• MSCs
• MSC‐Exos
• aGVHD
• autophagy
• inflammatory response

• Animals
• Exosomes/metabolism
• Graft vs Host Disease/therapy
• Rats
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Rats, Wistar
• Male
• Rats, Sprague-Dawley
• Mesenchymal Stem Cell Transplantation/methods
• T-Lymphocytes, Regulatory/immunology
• Bone Marrow Cells/cytology
• Autophagy

• 2020Y9027 Joint Fund Project for the Innovation of Science and Technology in Fujian Province
• 2020J011062 National Science Foundation of Fujian Province
• 22GSSYB-6 Gansu Provincial Hospital Intra-Hospital Research Fund Project
• NHCDP2022008 The 2022 Master/Doctor/Postdoctoral program of NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor
• 20224BAB206077 the Natural Science Foundation of Jiangxi Province

• Experimental colitis
• Intraperitoneal injection
• Mesenchymal stem cells
• Mesenteric lymph nodes
• TGF-β1
• Treg cells

• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/metabolism
• Transforming Growth Factor beta1/metabolism
• Animals
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/cytology
• Humans
• Colitis/therapy
• Colitis/chemically induced
• Colitis/metabolism
• Colitis/pathology
• Mesenchymal Stem Cell Transplantation/methods
• Mice
• Lymph Nodes/metabolism
• Th17 Cells/metabolism
• Th17 Cells/immunology
• Cell Differentiation
• Umbilical Cord/cytology
• Mesentery/metabolism
• Mice, Inbred C57BL
• Mice, Inbred BALB C
• Male
• Inflammatory Bowel Diseases/therapy
• Inflammatory Bowel Diseases/metabolism
• Inflammatory Bowel Diseases/pathology

• 82073928 National Natural Science Foundation of China
• 82104184 National Natural Science Foundation of China
• BK20232035 Leading technology foundation research project of Jiangsu province
• BK20192005 Leading technology foundation research project of Jiangsu province
• 22HHXBSS00005 Haihe Laboratory of Cell Ecosystem Innovation Fund
• 202110006 Nanjing Scientific and Technological Special Project for Life and Health
• SKLNMZZ202302 the Project of State Key Laboratory of Natural Medicines, China Pharmaceutical University
• 2632023TD03 Fundamental Research Funds for the Central Universities

• Cytokines
• Inflammation
• Inflammatory bowel disease (IBD)
• Intestinal integrity
• Mesenchymal stem/stromal cells (MSCs)

• Animals
• Inflammatory Bowel Diseases/therapy
• Inflammatory Bowel Diseases/metabolism
• Inflammatory Bowel Diseases/pathology
• Cell Differentiation
• Mesenchymal Stem Cells
• Treatment Outcome
• Cell- and Tissue-Based Therapy
• Mesenchymal Stem Cell Transplantation/methods

• anti-apoptosis
• central nervous system
• immunomodulation
• mesenchymal stem cells (MeSH ID D059630)
• regenerative medicine

• stem-cell research
• mesenchymal stem cells

• Adipose Tissue
• Cell Differentiation/genetics
• Humans
• Mesenchymal Stem Cells
• Regenerative Medicine
• Umbilical Cord

• Vingroup Scientific Research and Clinical Application Fund (Grant number: PRO.19.47)

We explored whether stem cell therapy was effective for animal models and patients with Crohn’s disease (CD).

We searched five online databases. The relative outcomes were analyzed with the aid of GetData Graph Digitizer 2.26 and Stata 16.0 software. The SYRCLE risk of bias tool and the MINORS tool were used to assess study quality.

We evaluated 46 studies including 28 animal works (n = 567) and 18 human trials (n = 360). In the animal studies, the disease activity index dramatically decreased in the mesenchymal stem cell (MSC) treatment groups compared to the control group. Rats and mice receiving MSCs exhibited longer colons [mice: standardized mean difference (SMD) 2.84, P = 0.000; rats: SMD 1.44, P = 0.029], lower histopathological scores (mice: SMD − 4.58, p = 0.000; rats: SMD − 1.41, P = 0.000) and lower myeloperoxidase levels (SMD − 6.22, P = 0.000). In clinical trials, stem cell transplantation reduced the CD activity index (SMD − 2.10, P = 0.000), the CD endoscopic index of severity (SMD − 3.40, P = 0.000) and simplified endoscopy score for CD (SMD − 1.71, P = 0.000) and improved the inflammatory bowel disease questionnaire score (SMD 1.33, P = 0.305) compared to control values. CD patients maintained high remission rates for 3–24 months after transplantation.

Stem cell transplantation is a valuable supplementary therapy for CD.

The online version contains supplementary material available at 10.1186/s13287-021-02533-0.

• Colon length
• Crohn’s disease
• Crohn’s disease activity index
• Histopathological score
• Remission rate
• Stem cells
• Systematic review and meta-analysis

• Colitis
• Dickkopf-1
• Endometrial regenerative cells
• Immunoregulation
• Mice

• MenSCs
• Polarization
• Pregnancy
• Proliferation
• TH17
• Treg

• autophagy
• bone marrow-derived neural progenitor cell
• disabled homolog 2-interacting protein
• exosomes
• microRNAR-32-3p
• microglial cell

Inflammatory bowel disease (IBD) is a chronic disabling inflammatory process that affects young individuals, with growing incidence. The etiopathogenesis of IBD remains poorly understood. A combination of genetic and environmental factors triggers an inadequate immune response against the commensal intestinal flora in IBD patients. Thus, a better understanding of the immunological mechanisms involved in IBD pathogenesis is central to the development of new therapeutic options.

Current pharmacological treatments used in clinical practice like thiopurines or anti-TNF are effective but can produce significant side effects and their efficacy may diminish over time. In fact, up to one third of the patients do not have a satisfactory response to these therapies. Consequently, the search for new therapeutic strategies targeting alternative immunological pathways has intensified. Several new oral and parenteral substances are in the pipeline for IBD.

In this review we discuss novel therapies targeting alternative pro-inflammatory pathways like IL-12/23 axis, IL-6 pathway or Janus Kinase inhibitors; as well as others modulating anti-inflammatory signalling pathways like transforming growth factor-β1 (TGF-β1). We also highlight new emerging therapies targeting the adhesion and migration of leukocytes into the inflamed intestinal mucosa by blocking selectively different subunits of α₄β₇ integrins or binding alternative adhesion molecules like MAdCAM-1. Drugs reducing the circulating lymphocytes by sequestering them in secondary lymphoid organs (sphingosine-1-phosphate (S1P) receptor modulators) are also discussed. Finally, the latest advances in cell therapies using mesenchymal stem cells or engineered T regs are reviewed. In addition, we provide an update on the current status in clinical trials of these new immune-regulating therapies that open a new era in the treatment of IBD.

• Crohn's disease
• Janus kinases
• adhesion molecules
• cell therapy
• inflammatory bowel disease
• therapy
• ulcerative colitis

• B lymphocytes
• Endometrial regenerative cells
• Immunoregulation
• Mice
• Ulcerative colitis

Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions of the gastrointestinal tract characterized by an exacerbated mucosal immune response. Macrophages play pivotal roles in the maintenance of gut homeostasis but they are also implicated in the pathogenesis of IBD. They are highly plastic cells and their activation state depends on the local environment. In the healthy intestine, resident macrophages display an M2 phenotype characterized by inflammatory energy, while inflammatory M1 macrophages dominate in the inflamed intestinal mucosa. In this regard, modifying the balance of macrophage populations into an M2 phenotype has emerged as a new therapeutic approach in IBD. Multipotent mesenchymal stromal cells (MSCs) have been proposed as a promising cell-therapy for the treatment of IBD, considering their immunomodulatory and tissue regenerative potential. Numerous preclinical studies have shown that MSCs can induce immunomodulatory macrophages and have demonstrated that their therapeutic efficacy in experimental colitis is mediated by macrophages with an M2-like phenotype. However, some issues have not been clarified yet, including the importance of MSC homing to the inflamed colon and/or lymphoid organs, their optimal route of administration or whether they are effective as living or dead cells. In contrast, the mechanisms behind the effect of MSCs in human IBD are not known and more data are needed regarding the effect of MSCs on macrophage polarization that would support the observation reported in the experimental models. Nevertheless, MSCs have emerged as a novel method to treat IBD that has already been proven safe and with clinical benefits that could be administered in combination with the currently used pharmacological treatments.

• IL-10
• M1/M2 macrophage polarization
• PGE2
• inflammatory bowel disease
• mesenchymal stem cells
• multipotent mesenchymal stromal cells

To assess the effect of sodium selenite on the severity of dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice.

Mice were randomly divided into four groups (n = 10/group): normal group, selenium (Se) group, chronic colitis group, and Se + chronic colitis group. The mice were sacrificed on day 26. Survival rates, clinical symptoms, colon length, and histological changes were determined. The percentages and absolute numbers of immune system cells in the lamina propria lymphocytes (LPL) of the colon, the expression of mRNA in colon tissue, and the concentrations of Th1, Th17, and Treg cytokines in LPL from the large intestine, were measured.

Se significantly ameliorated the symptoms of colitis and histological injury (P < 0.05 each), increasing the proportions of neutrophils and CD4⁺ CD25⁺ T cells (P < 0.05 each) and decreasing the proportions of γδT cells, CD4⁺, CD4⁺CD44⁺, and CD4⁺ CD69⁺ T cells in LPL (P < 0.05 each). Moreover, Se reduced the expression of IL-6, IFN-γ, IL-17A, IL-21, T-bet, and RORγt (P < 0.05 each), but enhanced the expression of IL-10 and Foxp3 (P < 0.05 each).

These results suggest that Se protects against DSS-induced chronic colitis perhaps by increasing the number of CD4(+)CD25(+) Tregs that suppress the secretion of proinflammatory cytokines and populations of Th1, Th17, and γδT cells.

• Sodium selenite
• Dextran sulfate sodium
• Chronic colitis

• Animals
• Antioxidants/pharmacology
• Antioxidants/therapeutic use
• Chronic Disease
• Colitis/chemically induced
• Colitis/drug therapy
• Colitis/immunology
• Colon/drug effects
• Colon/immunology
• Colon/pathology
• Cytokines/metabolism
• Dextran Sulfate/toxicity
• Disease Models, Animal
• Flow Cytometry
• Humans
• Intestinal Mucosa/drug effects
• Intestinal Mucosa/immunology
• Intestinal Mucosa/pathology
• Intraepithelial Lymphocytes/drug effects
• Intraepithelial Lymphocytes/immunology
• Male
• Mice
• Mice, Inbred C57BL
• Sodium Selenite/pharmacology
• Sodium Selenite/therapeutic use
• T-Lymphocytes, Regulatory/drug effects
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/metabolism
• Th1 Cells/drug effects
• Th1 Cells/immunology
• Th1 Cells/metabolism
• Th17 Cells/drug effects
• Th17 Cells/immunology
• Th17 Cells/metabolism
• Trace Elements/pharmacology
• Trace Elements/therapeutic use

• cell therapy
• dextran sulfate sodium–induced colitis
• immunosuppression
• inflammatory bowel disease
• toll-like receptors
• umbilical cord–derived mesenchymal stromal cells

• IL-17
• SLE
• hUC-MSCs
• prostaglandin E2

Mesenchymal stromal cells (MSC) have gained immense attraction in regenerative medicine, tissue engineering, and immunotherapy. This is based on their differentiation potential and the supply of pro-regenerative and immunomodulatory signals. MSC can be isolated from a multitude of tissue sources, but mainly bone marrow, adipose tissue, and birth-associated tissues (e.g., umbilical cord, cord blood, placenta) appear to be relevant for clinical translation in immune-mediated disorders. However, only a few studies directly compared the immunomodulatory potency of MSC from different tissue sources. This review compiles the current literature regarding the similarities and differences between these three sources for MSCs with a special focus on their immunomodulatory effects on T-lymphocyte subsets and monocytes, macrophages, and dendritic cells.

• T cells
• adipose tissue
• bone marrow
• immunomodulation
• macrophages
• mesenchymal stromal cells
• regulatory T cells
• umbilical cord

• Cell therapy
• Crohn's disease
• Inflammatory bowel disease
• Mesenchymal stromal cells
• Regenerative medicine
• Translational research
• Ulcerative colitis

Utilization of mesenchymal stromal cells (MSCs) for the treatment of Crohn’s disease and ulcerative colitis is of translational interest. Safety of MSC therapy has been well demonstrated in early phase clinical trials but efficacy in randomized clinical trials needs to be demonstrated. Understanding MSC mechanisms of action to reduce gut injury and inflammation is necessary to improve current ongoing and future clinical trials. However, two major hurdles impede the direct translation of data derived from animal experiments to the clinical situation: (1) limitations of the currently available animal models of colitis that reflect human inflammatory bowel diseases (IBD). The etiology and progression of human IBD are multifactorial and hence a challenge to mimic in animal models; and (2) Species specific differences in the functionality of MSCs derived from mice versus humans. MSCs derived from mice and humans are not identical in their mechanisms of action in suppressing inflammation. Thus, preclinical animal studies with murine derived MSCs cannot be considered as an exact replica of human MSC based clinical trials. In the present review, we discuss the therapeutic properties of MSCs in preclinical and clinical studies of IBD. We also discuss the challenges and approaches of using appropriate animal models of colitis, not only to study putative MSC therapeutic efficacy and their mechanisms of action, but also the suitability of translating findings derived from such studies to the clinic.

• Mesenchymal stromal cells
• Inflammatory bowel disease
• Colitis
• Animal model
• Crohn’s disaese

• Animals
• Clinical Trials as Topic
• Disease Models, Animal
• Humans
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/metabolism
• Inflammatory Bowel Diseases/physiopathology
• Inflammatory Bowel Diseases/surgery
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/immunology
• Mesenchymal Stem Cells/metabolism
• Mice
• Phenotype
• Species Specificity

• Nutraceuticals

• Immunomodulatory properties
• Lentiviral transduction
• Wharton’s Jelly-derived Mesenchymal Stem Cells

• Biobanking
• Ethics
• Experimental treatment
• Gastroenterology
• Medical tourism
• Stem-cell research