Stem Cell-derived Exosomes Use in Ulcerative Colitis

What is Ulcerative Colitis? 

Ulcerative colitis (UC) is a major form of inflammatory bowel disease (IBD), characterized by chronic inflammation and ulcers of the colonic mucosa with variable extension from the rectum toward the cecum. 

The etiology of the disease is complicated and the major pathogenic mechanism is the uncontrolled activation of innate and adaptive immune responses. 

Pathogenesis & Immune overactivation

Pathogenic factors activate CD4+ T cells that differentiate into CD4+ T-helper (Th) cells, including Th1 and Th17 cells, and induce the generation of pro-inflammatory M1 macrophages or other pro-inflammatory cells. 

These immune cells secrete a variety of inflammatory cytokines that provoke intestinal epithelial inflammatory cells to infiltrate and chronic colitis. 

This intestinal epithelial inflammation can be repressed by the differentiation of CD4+ FoxP3+ regulatory T cells (Tregs) and the supplementary of CD4+ Th2 cells. TGF-β and IL-10 released by Tregs can regulate the immune response and accelerate the repair of the colonic mucosa. 

Current First Line Therapies

The first line of therapy consists of the use of oral medications, mainly the use of mesalamine (5-aminosalicylic acid), which may also prevent the development of colorectal cancer. 

When this treatment does not decrease the disease activity, corticosteroids, immunosuppressive agents, and biologics, such as anti-tumor necrosis factor-alpha (TNF-α) antibodies, anti-integrin antibodies, anti-interleukin (IL) 12–23 antibodies), and/or non-biologic small molecule tofacitinib may be used.

Mesenchymal Stem Cells 

Mesenchymal stem cells (MSCs) therapy is a novel treatment option for UC and a wide range of diseases with an excessive immune response due to the powerful immunomodulation and immunosuppression properties that they possess, and their capacity for tissue regeneration and repair. 

Their therapeutic mechanism mainly focuses on cell-to-cell interactions and paracrine activities. MSC-derived exosomes have been identified as a type of paracrine interaction, exerting strong immunomodulatory effects. Recent studies suggest that the therapeutic impact of MSCs is majorly dependent on exosomes.

Clinical Trials

There have been several phases I/II/III clinical trials that showed transplantation of both autologous and allogeneic MSCs could significantly ameliorate IBD. The local and intravenous administration of BM-MSCs showed no severe adverse events and could significantly induce healing of perianal fistulas and decrease local and systemic inflammation and scores of disease activity index (DAI) in IBD patients.

Another study showed that using human umbilical cord (hUC)-MSCs could alleviate endoscopic indices and inhibit lymphoid infiltration via inducing immunosuppressive responses in patients with refractory IBD. 

MSCs-derived Exosomes

Exosomes are lipid bilayer extracellular vesicles (EVs) secreted by a broad range of cell types such as MSCs. Their composition is highly dependent on the parental cells.  Some components exist in almost all exosomes, and some are tissue- and cell-specific.

Stem cell-derived exosomes have been demonstrated to not only reiterate the therapeutic properties of origin cells but also donate advantages over them. They show potential to overcome limitations of stem cell therapy, like restricted engraftment and low survival rate. 

Studies have shown that intravenously injected hUC-MSC-exosomes can home to the colon tissue and increase the survival rate and alleviate the severity of UC symptoms, including the destroyed integrity of colon structure, and increased infiltration of inflammatory cells in mice by regulating the immune response.  

Source:

Guo G, Tan Z, Liu Y, Shi F, She J. The therapeutic potential of stem cell-derived exosomes in the ulcerative colitis and colorectal cancer. Stem Cell Res Ther. 2022 Apr 1;13(1):138. doi: 10.1186/s13287-022-02811-5. PMID: 35365226; PMCID: PMC8973885. 

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