Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Available drugs aim to suppress gut inflammation. These drugs have significantly delayed disease progression and improved patients’ quality of life. However, the disease continues to progress, underscoring the need to develop novel therapies. Aside from chronic gut inflammation, IBD patients also experience a leaky gut problem due to damage to the intestinal epithelial layer. In this regard, epithelial regeneration and repair are mediated by intestinal stem cells. However, no therapies are available to directly enhance the intestinal stem cells’ regenerative and repair function. Recently, it was shown that active vitamin D, i.e., 1,25-dihydroxyvitamin D or 1,25(OH)2D, was necessary to maintain Lgr5+ intestinal stem cells, actively cycling under physiological conditions. In this study, we used two strategies to investigate the role of 1,25(OH)2D in intestinal stem cells’ regenerative function. First, to avoid the side effects of systemic high 1,25(OH)2D conditions, we used our recently developed novel strategy to deliver locally high 1,25(OH)2D concentrations specifically to inflamed intestines. Second, because of the Lgr5+ intestinal stem cells’ active cycling status, we used a pulse-and-chase strategy via 5-bromo-2′-deoxyuridine (BrdU) labeling to trace the Lgr5+ stem cells through the whole epithelial regeneration process. Our data showed that locally high 1,25(OH)2D concentrations enhanced intestinal stem cell migration. Additionally, the migrated cells differentiated into mature epithelial cells. Our data, therefore, suggest that local delivery of high 1,25(OH)2D concentrations is a promising strategy to augment intestinal epithelial repair in IBD patients.
Highlights
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut
To test the above hypothesis, we proposed a novel strategy in which inflammation-homing CD11b+Gr1+ monocytes [22,23] and macrophages were transduced with a lentiviral vector to overexpress the cytochrome P450 family 27 subfamily B member 1 (CYP27B1) [24]
A recent study showed that a combination of interleukin-13 (IL-13), granulocytecolony-stimulating factor (G-CSF), and granulocyte-macrophage-colony-stimulating factor
Summary
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. It is generally accepted that IBD is caused by aberrant immune responses to intestinal bacteria [1]. Leaky gut is still a challenge to IBD treatment In this regard, epithelial regeneration and repair are mediated by intestinal stem cells [1,8]. To test the above hypothesis, we proposed a novel strategy in which inflammation-homing CD11b+Gr1+ monocytes [22,23] and macrophages were transduced with a lentiviral vector to overexpress the cytochrome P450 family 27 subfamily B member 1 (CYP27B1) [24] Such engineered cells were named MAC-CYP cells. We reasoned that the MACCYP cells would home to inflamed intestines and de novo produce locally high 1,25(OH)2D concentrations, suppressing the intestinal inflammation in IBD patients. This study hypothesized that locally high 1,25(OH)2D concentrations would enhance intestinal stem cells’ regenerative functions. To test this hypothesis, we used two strategies. Because the Lgr5+ intestinal stem cells are actively proliferating, we used a pulse-and-chase strategy via 5-bromo-2 -deoxyuridine (BrdU) labeling to trace Lgr5+ stem cells through the whole epithelial regeneration process
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