The therapeutic potential of stem cell-derived exosomes in the ulcerative colitis and colorectal cancer

Abstract

Background: Mesenchymal stem cells (MSCs) therapy is a novel treatment strategy for cancer and a wide range of diseases with an excessive immune response such as ulcerative colitis (UC), due to its powerful immunomodulatory properties and its capacity for tissue regeneration and repair. One of the promising therapeutic options can focus on MSC-secreted exosomes (MSC-Exo), which have been identified as a type of paracrine interaction. In light of a wide variety of recent experimental studies, the present review aims to seek the recent research advances of therapies based on the MSC-Exo for treating UC and colorectal cancer (CRC).

Methods: A systematic literature search in MEDLINE, Scopus, and Google Scholar was performed from inception to December 2021 using the terms [("colorectal cancer" OR "bowel cancer" OR "colon cancer" OR "rectal cancer") AND (exosome) AND (stem cell) AND ("inflammatory bowel disease" OR "Crohn's disease" OR "colitis")] in titles and abstracts.

Findings: Exosomes derived from various sources of MSCs, including human umbilical cord-derived MSCs (hUC-MSCs), human adipose-derived MSCs (hAD-MSCs), human bone marrow-derived MSCs (hBM-MSCs), and olfactory ecto-MSCs (OE-MSCs), have shown the protective role against UC and CRC. Exosomes from hUC-MSCs, hBM-MSCs, AD-MSCs, and OE-MSCs have been found to ameliorate the experimental UC through suppressing inflammatory cells including macrophages, Th1/Th17 cells, reducing the expression of proinflammatory cytokines, as well as inducing the anti-inflammatory function of Treg and Th2 cells and enhancing the expression of anti-inflammatory cytokines. In addition, hBM-MSC-Exo and hUC-MSC-Exo containing tumor-suppressive miRs (miR-3940-5p/miR-22-3p/miR-16-5p) have been shown to suppress proliferation, migration, and invasion of CRC cells via regulation of RAP2B/PI3K/AKT signaling pathway and ITGA2/ITGA6.

Key messages: The MSC-Exo can exert beneficial effects on UC and CRC through two different mechanisms including modulating immune responses and inducing anti-tumor responses, respectively.

Keywords: Colorectal cancer; Exosome; Mesenchymal stem cells; Ulcerative colitis.

Fig. 1

Schematic depicting the biogenesis, structure, and major molecular components of exosomes. Exosomes are lipid bilayer extracellular vesicles with diameters typically between 30 and 120 nm. Exosome biogenesis initiates when a portion of the plasma membrane buds into the cell to create an early endosome that transforms into late endosomes termed multivesicular bodies (MVB) containing a large number of exosomes. In the meantime, transmembrane and surface proteins located on the plasma membrane are placed into the invaginating membrane, while the cytosolic biologics are enveloped within the exosomes. After fusion with the plasma membrane and through the exocytosis, MVBs release the exosomes into the extracellular space. The payload of exosomes can include proteins, cytoskeletal proteins, signaling molecules, receptors, ligand, tetraspanins, miRs, mRNAs, and other bioactive compounds. They can also carry various immunoregulatory (like miRs) and immunosuppressive (like surface proteins) as well as anti-tumor (like miRs) and tumorigenic (like surface proteins) mediators

Fig. 2

The modulatory effect of MSC-Exo on the dysregulated immune system components in the experimental UC. The hUC-MSC-Exo inhibit inflammatory macrophages while promoting the anti-inflammatory activity of Th2 cells. Over-activated Th1/Th17 cells can be suppressed by hBM-MSC-Exo, hUC-MSC-Exo, and OE-MSC-Exo. The anti-inflammation activity of Treg cells can be improved by hBM-MSC-Exo, hAD-MSC-Exo, and OE-MSC-Exo. Over-expressed proinflammatory cytokines and hUC-MSC-Exo, hAD-MSC-Exo, and OE-MSC-Exo can reduce over-expressed proinflammatory cytokines while increasing the expression of pro-inflammatory cytokines

Fig. 3

A schematic view of the exosome therapy for CRC treatment using MSC-derived exosomes containing tumor-suppressive miRs