Stem Cell Therapy in Inflammatory Bowel Disease: A Review of Achievements and Challenges

Abstract

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.

Graphic Abstract

Keywords:

• stem cells
• mesenchymal stromal cells
• HSCs
• immunosuppression
• inflammatory bowel disease
• ulcerative colitis
• Crohn’s disease

Abbreviations

ASCs, adipose MSCs; ASTIC study, autologous stem cell international Crohn ‘s disease trial; ATRA, all-trans retinoic acid; BM-MSCs, Bone marrow MSCs; CD, Crohn’s disease; CDAI, Crohn’s disease activity index; CRISPR-Cas9, Clustered Regularly Interspersed Short Palindromic Repeats-Cas9; CXCR4, CXC chemokine receptor 4; DCs, Dendritic cells; ECs, endothelial cells; EMT, epithelial-mesenchymal transition; ESCs, embryonic SCs; EV, extracellular vesicle; FGF, fibroblast growth factor; HSCs, hematopoietic stem cells; HSCT, HSCs transplantation; IBD, Inflammatory bowel disease; ICAM1, intercellular adhesion molecule 1; ICAM1-MSCs, intercellular adhesion molecule 1-overexpressing MSCs; IDO, indoleamine 2,3-dioxygenase; IECs, intestinal epithelial cells; IFN- γ, interferon- γ; IL-10, interleukin-10; IL-12, interleukin-12; IL-17, interleukin-17; IL-1β, interleukin-1β; IL-23, interleukin-23; IL-37b, interleukin-37b; iMSCs, MSCs derived from iPSCs; iPSCs, IPSCs; ISCs, ISCs; LEC, lymphatic endothelial cell; Lgr5+, leucine rich repeat containing G protein coupled receptor 5; LIF, leukemia inhibitory factor; MNM, modified neuronal medium; MSCs, Mesenchymal SCs; MSCT, MSCs transplantation; MtSCs, intestinal resident MSCs; PBSCs, Peripheral blood SCs; PDGF, platelet-derived growth factor; pESCs, Parthenogenetic embryonic SCs; PFCD, perianal fistula Crohn’s disease; PGE2, prostaglandin E2; PLGA, poly lactic-co-glycolic acid; SCs, stem cells; SDF-1, stromal derived factor 1; STAT-3, signal transducer and activator of translation-3; tDC, tolerogenic dendritic cell; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; TSG-6, tumor necrosis factor α stimulated gene-6; UC, Ulcerative colitis; UCBSCs, Umbilical Cord Blood SCs; VCAM1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor.

Acknowledgments

The authors thank prof. Yu-Qiang Nie for editing the manuscript.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by Science and Technology Innovation Committee of Shenzhen (No. JCYJ20200109150700942, No. JCYJ20150403101028164, No. JCYC20170307100911479, No. JCYJ20190807145617113 and No. JCYJ20210324113802006), the Guangdong Basic and Applied Basic Research Foundation (No. 2020A1515011581) and National Natural Science Foundation of China (No. 81800489).