Since anal fistulas can be challenging to treat; numerous innovative treatments have been proposed, including stem cell therapy. This systematic review aimed to assess pooled rates of fistula healing and adverse events associated with stem cell treatment.

In this PRISMA-compliant systematic review we searched PubMed and Scopus for observational and randomized studies reporting outcomes of stem cell treatment for anal fistulas. The main outcome measures were successful healing and adverse effects of stem cell therapy.

In total, 43 studies incorporating 1160 patients (53.6% male) were included. Underlying fistula etiologies were Crohn's disease (30 studies) and cryptoglandular disease (12 studies). The main origin of stem cells was from adipose tissue (34 studies) or bone marrow (6 studies). The median follow-up duration was 12 months. The combined overall pooled healing rate was 58.1% (95% confidence interval (CI) 51.5-64.7%). The pooled healing rate for Crohn's fistulas was 60.4% (95% CI 54.7-66.2%) with adipose-derived stem cells and 63.6% (95% CI 49.4-77.7%) with bone-marrow-derived cells. The pooled healing rate for cryptoglandular fistulas was 53.8% (95% CI 35.5-72.2%) with adipose-derived stem cells. The pooled complication rate was 37.3% (95% CI 27.1-47.5%). Stem cells were associated with higher odds of anal fistula healing (odds ratio (OR): 1.81, p = 0.003) and similar odds of complications (OR: 1, p = 0.986) compared with controls.

Stem cell treatment of anal fistulas was associated with promising results. The healing rate in Crohn's anal fistulas was higher than in cryptoglandular fistulas. Bone-marrow-derived stem cells were associated with marginally better outcomes than were adipose-derived cells. This finding suggests that the autoimmune inflammatory etiology of Crohn's disease may respond better to autologous myoblasts than does the infectious etiology of cryptoglandular fistulas.

Complex wounds represent a challenge to global health, incurring significant healthcare costs and compromising patients' quality of life. Recently, research has investigated the potential of adipose tissue-derived stem cells (ASC) for therapeutic stem cells' immunomodulatory properties. This study aimed to evaluate the effect of sequential applications of ASC in an experimental model of a complex wound.

Thirty male Wistar rats were subjected to a complex wound model of enterocutaneous fistula. After 4 weeks, the rats were divided into 3 groups: control, 2 applications of culture medium, and 2 applications of 1 × 106 allogeneic ASC. The animals were euthanized and analyzed 4 weeks after the first application regarding the macroscopic reduction of the wound, histopathologic changes, and gene expression related to wound healing (Cd68, Il1rap, Il10, Mmp3, Mmp9, and Tnf).

Animals treated with ASC showed a reduction in wound diameter of 68% compared with the control group (P = 0.002) and a reduction of 65% compared with the culture medium group (P = 0.011). The ASC group also showed a more than 100% increase in blood vessel count compared with the control group (P = 0.02). Gene expression analysis showed a decrease in the Mmp9 levels in the ASC group compared with the control group.

This study demonstrated that the treatment with ASC improves the healing of enterocutaneous fistula wounds.

Perianal lesions of Crohn's disease (CD) are complex and disabling conditions. Mesenchymal stem cell (MSC)-based therapies have emerged as an innovative approach in managing refractory perianal fistulizing CD. We conducted a systematic review and meta-analysis to describe and compare combined remission and clinical outcomes of MSC-based therapies, and then whether one approach stands out from the rest.

We searched in MEDLINE, EMBASE and CENTRAL (up to December 31, 2023) all prospective studies assessing a local injection of MSC-based therapy in perianal fistulas of CD. The primary outcome was achievement of combined remission. MSC-based therapy strategies were compared.

Twenty-five studies were included in the meta-analysis, enrolling 596 patients with perianal fistulizing CD. The combined remission rate at 3, 6 and 12 months were 36.2% (95% confidence interval (CI), 24.5-49.7), 57.9% (95% CI 51.3-64.2) and 52% (95% CI 38.8-64.8), respectively. MSC-based therapies demonstrated a significant effect in achieving combined remission compared to placebo at 3 months (relative risk (RR) = 1.6; 95% CI 1.0-2.8) and at 6 months (RR = 1.5; 95% CI 1.1-1.9). At 6 months, the combined remission rate was 57.2% (95% CI 47.2-66.6) for adipose-derived stem cells (ASCs) and 55.7% (95% CI 26.4-81.5) for bone marrow-derived stem cells (BMSCs). In the network meta-analysis, allogeneic ASCs and BMSCs did not demonstrate superiority over each other (RR = 0.74; 95% CI 0.31-1.77).

MSC-based therapies are effective for achieving combined remission of refractory and/or complex perianal fistulizing CD. The optimal efficacy effect is reached after 6 months of treatment. No superiority has yet been demonstrated between ASCs and BMSCs therapies.

Crohn's disease (CD) is a chronic, inflammatory bowel disease with a wide range of presentations, including perianal disease. Presentation is variable, ranging from skin tags to complex fistulas, strictures, and nonhealing wounds. Symptoms of perianal CD can be devastating and may impact quality of life. Optimal management requires coordinated medical and surgical therapy. When possible, conservative treatment of perianal disease should be attempted. However, surgical treatment is often required, and some patients may ultimately require total proctocolectomy with permanent diversion due to the severity of disease. Even with close attention and treatment, disease can be recurrent, and complications of treatment are sometimes worse than the initial presentation. Novel treatments, including use of mesenchymal stem cells and autologous fat grafting, hold some promise, but are not yet widely available. Thorough knowledge of treatment options, careful patient selection, coordination between medical and surgical providers, and setting realistic expectations are important in the successful treatment of difficult perineal CD.

Perianal fistulizing Crohn's disease is one of the most disabling phenotypes of Crohn's disease, due to the severe impairment in quality of life including social and personal wellbeing. A multimodal approach with patient-tailored care is the key to optimal management of this condition. Medical therapy is needed to optimize the luminal disease, and surgical intervention is required to control any associated perianal sepsis and attempt palliative or definitive fistula repair. While several medical and surgical options are available, the majority of patients continue to have symptomatic disease. Fortunately, this continues to drive novel innovations which are revolutionizing the treatment and outcomes of perianal fistulizing Crohn's disease. However, there continues to be a need for randomized trials and consistent metrics utilized for classification and treatment outcomes in order to accurately describe optimal treatment outcomes.

Crohn's disease (CD) causes gastrointestinal symptoms (i.e., diarrhea and abdominal pain), systemic symptoms (i.e., fatigue, anemia, weight loss, and fever), and perianal fistulas that produce anal pain. Because of the frequent occurrence of diarrhea and ulcers in the rectum, CD is often exacerbated by perianal abscesses and/or fistulas. Perianal fistulizing CD (PFCD) has an unknown etiology and recurring symptoms such as pain and discharge, which seriously affects the patient's quality of life (QOL). In the past, radical surgery was performed for PFCD, but due to the risk of anal sphincter impairment, conservative therapy using antibiotics and immunosuppressive medications is currently the first treatment option. PFCD management has greatly improved with the use of biologics such as the antitumor necrosis factor alpha (TNF-α) antibodies infliximab and adalimumab. In this review, the results of the administration of anti-TNF-α (certolizumab pegol), anti-interleukin-12/23 (ustekinumab), and anti-α4β7 integrin antibodies (vedolizumab) were evaluated. Our investigation showed that these medications may be effective for maintenance therapy to prevent the recurrence of anal fistulas. In addition to biologics, molecular target drugs and even regenerative medicine using mesenchymal stem cells have been introduced to further expand the treatment options for consideration by medical personnel. We herein discuss the management of PFCD by focusing on studies conducted in the United States and Europe where researchers used recommended guidelines and consensus statements to evaluate the efficacy of each medication and published their findings in peer-reviewed journals.

Current therapies for complex Crohn's perianal fistulas (CPF) have a limited ability to achieve long-term healing. Darvadstrocel (DVS) is an expanded allogeneic adipose-derived mesenchymal stem cell therapy that has demonstrated efficacy in treating complex CPF in clinical trials. There are, however, limited long-term comparative data with standard of care (SoC). The aim of this study was to combine clinical trial data and real-world evidence using statistical methodologies to predict long-term effectiveness of DVS versus SoC in patients with CPF.

Data were pooled from a clinical trial (ADMIRE-CD) and two retrospective chart review studies (INSPECT and PREFACE). Predictive statistical models extrapolated clinical outcomes beyond observed follow-up using parametric curves, which were implemented into a semi-Markov model to obtain the number of patients in remission. The setting was multinational and multicenter. ADMIRE-CD was conducted in 49 hospitals in 7 European countries and Israel. INSPECT used data from the ADMIRE study. PREFACE involved patients from Belgium, France, Germany, Italy, and Spain. The participants were patients with complex CPF treated with DVS or SoC. Times to remission and relapse (clinical, and clinical plus patient-centric remission) were analyzed. Additionally, the proportion of patients in clinical and patient-centric remission was examined.

In total, 513 patients were included in the analysis (ADMIRE-CD [N = 200] and PREFACE [N = 313]). Patients in ADMIRE-CD and PREFACE were similar in age (median [interquartile range, IQR], 36 [20.0] versus 36 [22.0] years, respectively) and gender (males, 54% and 52%, respectively). The median (IQR) duration of Crohn's disease was 9.4 [11.3] years for patients in ADMIRE-CD and 6.5 [12.9] years for patients in PREFACE. The estimated time to remission was shorter for patients treated with DVS versus SoC. The estimated time to relapse was longer for patients treated with DVS versus SoC. A higher estimated proportion of patients treated with DVS versus SoC had clinical and patient-centric remission at 24 months (48% and 35%, respectively) and 48 months (49% and 32%, respectively).

This novel approach enabled pooled data from a clinical trial and real-world settings to predict long-term effectiveness of DVS versus SoC in patients with complex CPF.

The insufficient and unspecific target of classical chemotherapies often leads to therapy resistance and cancer recurrence. Over the past decades, discoveries about mesenchymal stem cell (MSC) biology have provided new potential approaches to improve cancer therapy. Researchers have utilised the multipotent, regenerative and immunosuppressive qualities of MSCs and tropisms towards inflammatory, hypoxic and malignant sites in various therapeutic applications. Although MSC-based therapies have generally been demonstrated safe, their effectiveness remains limited when these cells are used alone. However, through genetic engineering, researchers have proven that MSCs can be modified to have specialised delivery roles to increase their therapeutic efficacy in cancer treatment. They can be made to overexpress therapeutic proteins through viral or non-viral genetic modification, which enhances their innate properties. Nevertheless, these engineering strategies must be optimised to increase therapeutic efficacy and targeting effectiveness while minimising any loss of MSC function. This review underscores the cutting-edge methods for engineering MSCs, discusses their promise and the difficulties in translating them into clinical settings, and offers some prospective suggestions for the future on achieving their full therapeutic potential.

Mesenchymal stem/stromal cells (MSCs) are distributed in various tissues and are used in clinical applications as a source of transplanted cells because of their easy harvestability. Although MSCs express numerous cell-surface antigens, single-cell analyses have revealed a highly heterogeneous cell population depending on the original tissue and donor conditions, including age and interindividual differences. This heterogeneity leads to differences in their functions, such as multipotency and immunomodulatory effects, making it challenging to effectively treat targeted diseases. The therapeutic efficacy of MSCs is controversial and depends on the implantation site. Thus, there is no established recipe for the transplantation of MSCs (including the type of disease, type of origin, method of cell culture, form of transplanted cells, and site of delivery). Our recent preclinical study identified appropriate MSCs and their suitable transplantation routes in a mouse model of inflammatory bowel disease (IBD). Three-dimensional (3D) cultures of MSCs have been demonstrated to enhance their properties and sustain engraftment at the lesion site. In this note, we explore the methods of MSC transplantation for treating IBDs, especially Crohn's disease, from clinical trials published over the past decade. Given the functional changes in MSCs in 3D culture, we also investigate the clinical trials using 3D constructs of MSCs and explore suitable diseases that might benefit from this approach. Furthermore, we discuss the advantages of the prospective isolation of MSCs in terms of interindividual variability. This note highlights the need to define the method of MSC transplantation, including interindividual variability, the culture period, and the transplantation route.

Mesenchymal Stromal Cells (MSCs) offer tremendous potential for the treatment of various diseases and their healing properties have been explored in hundreds of clinical trials. These trails primarily focus on immunological and neurological disorders, as well as regenerative medicine. Adipose tissue is a rich source of mesenchymal stromal cells and methods to obtain and culture adipose-derived MSCs (AD-MSCs) have been well established. Promising results from pre-clinical testing of AD-MSCs activity prompted clinical trials that further led to the approval of AD-MSCs for the treatment of complex perianal fistulas in Crohn's disease and subcutaneous tissue defects. However, AD-MSC heterogeneity along with various manufacturing protocols or different strategies to boost their activity create the need for standardized quality control procedures and safety assessment of the intended cell product. High-resolution transcriptomic methods have been recently gaining attention, as they deliver insight into gene expression profiles of individual cells, helping to deconstruct cellular hierarchy and differentiation trajectories, and to understand cell-cell interactions within tissues. This article presents a comprehensive overview of completed clinical trials evaluating the safety and efficacy of AD-MSC treatment, together with current single-cell studies of human AD-MSC. Furthermore, our work emphasizes the increasing significance of single-cell research in elucidating the mechanisms of cellular action and predicting their therapeutic effects.

Inflammatory bowel disease remains a difficult disease to effectively treat, especially fistulizing Crohn's disease. Perianal fistulas in the setting of Crohn's disease remain an area of unmet need with significant morbidity in this patient population. Up to one third of Crohn's patients will have perianal fistulizing disease and current medical and surgical interventions are of limited efficacy. Thus, most patients experience significant morbidity, narcotic use, and loss of employment and end up with multiple surgical interventions. Mesenchymal stem cells (MSCs) have shown efficacy in phase 3 clinical trials, but considerable infrastructure challenges make MSCs limited with regard to scalability in clinical practice. Extracellular vesicles, being derived from MSCs and capturing the secretome functionality of MSCs, offer similar physiological utility regarding mechanism, while also providing an off the shelf regenerative medicine product that could be widely used in daily clinical practice.

Perianal fistulas (PF) affect one-third patients with Crohn's disease (CD) with limited therapeutic options. There is dearth of literature on safety and efficacy of bone marrow-derived mesenchymal stromal cells (BMSCs) in this population.

An open-label, phase I/II, single-arm study was conducted involving local administration of human allogeneic bone marrow-derived mesenchymal stromal cells in perianal fistula of patients with Crohn's disease refractory to standard therapies. Clinical severity and biomarkers were assessed at baseline and periodically until week 104 , and MRI at week 24 and 104. Primary and secondary objectives were to assess safety and efficacy respectively. Fistula remission was complete closure of fistula openings with < 2 cm perianal collection on MRI, and fistula response was decrease in drainage by ≥ 50%. Change in perianal disease activity index, quality-of-life and Van Assche index on MRI over time was assessed using mixed-effect linear regression model.

Ten patients (male:8, mean age:27.4 ± 12.0years) were recruited. Self-resolving procedure-related adverse events occurred in three patients, with no follow-up adverse events. In intention to treat analysis at week 24, two patients (20%) achieved fistula remission and seven (70%) had fistula response. At week 52, two (20%) patients were in remission and seven (70%) maintained response. At 104 weeks, two (20%) patients maintained response and one (10%) was in remission. Statistically significant decrease in perianal disease activity index (P = 0.008), Van Assche Index (P = 0.008) and improvement in quality-of-life (P = 0.001) were observed over time.

Allogeneic BMSCs are safe and effective for the treatment of perianal fistulizing CD with significant improvement in clinical severity and radiological healing.

The study was prospectively registered on Clinical trials registry - India (CTRI), CTRI/2020/01/022743 on 14 January 2020, http://ctri.nic.in .

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that may progress to cirrhosis and hepatocellular carcinoma but has no available treatment. Mesenchymal stem cells (MSCs) have become increasingly prominent in cell therapy. Human umbilical cord MSCs (hUC-MSCs) are considered superior to other MSCs due to their strong immunomodulatory ability, ease of collection, low immune rejection, and no tumorigenicity. Though hUC-MSCs have received increasing attention in research, they have been rarely applied in any investigations or treatments of NASH and associated fibrosis. Therefore, this study evaluated the therapeutic efficacy of hUC-MSCs in C57BL/6 mice with diet-induced NASH. At week 32, mice were randomized into two groups: phosphate-buffered saline and MSCs, which were injected into the tail vein. At week 40, glucose metabolism was evaluated using glucose and insulin tolerance tests. NASH-related indicators were examined using various biological methods. hUC-MSC administration alleviated obesity, glucose metabolism, hepatic steatosis, inflammation, and fibrosis. Liver RNA-seq showed that the expression of the acyl-CoA thioesterase (ACOT) family members Acot1, Acot2, and Acot3 involved in fatty acid metabolism were altered. The cytochrome P450 (CYP) members Cyp4a10 and Cyp4a14, which are involved in the peroxisome proliferator-activator receptor (PPAR) signaling pathway, were significantly downregulated after hUC-MSC treatment. In conclusion, hUC-MSCs effectively reduced Western diet-induced obesity, NASH, and fibrosis in mice, partly by regulating lipid metabolism and the PPAR signaling pathway.

Crohn-related rectovaginal fistulas are notoriously difficult to treat. Studies of mesenchymal stem cells for the treatment of perianal Crohn fistulizing disease have largely excluded rectovaginal fistulas. The aim of this study was to determine the safety and efficacy of mesenchymal stem cells for refractory rectovaginal fistulizing Crohn disease.

A phase IB/IIA randomized control trial was performed in a 3:1, single-blinded study. Patients included were adult women with an anovaginal/rectovaginal fistula in the setting of Crohn disease. Seventy-five million mesenchymal stem cells were administered with a 22G needle after curettage and primary closure of the fistula tract at day 0 and month 3. Adverse and serious adverse events were recorded at post-procedure day 1, week 2, week 6, month 3, month 6, and month 12, along with clinical healing, magnetic resonance imaging, and patient-reported outcomes.

A total of 19 patients were enrolled and treated-15 treatment and 4 control. There were no adverse or serious adverse events related to mesenchymal stem cell therapy. At 6 months, 50% of the treatment group and 0% of the control had complete clinical and radiographic healing; 91.7% of the treatment group had improvement at 6 months with only one patient having a lack of response, whereas only 50% of the control group had improvement at 6 months.

Bone marrow-derived mesenchymal stem cells offer a safe alternative treatment approach for rectovaginal fistulas in the setting of Crohn disease. Complete healing was achieved in half of the patients.

Perianal fistulizing Crohn's disease is notoriously difficult to treat. Recent studies of mesenchymal stem cells have demonstrated safety and efficacy of this novel treatment approach. However, no studies to date have included pediatric patients. We sought to determine safety and efficacy of mesenchymal stem cells for pediatric perianal fistulizing Crohn's disease.

This was a phase I clinical trial to evaluate safety and feasibility of mesenchymal stem cells in pediatric perianal Crohn's patients 13 to 17 years of age. At the time of an exam under anesthesia, following curettage of the fistula tract and closure of the internal opening with absorbable suture, 75 million mesenchymal stem cells were administered with a 22-gauge needle. This was repeated at 3 months if complete clinical and radiographic healing were not achieved. Adverse and serious adverse events at were measured at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per magnetic resonance imaging, and patient-reported outcomes were measured at the same time points.

Seven pediatric patients were enrolled and treated (6 male; median age of 16.7 years). There were no adverse or serious adverse events related to the investigational product or injection procedure. At 6 months, 83% had complete clinical and radiographic healing. The perianal Crohn's Disease Activity Index, Wexner incontinence score, and Van Assche score had all decreased at 6 months.

Bone marrow-derived mesenchymal stem cells offer a safe, and likely effective, treatment approach for pediatric perianal fistulizing Crohn's disease.

Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised facilities for cell revival before administration. Human amnion epithelial cells (hAEC) are non-MSC cells with therapeutic properties. The primary aim of this study was safety of hAEC therapy. Secondary aims included hAEC efficacy, feasibility of the protocol and impact on quality of life.

A phase I open label study of ten adults with active complex Crohn's perianal fistulas refractory to conventional treatment, including anti-tumour necrosis factor alpha therapy, was undertaken. A single dose of hAEC was injected into the fistula tract(s) after surgical closure of the internal opening(s). Study outcomes were assessed at week 24 with follow up for at least 52 weeks.

Local injection of hAEC was safe, well tolerated and the injection procedure was feasible. Complete response occurred in 4 patients, and a partial response in an additional 4 patients. There was a mean reduction in the Perianal Disease Activity Index of 6.5 points (95% CI -9.0 to -4.0, p = 0.0002, paired t-test), modified Van Assche MRI Index of 2.3 points (95% CI -3.9 to -0.6, p = 0.012, paired t-test) and a mean improvement of 15.8 points (95% CI 4.9 to 26.8, p = 0.010, paired t-test) in quality of life using the Short IBD-Questionnaire in complete responders.

Local injection of hAEC therapy for refractory complex perianal fistulising Crohn's disease appears safe, well-tolerated, feasible and demonstrated improvement. Quality of life is improved in those who achieve complete fistula healing.

This study was funded by competitive research grant funding from the Gastroenterological Society of Australia Seed Grant 2018.

Utilizing adipose tissue and adipose-derived stem cells (ADSCs) turned into a promising field of allograft in recent years. The therapeutic potential of adipose tissue and ADSCs is governed by their molecular secretions, ability to sustain multi-differentiation and self-renewal which are pivotal in reconstructive, genetic diseases, and cosmetic goals. However, revisiting the existing functional capacity of adipose tissue and ADSCs and their intricate relationship with allograft is crucial to figure out the remarkable question of safety to use in allograft due to the growing evidence of interactions between tumor microenvironment and ADSCs. For instance, the molecular secretions of adipose tissue and ADSCs induce angiogenesis, create growth factors, and control the inflammatory response; it has now been well determined. Though the existing preclinical allograft studies gave positive feedback, ADSCs and adipose tissue are attracted by some factors of tumor stroma. Moreover, allorecognition is pivotal to allograft rejection which is carried out by costimulation in a complement-dependent way and leads to the destruction of the donor cells. However, extensive preclinical trials of adipose tissue and ADSCs in allograft at molecular level are still limited. Hence, comprehensive immunomodulatory analysis could ensure the successful allograft of adipose tissue and ADSCs avoiding the oncological risk.

The pathophysiology of psoriasis is a highly complicated one. Due to the disease's specificity, it not only affects the patient's skin negatively but also manifests systemic pathological changes. These clinical symptoms seriously harm the patient's physical and mental health. IFN, a common immunomodulatory factor, has been increasingly demonstrated to have a significant role in the development of psoriatic skin disease. Psoriasis is connected with a variety of immunological responses. New targets for the therapy of autoimmune skin diseases may emerge from further research on the mechanics of the associated IFN upstream and downstream pathways. Different forms of IFNs do not behave in the same manner in psoriasis, and understanding how different types of IFNs are involved in psoriasis may provide a better notion for future research. This review focuses on the involvement of three types of IFNs in psoriasis and related therapeutic investigations, briefly describing the three IFNs' production and signaling, as well as the dual effects of IFNs on the skin. It is intended that it would serve as a model for future research.

The aim of the study was to evaluate the efficacy and safety of allogeneic umbilical cord-derived mesenchymal stem cells (TH-SC01) for complex perianal fistula in patients with Crohn's disease (CD).

This was an open-label, single-arm clinical trial conducted at Jinling Hospital. Adult patients with complex treatment-refractory CD perianal fistulas (pfCD) were enrolled and received a single intralesional injection of 120 million TH-SC01 cells. Combined remission was defined as an absence of suppuration through an external orifice, complete re-epithelization, and absence of collections larger than 2 cm measured by magnetic resonance imaging (MRI) at 24 weeks after cell administration.

A total of 10 patients were enrolled. Six patients (60.0%) achieved combined remission at 24 weeks. The number of draining fistulas decreased in 9 (90.0%) and 7 (70.0%) patients at weeks 12 and 24, respectively. Significant improvement in Perianal Crohn Disease Activity Index, Pelvic MRI-Based Score, Crohn Disease Activity Index, and quality of life score were observed at 24 weeks. No serious adverse events occurred. The probability of remaining recurrence-free was 70% at week 52.

The study demonstrated that local injection of TH-SC01 cells might be an effective and safe treatment for complex treatment-refractory pfCD after conventional and/or biological treatments fail (ClinicalTrials.gov ID, NCT04939337).

The study was retrospectively registered on www.

gov (NCT04939337) on June 25, 2021.

Enterocutaneous fistula (ECF) is a condition in which there is an abnormal connection between the intestinal tract and the skin. It can lead to high morbidity and mortality rates despite the availability of therapeutic options. Stem cells have emerged as a potential strategy to treat ECF. This study aimed to evaluate the effect of adipose tissue-derived stem cells (ASC) on ECF in an experimental model.

ECF was induced in 21 Wistar rats, and after one month, they were divided into three groups: control group (C), culture medium without ASC group (CM), and allogeneic ASC group (ASC). After 30 days, the animals underwent macroscopic analysis of ECF diameter and histopathological analysis of inflammatory cells, tissue fibrosis, and vascular density.

The study found a 55% decrease in the ECF diameter in the ASC group (4.5 ± 1.4 mm) compared to the control group (10.0 ± 2.1 mm, p = 0.001) and a 59.1% decrease in the CM group (11.0 ± 4.3 mm, p = 0.003). The fibrosis score in the ASC group was 20.9% lower than the control group (p = 0.03). There were no significant differences in inflammation scores among the three groups.

This study suggests that ASC treatment can reduce ECF diameter, and reduction in tissue fibrosis may be a related mechanism. Further studies are needed to understand the underlying mechanisms fully.

Fistulizing perianal Crohn's disease poses a treatment challenge, and researchers postulate that this phenotype in young male patients could have a worst outcome.

Thus, the aim of this study was to assess whether sex influences the response to treatment for these patients.

This systematic review (PROSPERO CRD42022319629) was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. We selected articles published in English, Spanish, Portuguese, and Italian between 2010 and 2020 in the PubMed and Science Direct databases. According to the PICO acronym, prospective studies in patients older than 18 years with the objective of treating fistulizing perianal Crohn's disease were selected. Studies in pediatric populations, retrospective, without treatment objectives, and that included only rectovaginal fistulas or a single sex were excluded. Study quality was assessed using the Cochrane risk of bias tool and Newcastle-Ottawa scale.

Of the 1887 articles found, 33 were included. Most studies used anti-TNF drugs as treatment (n=11). Ten studies had subgroup analyses; of them, the two studies reporting sex differences used infliximab and adalimumab as treatment and showed that women had a longer fistula closure time than men.

This systematic review showed that few data corroborate the difference between sexes in the treatment of fistulizing perianal Crohn's disease, possibly having a greater relationship with the phenotype. However, considering the lack of results, further studies with this objective and with standardization of fistulas and response assessment methods are needed.

Crohn's disease (CD) is an inflammatory bowel disease that can affect any part of the intestine. There is currently no recognized cure for CD because its cause is unknown. One of the modern approaches that have been suggested for the treatment of CD and other inflammatory-based disorders is cell therapy.

Search terms were stem cell therapy, CD, adipose-derived stem cells, mesenchymal stem cells, and fistula. Of 302 related studies, we removed duplicate and irrelevant papers and identified the ones with proper information related to our scope of the research by reviewing all the abstracts and categorizing each study into the proper section.

Nowadays, stem cell therapy is widely implied in treating CD. Although mesenchymal and adipose-derived tissue stem cells proved to be safe in treating Crohn's-associated fistula, there are still debates on an optimal protocol to use. Additionally, there is still a lack of evidence on the efficacy of stem cell therapy for intestinal involvement of CD. Future investigations should focus on preparing a standard protocol as well as luminal stem cell therapy in patients.

Mesenchymal stem cells have been used for the treatment of perianal Crohn's fistulizing disease by direct injection. However, no studies to date have included patients with proctitis, anal canal involvement, and multiple branching tracts.

This study aimed to determine safety and efficacy of mesenchymal stem cells for refractory perianal Crohn's disease.

Phase IB/IIA randomized controlled trial.

Tertiary IBD referral center.

Adult Crohn's disease patients with perianal fistulizing disease.

Seventy-five million mesenchymal stem cells were administered with a 22-G needle by direct injection after curettage and primary closure of the fistula tract. A repeat injection of 75 million mesenchymal stem cells at 3 months was given if complete clinical and radiographic healing were not achieved.

Adverse and serious adverse events occurred at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per MRI, and patient-reported outcomes were collected at the same time points.

A total of 23 patients were enrolled and treated; 18 were treatment patients and 5 were control. There were no adverse or serious adverse events reported related to mesenchymal stem cell therapy. At 6 months, 83% of the treatment group and 40% of the control group had complete clinical and radiographic healing. The perianal Crohn's disease activity index, Wexner incontinence score, and VanAssche score had all significantly decreased in treatment patients at 6 months; none significantly decreased in the control group.

Single institution and single blinded.

Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal fistulizing Crohn's disease. See Video Abstract at http://links.lww.com/DCR/C128 .

ANTECEDENTES:Las células madre mesenquimales se han utilizado para el tratamiento de la enfermedad fistulizante de Crohn perianal mediante inyección dirigida. Sin embargo, ningún estudio hasta la fecha ha incluido pacientes con proctitis, afectación del canal anal y vías de ramificación múltiples.OBJETIVO:Determinar la seguridad y eficacia de las células madre mesenquimales para la enfermedad de Crohn perianal refractaria.DISEÑO:Ensayo de control aleatorizado de fase IB/IIA.AJUSTES:Centro de referencia de enfermedad inflamatoria intestinal terciaria.PACIENTES:Pacientes adultos con enfermedad de Crohn con enfermedad fistulizante perianal.INTERVENCIÓN:Se administraron 75 millones de células madre mesenquimales con una aguja 22G mediante inyección directa después del legrado y cierre primario del trayecto de la fístula. Se administró una inyección repetida de 75 millones de células madre mesenquimales a los 3 meses si no se lograba una curación clínica y radiográfica completa.PRINCIPALES MEDIDAS DE RESULTADOS:eventos adversos y adversos graves en el día 1, la semana 2, la semana 6, el mes 3, el mes 6 y el mes 12 después del procedimiento. Curación clínica, curación radiográfica por imagen de resonancia magnética y resultados informados por el paciente en los mismos puntos de tiempo.RESULTADOS:Un total de 23 pacientes fueron reclutados y tratados; 18 fueron de tratamiento y 5 de control. No se informaron eventos adversos o adversos graves relacionados con la terapia con células madre mesenquimales. A los seis meses, el 83 % del grupo de tratamiento y el 40 % del control tenían una curación clínica y radiográfica completa. El índice de actividad de la enfermedad de Crohn perianal, la puntuación de incontinencia de Wexner y la puntuación de VanAssche habían disminuido significativamente en los pacientes de tratamiento a los seis meses; ninguno disminuyó significativamente en el grupo de control.LIMITACIONES:Institución única y simple ciego.CONCLUSIONES:Las células madre mesenquimales derivadas de la médula ósea ofrecen un d tratamiento alternativo seguro y eficaz para la enfermedad de Crohn fistulizante perianal grave. Consulte Video Resumen en http://links.lww.com/DCR/C128 . (Traducción-Dr Yolanda Colorado ).

Rotator cuff tendinopathy is a common musculoskeletal disorder that imposes significant health and economic burden. Stem cell therapy has brought hope for tendon healing in patients with final stage rotator cuff tendinopathy. Some clinical trials have confirmed the effectiveness of stem cell therapy for rotator cuff tendinopathy, but its application has not been promoted and approved. There are still many issues that should be solved prior to using stem cell therapy in clinical applications. The optimal source and dose of stem cells for rotator cuff tendinopathy should be determined. We also proposed novel prospective approaches that can overcome cell population heterogeneity and standardize patient types for stem cell applications.

This review explores the optimal sources of stem cells for rotator cuff tendinopathy and the principles for selecting stem cell dosages. Key strategies are provided for stem cell population standardization and recipient selection.

This study provides an overview of the development of the first drug authorized for use in cell therapy.

We analyze the case of darvadstrocel, an example of a successful cell-therapy drug used worldwide to treat Crohn's perianal fistula. A bibliographic-historical analysis of the first cellular treatment approved by the EMA, including relevant aspects concerning the authors, who were involved in the whole process. We would like to highlight the following messages: Development: The article describes the development process of the drug, from initial concept through the clinical trial phases. Learning from failure: In describing the development of darvadstrocel, the authors highlight the importance of learning from failures, which is crucial to achieving successful outcomes. Collaboration: The article underscores the need for collaboration between public and private institutions to facilitate the advancement of cell-therapy drugs and ensure efficiency while adhering to regulatory guidelines.

Regulatory requirements play a crucial role in the design and development of advanced therapies such as cell-therapy drugs. The findings of this study underscore the significance of appropriate disease application, meticulous donor selection, robust manufacturing processes, and proper therapy administration. Only by adopting these measures can cell-therapy drugs successfully complete all phases of the clinical trial process.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory diseases of the gastrointestinal tract. Repeated inflammation can lead to complications, such as intestinal fistula, obstruction, perforation, and bleeding. Unfortunately, achieving durable remission and mucosal healing (MH) with current treatments is difficult. Stem cells (SCs) have the potential to modulate immunity, suppress inflammation, and have anti-apoptotic and pro-angiogenic effects, making them an ideal therapeutic strategy to target chronic inflammation and intestinal damage in IBD. In recent years, hematopoietic stem cells (HSCs) and adult mesenchymal stem cells (MSCs) have shown efficacy in treating IBD. In addition, numerous clinical trials have evaluated the efficiency of MSCs in treating the disease. This review summarizes the current research progress on the safety and efficacy of SC-based therapy for IBD in both preclinical models and clinical trials. We discuss potential mechanisms of SC therapy, including tissue repair, paracrine effects, and the promotion of angiogenesis, immune regulation, and anti-inflammatory effects. We also summarize current SC engineering strategies aimed at enhancing the immunosuppressive and regenerative capabilities of SCs for treating intestinal diseases. Additionally, we highlight current limitations and future perspectives of SC-related therapy for IBD.

Anal fistulas are common anorectal conditions, and surgery is the primary treatment option. In the last 20 years of literature, there exist a large number of surgical procedures, especially for the treatment of complex anal fistulas, as they present more recurrences and continence problems than simple anal fistulas. To date, there are no guidelines for choosing the best technique. We conducted a recent literature review, mainly the last 20 years, based on the PubMed and Google Scholar medical databases, with the goal of identifying the surgical procedures with the highest success rates, lowest recurrence rates, and best safety profiles. Clinical trials, retrospective studies, review articles, comparative studies, recent systematic reviews, and meta-analyses for various surgical techniques, as well as the latest guidelines of the American Society of Colon and Rectal Surgeons, the Association of Coloproctology of Great Britain and Ireland, and the German S3 guidelines on simple and complex fistulas were reviewed. According to the literature, there is no recommendation for the optimal surgical technique. The etiology, complexity, and many other factors affect the outcome. In simple intersphincteric anal fistulas, fistulotomy is the procedure of choice. In simple low transsphincteric fistulas, the patient's selection is crucial in order to perform a safe fistulotomy or another sphincter-saving technique. The healing rate in simple anal fistulas is higher than 95% with low recurrence and without significant postoperative complications. In complex anal fistulas, only sphincter-saving techniques should be used; the optimal outcomes are obtained by the ligation of the intersphincteric fistulous tract (LIFT) and rectal advancement flaps. Those techniques assure high healing rates of 60-90%. The novel technique of the transanal opening of the intersphincteric space (TROPIS) is under evaluation. The novel sphincter-saving techniques of fistula laser closure (FiLac) and video-assisted anal fistula treatment (VAAFT) are safe, with reported healing rates ranging from 65% to 90%. Surgeons should be familiar with all sphincter-saving techniques in order to face the variability of the fistulas-in-ano. Currently, there is no universally superior technique that can treat all fistulas.

Treating complex perianal fistulas in Crohn's disease patients remains a challenge. Classical surgical treatments for Crohn's disease fistulas have been extrapolated from cryptoglandular fistulas treatment, which have different etiology, and this might interfere with its effectiveness, in addition, they increase fecal incontinence risk. Recently, new surgical techniques with support from biological approaches, like stem cells, have been developed to preserve the function of the sphincter. We have performed a systematic literature review to compare the results of these different techniques in the treatment of Crohn's or Cryptoglandular fistula.

PubMed, EMBASE, Database of Abstracts of Reviews of Effectiveness, Cochrane Central Register of Controlled Trials were searched systematically for relevant articles. We included randomized controlled trials and observational studies that referred to humans, were written in English, included adults 18+ years old, and were published during the 10-year period from 2/01/2010 to 2/29/2020. Evidence level was assigned as designated by the Scottish Intercollegiate Guidelines Network.

Of the 577 citations screened, a total of 79 were ultimately included in our review. In Crohn's disease patients, classical techniques such as primarily seton, Ligation of Intersphincteric Fistula Tracks, or lay open, healing rates were approximately 50-60%, while in cryptoglandular fistula were around, 70-80% for setons or flaps. In Crohn's disease patients, new surgical techniques using derivatives of adipose tissue reported healing rates exceeding 70%, stem cells-treated patients achieved higher combined remission versus controls (56.3% vs 38.6%, p = 0.010), mesenchymal cells reported a healing rate of 80% at week 12. In patients with cryptoglandular fistulas, a healing rate of 70% using derivatives of adipose tissue or platelets was achieved, and a healing rate of 80% was achieved using laser technology. Fecal incontinence was improved after the use of autologous platelet growth factors and Nitinol Clips.

New surgical techniques showed better healing rates in Crohn's disease patients than classical techniques, which have better results in cryptoglandular fistula than in Crohn's disease. Healing rates for complex cryptoglandular fistulas were similar between the classic and new techniques, being the new techniques less invasive; the incontinence rate improved with the current techniques.

Perianal fistula is a debilitating disease and challenging condition to treat. Recently, the use of stem cells has been shown to improve healing of fistulas.

The aim was to examine the use of an umbilical cord-derived stem cell graft in a pilot study as a novel scaffold/stem inlay implanted into fistula repairs for anovaginal fistula to examine healing rates.

This was a pilot study.

This study took place in a colorectal surgery practice.

Patients with anovaginal fistula consented to participate. Cryopreserved umbilical cord tissue graft with viable cells was incorporated as an inlay using a previously reported technique by the authors. Demographic data including history of previous repairs and IBD were included. All patients were followed for a minimum of 6 weeks.

The primary measures were safety and efficacy of novel stem cell graft in the treatment of anovaginal fistula.

From September 2017 to September 2019, 15 patients underwent anovaginal fistula repair. Three of these patients underwent a second repair, for a total of 18 repairs. No patient was intentionally diverted, but 3 patients presented for repair with a preexisting stoma. The majority of repairs were previous repair failures (12; 67%), and 7 repairs were performed on 5 patients with IBD. Median follow-up was 30 (6-104) weeks. The safety profile for cryopreserved umbilical cord tissue graft was excellent as no adverse events occurred. Overall complete healing rate was 39%, and 12 (67%) repairs resulted in improvement of symptoms.

This was a small pilot study.

This is the largest series using cryopreserved umbilical cord graft for anovaginal fistula repair. The use of umbilical cord was safe and effective at closing defects. Randomized studies are necessary to determine added benefits over current standard of care. See Video Abstract at http://links.lww.com/DCR/B896 .

ANTECEDENTES:La fístula perianal es una enfermedad debilitante y una afección difícil de tratar. Recientemente, se ha demostrado que el uso de células madre mejora la curación de las fístulas.OBJETIVO:Deseamos examinar el uso de un injerto de células madre derivadas de cordón umbilical en un estudio piloto como una nueva matriz/injerto de células madre implantado en reparaciones de fístula para fístula anovaginal para examinar las tasas de curación.DISEÑO:Este fue un estudio piloto.ESCENARIO:Este estudio se llevó a cabo en una clínica de cirugía colorrectal.PACIENTES:Se obtuvo consentimiento informado de pacientes con fístula anovaginal. El injerto de tejido de cordón umbilical criopreservado con células viables se incorporó como incrustación utilizando una técnica previamente informada por los autores. Se incluyeron datos demográficos que incluían antecedentes de reparaciones previas y enfermedad inflamatoria intestinal. Todos los pacientes fueron seguidos durante un mínimo de 6 semanas.PRINCIPALES MEDIDAS DE RESULTADO:Las principales medidas fueron la seguridad y la eficacia del nuevo injerto de células madre en el tratamiento de la fístula anovaginal.RESULTADOS:Desde 9/2017-9/2019, 15 pacientes fueron sometidas a reparación de fístula anovaginal. Tres de estos pacientes fueron sometidos a una segunda reparación, para un total de 18 reparaciones. Ningún paciente fue derivado intencionalmente mientras que 3 pacientes se presentaron para reparación con un estoma preexistente. La mayoría de las reparaciones fueron fallas de reparaciones previas (12, 67%) y se realizaron siete reparaciones en 5 pacientes con enfermedad inflamatoria intestinal (EII). La mediana de seguimiento fue de 30 semanas (6-104). El perfil de seguridad del injerto de tejido de cordón umbilical criopreservado fue excelente ya que no se produjeron efectos adversos. La tasa general de curación completa fue del 39% y 12 (67%) reparaciones dieron como resultado una mejoría de los síntomas.LIMITACIONES:Este fue un pequeño estudio piloto.CONCLUSIÓNES:Ésta es la serie más grande de utilización de injerto de cordón umbilical criopreservado para la reparación de una fístula anovaginal. La utilización del cordón umbilical resultó segura y eficaz para cerrar defectos. Se necesitan estudios aleatorizados para determinar los beneficios adicionales sobre el estándar de atención actual. Consulte Video Resumen en http://links.lww.com/DCR/B896 . (Traducción-Dr. Jorge Silva Velazco ).

Primary sclerosing cholangitis (PSC) is a progressive liver disease for which there is no effective therapy. Hepatocytes and cholangiocytes from a PSC patient were cocultured with mesenchymal stem cells (MSCs) to assess in vitro change. A single patient with progressive PSC was treated with 150 million MSCs via direct injection into the common bile duct. Coculture of MSCs with cholangiocytes and hepatocytes showed in vitro improvement. Local delivery of MSCs into a single patient with progressive PSC was safe. Radiographic and endoscopic evaluation showed stable distribution of multifocal structuring in the early postoperative period. MSCs may be effective for the treatment of PSC.

Refractory perianal Crohn's disease remains notoriously difficult to treat. We developed a novel technology using a commercially available bioabsorbable fistula plug to deliver autologous adipose-derived mesenchymal stem cells.

This study aimed to assess therapeutic safety and feasibility in the completed STOMP (stem cells on matrix plugs) phase 1 clinical trial.

Prospective single-arm phase I clinical trial.

Tertiary academic medical center.

Adults (aged 18-65 y) with complex single-tract Crohn's disease perianal fistula who have failed conventional therapy were included in this study.

Autologous adipose-derived mesenchymal stem cells were isolated, ex vivo culture expanded, and seeded onto a commercially available bioabsorbable fistula plug. Six weeks later, patients returned to the operating room for removal of the seton and placement of the stem cell-loaded plug.

Patients were followed up for a total of 8 visits through 12 months. Safety was the primary end point; clinical healing and MRI response were secondary end points.

Twenty patients (12 females; mean age 36 y) were treated with the stem cell-loaded plug. Of the 20 patients enrolled, 3 were not included in the 12-month analysis because of study withdrawal. Through 12 months, no patient experienced a serious adverse event related to the stem cell-loaded plug. Four patients experienced 7 serious adverse events and 12 patients experienced 22 adverse events. Complete clinical healing occurred in 14 of 18 patients at 6 months and 13 of 17 patients at 12 months. MRI response was observed in 12 of 18 patients at 6 months.

The main limitations were the small sample size and restrictive inclusion criteria.

A stem cell-loaded plug can safely and effectively deliver cell-based therapy for patients with single-tract fistulizing perianal Crohn's disease. See Video Abstract at http://links.lww.com/DCR/C70 .

ANTECEDENTES:La enfermedad de Crohn perianal refractaria sigue siendo notoriamente difícil de tratar. Desarrollamos una tecnología novedosa utilizando un tapón de fístula bioabsorbible disponible comercialmente para administrar células madre mesenquimales derivadas de tejido adiposo autólogo.OBJETIVO:Evaluar la seguridad y viabilidad terapéutica en el ensayo finalizado STOMP.DISEÑO:Ensayo clínico prospectivo de fase I de un solo brazo.AJUSTE:Centro médico académico terciario.PACIENTES:Adultos (18-65) con fístula perianal compleja de la enfermedad de Crohn de un solo tracto que han fracasado con la terapia convencional.INTERVENCIÓN:Se aislaron células madre mesenquimales derivadas de tejido adiposo autólogo, se expandieron en cultivo ex vivo y se sembraron en un tapón de fístula bioabsorbible disponible comercialmente. Seis semanas después, los pacientes regresaron al quirófano para retirar el setón y colocar el tapón cargado de células madre.PRINCIPALES MEDIDAS DE RESULTADO:Los pacientes fueron seguidos durante un total de 8 visitas durante 12 meses. La seguridad fue el criterio principal de valoración; la curación clínica y la respuesta a la resonancia magnética fueron criterios de valoración secundarios.RESULTADOS:Veinte pacientes (12 mujeres, edad media 36 años) fueron tratados con el tapón cargado de células madre. De los 20 pacientes inscritos, tres no se incluyeron en el análisis de 12 meses porque se retiraron del estudio. A lo largo de 12 meses, ningún paciente experimentó un evento adverso grave relacionado con el tapón cargado de células madre. Cuatro pacientes experimentaron 7 eventos adversos graves y 12 pacientes experimentaron 22 eventos adversos. La curación clínica completa ocurrió en 14 de 18 pacientes a los 6 meses y en 13 de 17 pacientes a los 12 meses. La respuesta a la resonancia magnética se observó en 12 de 18 pacientes a los 6 meses.LIMITACIONES:Las principales limitaciones son el tamaño pequeño de la muestra y los criterios de inclusión restrictivos.CONCLUSIONES:Un tapón cargado de células madre se puede administrar de manera segura y efectiva, una terapia basada en células para pacientes con enfermedad de Crohn perianal fistulizante de un solo tracto. Consule Video Resumen en http://links.lww.com/DCR/C70 . (Traducción- Dr. Yesenia Rojas-Khalil ).

Mesenchymal stem cell-derived exosomes (MSC-Exos) have attracted much attention as a potential cell-free therapy for ulcerative colitis (UC), mainly due to their anti-inflammatory, tissue repair, and immunomodulatory properties. Although intravenous injection of MSC-Exos is able to improve UC to a certain extent, oral administration of exosomes is the preferred method to treat gastrointestinal diseases such as UC. However, exosomes contain proteins and nucleic acids that are vulnerable to degradation by the gastrointestinal environment, making oral administration difficult to implement. Layer-by-layer (LbL) self-assembly technology provides a promising strategy for the oral delivery of exosomes. Therefore, an efficient LbL-Exos self-assembly system was constructed in this study for the oral delivery of exosomes targeted to the colon to improve UC treatment. Biocompatible and biodegradable N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) and oxidized konjac glucomannan (OKGM) polysaccharides were used as the outer layers to provide colon targeting and to protect exosomes from degradation. Similar to plain exosomes, LbL-Exos had a similar structure and features, but LbL provided controlled release of exosomes in the inflammatory colon. Compared with intravenous administration, oral administration of LbL-Exos could effectively alleviate UC using half the number of exosomes. Mechanistic studies showed that LbL-Exos were internalized by macrophages and intestinal epithelial cells to exert anti-inflammatory and tissue repair effects and therefore alleviate UC. Furthermore, the LbL-Exos system was able to improve UC via MAPK/NF-κB signaling pathway inhibition. Overall, our data show that LbL-MSC-Exos can alleviate UC after oral administration and therefore may constitute a new strategy for UC treatment in the future.

Recently, mesenchymal stem/stromal cells (MSCs) therapy has become an emerging therapeutic modality for the treatment of inflammatory bowel disease (IBD), given their immunoregulatory and pro-survival attributes. MSCs alleviate dysregulated inflammatory responses through the secretion of a myriad of anti-inflammatory mediators, such as interleukin 10 (IL-10), transforming growth factor-β (TGFβ), prostaglandin E2 (PGE2), tumor necrosis factor-stimulated gene-6 (TSG-6), etc. Indeed, MSC treatment of IBD is largely carried out through local microcirculation construction, colonization and repair, and immunomodulation, thus alleviating diseases severity. The clinical therapeutic efficacy relies on to the marked secretion of various secretory molecules from viable MSCs via paracrine mechanisms that are required for gut immuno-microbiota regulation and the proliferation and differentiation of surrounding cells like intestinal epithelial cells (IECs) and intestinal stem cells (ISCs). For example, MSCs can induce IECs proliferation and upregulate the expression of tight junction (TJs)-associated protein, ensuring intestinal barrier integrity. Concerning the encouraging results derived from animal studies, various clinical trials are conducted or ongoing to address the safety and efficacy of MSCs administration in IBD patients. Although the safety and short-term efficacy of MSCs administration have been evinced, the long-term efficacy of MSCs transplantation has not yet been verified. Herein, we have emphasized the illumination of the therapeutic capacity of MSCs therapy, including naïve MSCs, preconditioned MSCs, and also MSCs-derived exosomes, to alleviate IBD severity in experimental models. Also, a brief overview of published clinical trials in IBD patients has been delivered.

Crohn's Disease (CD), which usually leads to anal fistulas among patients, is the most important inflammatory bowel disease that causes morbidity in many people around the world. This review article proposes using MSCs as a hopeful therapeutic strategy for CD and anal fistula treatment in both preclinical and clinical conditions. Finally, darvadstrocel, a cell-based medication to treat complex anal fistulas in adults, as the only European Medicines Agency (EMA)-approved product for the treatment of anal fistulas in CD is addressed. Although several common therapies, such as surgery and anti-tumor necrosis factor-alpha (TNF-α) drugs as well as a combination of these methods is used to improve this disease, however, due to the low effectiveness of these treatments, the use of new strategies with higher efficiency is still recommended. Cell therapy is among the new emerging therapeutic strategies that have attracted great attention from clinicians due to its unique capabilities. One of the most widely used cell sources administrated in cell therapy is mesenchymal stem cell (MSC). This review article will discuss preclinical and clinical studies about MSCs as a potent and promising therapeutic option in the treatment of CD and anal fistula.

Mesenchymal stem cells (MSCs) have been used for the treatment of perianal Crohn's fistulizing disease by direction injection. No studies to date have included patients with an ileal pouch anal anastomosis (IPAA) in situ.

A phase IB/IIA randomized control trial of bone marrow derived allogeneic MSCs via direct injection to treat adult patients with a peripouch fistula(s) was conducted. 75 million MSCs were administered with a 22G needle; repeat injection at 3 months was given if complete clinical and radiographic healing were not achieved. Adverse and serious adverse events at post procedure day 1, week 2, week 6, month 3, month 6 and month 12 were assessed. Clinical healing, radiographic healing per pelvic MRI, and patient reported outcomes were assessed at the same time points.

A total of 22 patients were enrolled and treated; 16 were treatment and 6 were control. There were no adverse or serious adverse events related to MSC therapy. At six months, 31% of the treatment group and 20% of the control had complete clinical and radiographic healing. When stratifying the treatment group into perianal (n=7) and anovaginal (n=8) fistulas, 6 month healing in the treatment groups was 57% and 0%, respectively. The perianal Crohn's disease activity index (PCDAI), Wexner incontinence score, and VanAssche score all significantly decreased in treatment patients at six months; only the PCDAI decreased in the control group.

Bone marrow derived allogeneic MSCs offer a safe and effective alternative treatment approach for peripouch fistulas in the setting of a Crohn's like phenotype of the pouch.

There have been no studies into the direct injection of mesenchymal stem cells (MSCs) for luminal ulcerative colitis (UC). Our aim was to investigate the efficacy of MSCs delivered locally via endoscopic delivery, as is done in the setting of perianal disease, to treat the local site of inflammation directly.

A phase IB/IIA randomized control clinical trial of remestemcel-L, an ex vivo expanded allogeneic bone marrow-derived MSC product, at a dose of 150 million MSCs versus placebo (2:1 fashion) delivered via direct injection using a 23-gauge sclerotherapy needle at the time of colonoscopy was designed to assess the safety and efficacy of endoscopic delivery of MSCs for UC. The main outcome measures were adverse events, Mayo score and Mayo endoscopic severity score at 2 weeks, 6 weeks and 3 months post-MSC delivery.

Six patients were enrolled and treated; four received MSCs and two placebo. All had been on prior anti-tumour necrosis factor or anti-integrin therapy. There were no adverse events related to MSCs. In the treatment group (n = 4), the Mayo endoscopic severity score decreased in all patients by 2 weeks after MSC delivery. At 3 months, all patients were extremely satisfied or satisfied with their MSC treatment based on the inflammatory bowel disease patient-reported treatment impact (IBD-PRTI), and treatment response was described as excellent or good in all patients. In the control group (n = 2), the Mayo endoscopic severity score did not increase as a result of being off alternative therapy. At 3 months, patients were dissatisfied according to the IBD-PRTI, and treatment response was poor or unchanged.

MSCs may offer a safe therapeutic option for the treatment of medically refractory UC. Early data suggest improved clinical and endoscopic scores by 2 weeks after MSC delivery.

Inflammatory bowel diseases (IBD) are chronic relapsing-remitting inflammatory diseases of the gastrointestinal tract that are typically categorized into two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). Although MSCs therapy has achieved encouraging outcomes in IBD therapy, objective responses are limited in colon fibrosis stenosis owing to the complicated microenvironment of CD and MSCs heterogeneity of quality. Here, we chose IFN-γ and kynurenic acid (KYNA) to overcome the low response and heterogeneity of human adipose-derived MSCs (hADSCs) to treat IBD and expand the therapeutic effects based on the excellent ability of IFN-γ and KYNA to promote indoleamine 2,3-dioxygenase-1 (IDO-1) signaling, providing a potential protocol to treat IBD and fibrosis disease.

hADSCs were isolated, cultured, and identified from human abdominal adipose tissue. The CD pathology-like acute colitis and chronic colon fibrosis rat model was induced by 2,4,6-trinitrobenzen sulfonic acid (TNBS). hADSCs were pretreated in vitro with IFN-γ and KYNA and then were transplanted intravenously at day 1 and 3 of TNBS administration in colitis along with at day 1, 15, and 29 of TNBS administration in chronic colonic fibrosis. Therapeutic efficacy was evaluated by body weights, disease activity index, pathological staining, real-time PCR, Western blot, and flow cytometry. For knockout of IDO-1, hADSCs were transfected with IDO-1-targeting small gRNA carried on a CRISPR-Cas9-lentivirus vector.

hADSCs treated with IFN-γ and KYNA significantly upregulated the expression and secretion of IDO-1, which has effectively ameliorated CD pathology-like colitis injury and fibrosis. Notably, the ability of hADSCs with IDO-1 knockout to treat colitis was significantly impaired and diminished the protective effects of the primed hADSCs with IFN-γ and KYNA.

Inflammatory cytokines IFN-γ- and KYNA-treated hADSCs more effectively alleviate TNBS-induced colitis and colonic fibrosis through an IDO-1-dependent manner. Primed hADSCs are a promising new strategy to improve the therapeutic efficacy of MSCs and worth further research.

Crohn's disease (CD) is an inflammatory bowel disease that causes inflammation and stricture, of any part of the mucosa and the gut wall. It forms skip lesions, sparing the areas in between the affected parts of the gastrointestinal tract. Crohn's disease could have one of three complications; fistula, intestinal obstruction due to stricture, or gastrointestinal inflammation presenting as severe diarrhoea. Stem cell therapy (SCT) is an innovative treatment that has been recently used in CD. The exact role of SCT in CD is still unclear. Stem cells modify the immunity of the patients or act as a "reset tool" for the immune system as in the case of systemically-injected stem cells, or regenerate the affected area of necrotic and inflammatory tissue as in the case of local injection into the lesion. Stem cells are a wide variety of cells including pluripotent stem cells or differentiated stem cells. The hazards range from rejection to symptomatic manifestations as fever or increase infection.  OBJECTIVES: The objective of this Cochrane systematic review is to assess the effects of stem cell transplantation compared to standard of care alone or with placebo on efficacy and safety outcomes in patients with refractory CD.

We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and clinical trial registries (Clinicaltrials.gov, World Health Organization-International Clinical Trials Registry Platform WHO ICTRP) from inception to 19 March 2021, without any language, publication year, or publication status restrictions. In addition, we searched references of included studies and review articles for further references. An update of the published studies was done during the writing of the review.

We included only randomised controlled trials (RCTs) that assessed the effectiveness and safety of SCT in refractory CD versus standard care alone (control) or with placebo.

Two review authors (SEN and SFA) independently screened the studies retrieved from the search results for inclusion, extracted data and assessed the risk of bias. Any disagreement was resolved through a consensus between the authors. We used standard methodological procedures expected by Cochrane.

We conducted our search on 19 March 2021 and identified 639 records. We added two records by a manual search of the published reviews on the topic to a total of 641 records. The Covidence program removed 125 duplicates making a total of 516 reports. Two review authors (SEN and SFA) screened titles and abstracts and excluded 451 records with the remaining 65 for full-text records screened independently by the two authors; only 18 studies were considered for inclusion.  We included seven RCTs with a total of 442 participants for the meta-analysis. The intervention group included 234 patients, and the control group included 208 patients. Nine trials are ongoing and, two abstracts are awaiting classification. All patients in the control and intervention groups received the standard therapy for CD. Only three studies used blinding methods for the control group in the form of a placebo, with one study of the three stated that the blinding method was inefficient. The patients and personnel were aware of the intervention in the rest of the four studies as they were open-label trials. However, the effect of unblinding was balanced by the low risk of detection bias in five of the included studies. The evidence is uncertain about the effect of SCT on achieving clinical remission as compared to control/placebo (risk ratio (RR) 1.88, 95% Confidence Interval (CI) 0.80 to 4.41; 3 studies; low-certainty evidence). The evidence is very uncertain about the effect of SCT on achieving Crohn's Disease Activity Index (CDAI) <150 at 24 weeks compared to control (RR1.02 95% CI 0.67 to 1.56; 4 studies; very-low certainty evidence). SCT is likely to achieve fistula closure as compared to the control/placebo both in the short term (RR 1.48, 95% CI 1.12 to 1.96); low-certainty evidence) and in the long term (RR 1.42, 95% CI 1.09 to 1.87; 4 studies; low-certainty evidence) follow-up. The evidence is very uncertain about the effect of SCT to cause no difference in the number of total adverse events as compared to the control/placebo (RR 0.99, 95% CI [0.88 to  1.13); 4 studies; very-low-certainty evidence). However, SCT is likely to increase the number of serious adverse events as compared to the control/placebo (RR 1.22, 95% CI 0.88 to 1.67; 7 studies; low-certainty evidence). The evidence is very uncertain about the effect of SCT to decrease the withdrawal due to adverse events as compared to the control/placebo (RR 0.78, 95% CI 0.32 to 1.89; 3 studies; very-low certainty evidence). Funding by pharmaceutical companies was found in three studies, with one including more than 50% of our studied population.

SCT shows an uncertain effect on clinical remission with low certainty of evidence. SCT shows an uncertain effect on CDAI score to reach <150 after 24 weeks of treatment, with very low certainty evidence. SCT shows beneficial effects on fistula-closure during short and long-term follow-up with low-certainty evidence in both outcomes. There was no change in the total number of adverse events with SCT as compared to control, with very low certainty evidence. While there was a moderate effect on increasing the number of serious adverse events in the SCT group, as compared to the control with low-certainty evidence. Withdrawal due to adverse events was slightly higher in the control group with very low certainty evidence. All the participants were refractory to standard medical treatment, but the number of participants was small, this may limit the generalizability of the results. Further research is needed for validation. More objective outcomes are needed in the assessment of stem cell effectiveness in the treatment of Crohn's disease, especially the intestinal CD subtype; with standardization of the dose, methods of stem cell preparation, route of administration, and inclusion criteria to the studies to achieve clear results.