Stomach ulcers are a complication of routine use of aspirin, Advil, or other non-steroidal anti-inflammatory drugs. Additionally, radiation therapy, or inflammatory bowel disease can also cause stomach ulcers, and these are painful and potentially dangerous for patients. Trying to get our heads around ulcers is not easy, but a new study by Manieri and colleagues have provided some understanding of ulcer formation and ways that mesenchymal stem cells (MSCs) might help heal these painful lesions.
Manieri and others used prostaglandin-deficient mice as a model system for ulcer formation. In these mice, their stomachs do not produce the prostaglandins that protect the layers of the stomach from being digested by its own acid and enzymes. Consequently, these mice are subject to so-called “penetrating ulcer formation,” or ulcers that penetrate the underlying muscular layer (muscularis propria). When Manieri and his colleagues took biopsies of the colon of these prostaglandin-deficient mice, they observed extensive necrosis of the upper and lower layers of the colon.
When these mice were treated with stable prostaglandin-I2 (PGI2) analogs, Manieri and others showed that they could ameliorate the damage to the colon. However, when this research group analyzed the ulcer beds in these mutant mice, they noticed that CD31+ endothelial cells, which form blood vessels, were found in very low numbers. This suggested that reduced blood vessel formation could be a key driver of penetrating ulcer formation. To confirm their hypothesis, the authors stained the wound sites for vascular endothelial growth factor (VEGF). They saw fewer VEGF+ cells in the mutant mice compared with wild-type animals, which suggests that impaired blood vessel production contributes to ulceration. To further test this hypothesis, Manieri and others treated wild-type mice with tivozanib (a VEGF receptor antagonist), which also caused smooth muscle necrosis in the colon.
Next Manieri and others injected MSCs from the colons of mice that showed increased expression of VEGF into the ulcerated colon of mutant mice. The MSCs dutifully migrated to the ulcer beds, and rescued the muscle necrosis phenotype. These results show that MSC administration can provide a soothing treatment prospect for patients who are dealing with gastrointestinal ulceration.
See N. A. Manieri et al., Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis. J. Clin. Invest. 10.1172/JCI81423 (2015).