulating wound healing and reducing tissue collagen content. However, the long-term efficacy, true benefits, and associated risks of steroid therapy have not been validated and require large-scale randomized trials for verification. Although tranilast, MMC, and BTX-A have been used, there is a lack of reliable clinical data on their safety and effectiveness in preventing post-ESD esophageal stenosis.

In addition, the placement of esophageal stents raises concerns such as stent migration, granulation tissue formation, esophageal ulceration, and even perforation. Further research is needed to study the materials, biocompatibility, and fixation of esophageal stents to overcome these challenges.

The application of stem cells can partially prevent esophageal stenosis after ESD. However, controlling the activity and differentiation direction of stem cells is challenging, and repeated use is necessary. In the future, it is crucial to develop methods to maintain the activity of stem cells and ensure their stability. ADSCs are easily isolated, exhibit paracrine activity, and can differentiate into various cell types. In addition, ADSCs can modulate keratinocyte–fibroblast interactions and enhance the quality of regenerated tissue by inhibiting excessive fibrosis.

However, due to technical challenges, high preparation costs, and limited large-scale and human experiments, ADSCs have not yet been utilized in clinical practice. The challenge of achieving effective stem cell adherence in the esophagus underscores the importance of developing advanced scaffolding solutions. Studies show that PGA sheets, with their notable adherence to esophageal lesions, offer potential in preventing stenosis post-ESD.^77,78

Therefore, combining stem cells with PGA sheets has emerged as a potential innovative approach to alleviate esophageal stenosis after ESD. Moving forward, it is crucial to address these challenges and strive for new breakthroughs.

Although regenerative medicine technology has shown potential in preventing esophageal stenosis after ESD, there are still several challenging issues that need to be addressed. First, most of the current methods are still in the animal experimentation stage. Considering the inherent differences between humans and animals, the effectiveness of this technology in humans may not be guaranteed, and its long-term efficacy remains uncertain. Extensive experiments are required to ensure safety and efficacy.

Second, the safety and effectiveness of many biomaterials have not been adequately validated, and there is a possibility of harm to the human body. Third, the preparation of biomaterials is not straightforward and lacks standardized protocols. Each hospital or research institute follows its own preparation experience and scheme, which may result in varying efficacy for patients. Furthermore, not all platforms have the capability to prepare biomaterials, hence the need for uniform preparation standards or mass production of specialized biomaterials should be considered as a future direction of research.

Conclusion

Stem cell-based therapies still require large-scale clinical trials to validate its effectiveness and safety in humans. However, its prospects are highly promising. In the future, it is essential to develop specific treatment plans based on each patient's individual condition to maximize the preventive benefits against esophageal stenosis after ESD.

Authors' Contributions

Conceptualization (lead) and writing—original draft (lead) by S.Y. Review and editing (equal) by L.Y. and W.G. Conceptualization (supporting) by J.H., D.Z., S.Z., X.S., W.L., and J.W.

Footnotes

Disclosure Statement

All the authors declare that there are no financial or nonfinancial interests that are directly or indirectly related to the study submitted for publication. All authors are not employed by institutions that have recently (within the past 5 years) or currently expect to make a profit or loss as a result of their publication.

Funding Information

No funding was received for this article.

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