Stem Cell Therapy for Inflammatory Bowel Disease

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Stem Cell Therapy for Inflammatory Bowel Disease

Stem Cell Therapy for Inflammatory Bowel Disease.

Inflammatory bowel disease ( IBD ) is a group of chronic inflammatory disorders of the gastrointestinal tract that includes Crohn’s disease ( CD ) and ulcerative colitis ( UC ).

IBD has multifaceted etiologies, including genetic predisposition, immune dysregulation, extragut flora, and environmental factors.

These factors disrupt the intestinal mucosal barrier, leading to chronic nonspecific inflammation, local structural changes, and intestinal dysfunction.

Repeated inflammation and microcirculation disturbance can lead to intestinal fistula, stricture, obstruction, perforation, gastrointestinal bleeding, sepsis and other complications, increasing the risk of intestinal cell cancer and death.

In recent years, the incidence of IBD in Asia, especially East Asia, has been increasing every year, resulting in an increasing number of patients.

Currently available IBD treatments include non-targeted therapies ( such as aminosalicylic acid, glucocorticoids, and immunomodulators) and targeted therapies (such as anti-TNF, anti-IL-12/IL-23, and anti-α4β7 integrin ).

Although biologically targeted therapies are effective for many patients, up to 30% of patients do not respond to initial therapy, and up to 50% of patients lose response over time.

In recent years, hematopoietic stem cells ( HSCs ) and mesenchymal stem cells ( MSCs ) have shown efficacy in treating IBD in preclinical models and clinical trials.

Studies have shown that various types of stem cells ( SC ) continuously generate and replace intestinal epithelial cells, immune cells, etc., thereby maintaining the integrity of the intestinal epithelium and the homeostasis of intestinal immunity.

Loss or abnormal activation of intestinal SCs can lead to intestinal epithelial dysfunction and immune dysfunction, which are key pathogenic factors of IBD.

Therefore, transplantation of SCs into the gut of patients may provide a potential therapeutic approach for IBD by repairing intestinal epithelial dysfunction and reestablishing immune homeostasis to achieve long-term remission.

Stem cells commonly used in IBD treatment

Various types of SCs, including HSCs, MSCs, intestinal stem cells (ISCs) and induced pluripotent stem cells ( iPSCs ), have been used to treat IBD.

Hematopoietic stem cells

Human HSCs have strong proliferation and differentiation capabilities, enabling them to differentiate into blood and immune cells, migrate to damaged tissues, and differentiate into various “structural cells” such as epithelial cells, endothelial cells, and fibroblasts. In addition, HSC also has the function of regulating blood, immune and tissue cells.

Hematopoietic stem cell transplantation ( HSCT ) can fully restore the hematopoietic and immune system, prevent abnormal differentiation of blood and immune cells, and has been used to treat blood cancers.

However, its application in the treatment of IBD is limited by some conditions, such as high immunogenicity, requirements for donor matching, bone marrow ablation therapy, strong invasiveness, many related adverse reactions, and high recurrence rate.

In addition, immunosuppression is required, which further increases its limitations.

Mesenchymal stem cells

Mesenchymal stem cells are pluripotent stem cells widely distributed throughout the human body, and these cells have the ability to actively proliferate and differentiate in multiple directions.

In addition, mesenchymal stem cells also have powerful immune regulation and tissue repair capabilities, as well as targeted and directional migration to damaged tissue sites.

They also have the ability to promote SC engraftment and provide hematopoietic support.

Studies have found that intestinal intrinsic mesenchymal stem cells ( MtSC ) in IBD patients show abnormal differentiation or exhaustion, and mesenchymal stem cell transplantation ( MSCT ), as a supplement or substitute for MtSC, can regulate immune cells and repair IEC, and has become The most widely used SC therapy for IBD.

There are several advantages to using MSCs for IBD therapy:

First, MSCs are low immunogenic and typically do not require matching or myeloablative therapy, allowing immunosuppressive therapy to be given as needed after transplantation.

Second, MSCs can be easily obtained from various sources, such as umbilical cord blood, peripheral blood, or fat, and can be easily isolated and cultured.

Third, mesenchymal stem cells can be administered through various methods, such as intravenous injection, intraperitoneal injection, subcutaneous injection or local injection, so that the best method can be selected according to the type of lesion, and the transplantation process is similar to ordinary drug injection.

intestinal stem cells

Intestinal epithelial cells ( IECs ) have a short lifespan of 3–5 days and rely on continuous division and recruitment of ISCs located in intestinal crypts to maintain the integrity of the intestinal epithelial barrier.

ISCs are pluripotent and can differentiate into various IECs and intestinal innate immune cells, such as T cells, B cells, and dendritic cells ( DCs ).

In response to intestinal mucosal injury, ISCs can proliferate and differentiate to repair the injured mucosa and regulate innate immune cells in the intestine, playing a crucial role in maintaining intestinal structure and function. Therefore, ISCs are an excellent source of stem cells for the treatment of IBD.

However, the extraction and in vitro culture of ISCs is challenging and requires complex procedures, including endoscopic transfusion, to ensure engraftment at intestinal lesion sites.

Induced pluripotent stem cells

iPSCs have similar morphology, function, and gene expression to embryonic stem cells (ESCs), and can be induced into various cell types, including iESCs, iMSCs, or iISCs, that exhibit similar functions to ESCs, MSCs, or ISCs . iPSCs have several advantages over ESCs, including avoiding ethical issues and immune rejection.

Studies have demonstrated the feasibility of using iPSCs to generate 3D intestinal tissue that closely resembles human intestinal tissue.

However, the fabrication process of iPSCs is complex and requires precise control, which may lead to high failure rates and uncertain safety.

Furthermore, although iPSCs can be induced into iESCs, iMSCs, or iISCs, their gene expression, phenotypic characteristics, proliferation, differentiation, apoptosis, and senescence may not be the same.

Parthenogenic embryonic stem cells

Due to ethical constraints, ESCs have a high risk of cancer, making it difficult to control and conduct clinical research on IBD.

To overcome these problems, physical and chemical methods can be used to stimulate oocytes to develop into parthenogenic blastocysts, resulting in pluripotent stem cells called pESCs.

Recent studies have shown that human pESCs can be successfully induced into intestinal epithelial stem cells, which brings hope for the treatment of IBD.

However, its preparation process is complex, requires precise control, has a high failure rate, and has uncertain safety. Therefore, their efficacy in the clinical setting remains to be verified.

Mechanisms of Stem Cell Therapy for IBD

Mechanistically, SC acts on IBD lesions by regulating immune cells and repairing the intestinal mucosal barrier, which directly combats chronic intestinal inflammation.

In addition, SCs can also play a beneficial role in enhancing intestinal microecology, solving microcirculation disorders, and preventing fibrosis and carcinogenesis.

Regulates the immune system

HSCT induces the differentiation of various types of immune cells, while MSCT and ISCT mainly regulate immune cells by secreting cytokines or vesicles.

For IBD patients, MSCs mainly regulate immune cells in the gut by secreting hormones or vesicles.

They regulate the polarization of macrophages to the M2 phenotype, inhibit the proliferation of Th1 and Th17 helper T cells, promote the differentiation of regulatory T cells, and inhibit the maturation and differentiation of DCs, ultimately inhibiting inflammation.

Stem Cell Therapy for Inflammatory Bowel Disease

Repair of intestinal mucosal barrier

Studies have shown that MSCs mainly repair the intestinal mucosal barrier by secreting cytokines or vesicles.

First, MSCs regulate the growth microenvironment of ISCs by secreting certain factors and promote their differentiation into IECs. Second, MSCs secrete factors that promote IEC repair and reduce intestinal wall permeability.

Furthermore, in animal models of IBD, MSC-secreted vesicles have been shown to inhibit the apoptosis of IECs by reducing the cleavage of caspase-3, caspase-8, and 9. In addition, MSCs can promote angiogenesis by promoting lymphatic endothelial cell ( LEC ) proliferation, migration, and lymphangiogenesis.

MSCs can also reduce the oxidative stress damage of tissue cells by inhibiting the production of endogenous toxins ( such as oxygen free radicals ).

Improve gut microbiome

The gut microbiota and host cells are interdependent and together constitute the gut microecology.

Intestinal microecological disturbance is the main pathogenesis of IBD, and the maintenance of intestinal microecological homeostasis largely depends on intestinal immunity and mucosal barrier function.

MSCs have indirect effects on the improvement of intestinal microecology through their effects on intestinal immunity and mucosal barrier function.

In addition, MSCs also secrete various antimicrobial peptides, such as IL-10, PGE2, IDO, and IL-17, which have shown antibacterial activity in multiple studies.

Promote angiogenesis

Microvascular dysfunction and endothelial barrier damage occur in IBD, which can affect colonic tissue perfusion and healing.

MSCs secrete various angiogenic factors, including vascular endothelial growth factor ( VEGF ), platelet-derived growth factor ( PDGF ), transforming growth factor β ( TGF-β ), and angiopoietin-1, which promote EC proliferation and new blood vessel formation.

In addition, MSCs can differentiate into vascular endothelial cells and promote angiogenesis.

Anti-fibrosis

Intestinal fibrosis is a common complication of IBD and often leads to intestinal strictures and obstructions in CD patients.

The TGF-β signaling pathway is the core mechanism driving intestinal fibrosis. It has been shown that BM-MSCs reverse TGF-β1-induced epithelial-mesenchymal transition (EMT) of IEC-6 cells through miR-200b, leading to intestinal fibrosis a significant reversal.

Clinical application of SC in IBD treatment

Currently, many studies have explored the potential of SCs in the treatment of IBD . These clinical studies mainly focused on MSCs and HSCs , and paid little attention to ISCs and iPSCs .

According to the clinical trial database of ClinicalTrials , so far, 34 clinical trials involving MSCs for the treatment of IBD have been registered and initiated .

HSCT

HSCT faces major challenges in terms of safety in treating IBD due to its complicated procedure and many adverse effects.

Therefore, HSCT is gradually being replaced by MSCT. Although most of the completed clinical studies have achieved certain curative effects, some studies also showed no response to IBD treatment and faced serious adverse reactions.

The ASTIC study was a multicenter, randomized phase III intervention study in which 23 patients with refractory CD received autologous HSCT and 22 patients received standard CD therapy (control ) .

The results showed that only 2 of 23 patients in the SC treatment group achieved clinical and endoscopic complete remission, while only 1 of 22 patients in the control group achieved clinical and endoscopic remission, with no statistical difference.

The study also found that all patients treated with SC experienced varying degrees of complications, with infection being the most common.

However, when the evaluation criteria were lowered, the proportion of patients who received HSCT who stopped using immunosuppressive drugs was significantly higher than that of the control group, the Crohn’s disease activity index (CDAI) was also significantly lower than the control group, and the quality of life and intestinal lesions were significantly lower than those in the control group.

Remissions were better than controls, suggesting that HSCT treatment still has a positive effect on these patients.

MSCT

The clinical research of MSCT mainly focuses on patients with refractory perianal fistula CD and refractory intestinal luminal IBD. MSCs can be derived from various tissues such as bone marrow, umbilical cord and adipose tissue.

Adipose tissue is an easily obtained and cultured source of MSCs that is increasingly used in clinical applications and currently accounts for one-third of all MSC sources.

The clinical application of MSCs in IBD can be roughly divided into two categories: topical application in CD and refractory intraluminal IBD.

Topical application of MSCs has been found to be effective in the treatment of refractory perianal fistula ( PFCD ) in Crohn’s disease.

The first MSC clinical formulation for PFCD, darvadstrocel/Cx601 (Takeda), has been approved in Europe for the treatment of patients with complex perianal fistulas in Crohn’s disease.

More optimized MSCs and derivatives are currently in clinical trials.

In a study of 212 patients with refractory, complicated and active anal fistulas, 107 patients received Cx601 and the remaining 105 received conventional treatment in the placebo group.

Results showed that 53 people ( 50% ) in the Cx601 group achieved remission compared with 36 people ( 34% ) in the placebo group.

Treatment-related adverse events occurred in 18 of 103 patients ( 17% ) in the Cx601-treated patients compared with 30 of 103 ( 29% ) in the placebo group.

The study concluded that Cx601 is an effective and safe treatment for patients with refractory, complex and active perianal fistulas.

For refractory intraluminal IBD, in a recent randomized controlled trial, 82 patients with refractory intraluminal IBD were enrolled and 41 patients were randomly assigned to receive MSCs.

After 12 months of treatment, the CDAI in the UC-MSC group was reduced by 62.5±23.2 compared with 23.6±12.4 in the control group.

In addition, the Harvey-Bradshaw index ( HBI ) of the UC-MSC group decreased by 3.4±1.2, while that of the control group decreased by 1.2±0.58.

The corticosteroid dose was also reduced by 4.2±0.84 mg/day in the UC-MSC group, compared with 1.2±0.35 mg/day in the control group.

These results suggest that MSCs are effective in the treatment of refractory intraluminal IBD.

ISCs and iPSCs

Recently, a research team at Tokyo Medical University reported that the world’s first “organoid” was successfully transplanted into the intestinal mucosa of a patient with refractory UC, marking the beginning of the era of organoid SC.

The team collected normal intestinal mucosa ( including ISCs ) from patients with the help of an endoscope , cultured them in vitro for about 1 month, and constructed “organoids” with a diameter of 0.1–0.2 mm.

The “organoids” are then transplanted endoscopically into the site of the intestinal lesion. According to reports, the patient’s intestinal symptoms have improved and he is currently in good condition.

Summary

Although current treatments for IBD can temporarily relieve clinical symptoms, achieving sustained remission remains a challenge.

SCs have the potential to directly ameliorate chronic intestinal inflammation by modulating immune cells and repairing the intestinal mucosal barrier.

SC can improve intestinal inflammatory injury and prevent IBD complications by positively affecting intestinal microecology, microcirculatory disturbance and fibrosis.

Currently, the research on SC in IBD is mainly concentrated in the preclinical stage, and the clinical application is limited to limited fistula and refractory IBD .

However, with the continuous maturity of SC technology, it is expected to become a routine ” weapon ” in clinical treatment and be applied to ordinary IBD patients in the future .

references:

1. Stem Cell Therapy in Inflammatory Bowel Disease: A Review of Achievements and Challenges. J Inflamm Res. 2023; 16: 2089–2119.

Stem Cell Therapy for Inflammatory Bowel Disease

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Stem Cell Therapy for Inflammatory Bowel Disease

Stem Cell Therapy for Inflammatory Bowel Disease