From the AGA Journals

Mesenteric adipose–derived stromal cell lactoferrin may mediate protective effects in Crohn’s disease

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Fat is not always bad

Inflammatory bowel disease (IBD), including Crohn’s disease, is a chronic inflammatory condition of the gastrointestinal tract that is often associated with changes in adipose tissue. However, the pathophysiological significance of fat wrapping in Crohn’s disease remains largely elusive. A correlation of IBD with obesity has been established by a number of studies, which report 15%-40% of adults with IBD are obese. Obesity is found to have a negative effect on disease activity and progression to surgery in patients with Crohn’s disease. In contrast, adipose-derived stromal or stem cells exhibit regenerative and anti-inflammatory function.

A recent study published in Cellular and Molecular Gastroenterology and Hepatology by Jill M. Hoffman and her colleagues highlighted the immune-modulatory function of adipose-derived stromal cells (ADSCs) in Crohn’s disease patients. They observed that patient-derived ADSCs promote colonocyte proliferation and exhibit distinct gene expression patterns, compared with healthy controls. The authors successfully identified ADSC-derived lactoferrin, an iron binding glycoprotein and an antimicrobial peptide, as a potential immunoregulatory molecule.

Dr. Amlan Biswas

They concluded that the disease-dependent alterations in mesenteric adipose tissue–derived ADSCs might have a protective role in the pathophysiology of Crohn’s disease. The study elegantly highlighted the therapeutic potential of lactoferrin in IBD and provided new insight into the biology of ADSC.

Amlan Biswas, PhD, is an instructor in pediatrics at Harvard Medical School, Boston, and is affiliated with Boston Children’s Hospital in the division of gastroenterology and nutrition. He has no conflicts of interest


 

FROM CMGH

Inflammatory bowel disease (IBD) and Crohn’s disease (CD), in particular, are characterized by an unusual ectopic extension of mesenteric adipose tissue. This intra-abdominal fat, also known as “creeping fat,” which wraps around the intestine during the onset of CD, is associated with inflammation and ulceration of the small or large intestine. The role of this fat in the development of CD, and whether it is protective or harmful, however, is not clear.

The current study demonstrates that adipose-derived stromal cells (ADSCs), the precursor cell population of adipose tissue, promote colonocyte proliferation and exhibit a differential gene expression profile in a disease-dependent manner. CD patient–derived ADSCs attenuated the severity of experimental colitis by releasing extracellular mediators, which exhibits a protective role for mesenteric adipose tissue during intestinal inflammation, according to Jill M. Hoffman, MD, and her colleagues at the University of California, Los Angeles. Increased expression and release of lactoferrin by ADSCs – an iron-binding glycoprotein and antimicrobial peptide usually found in large quantities in breast milk – was shown to be a likely mediator that could regulate inflammatory responses during CD. These results were published in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2018.02.001).

Intestinal inflammation is primarily mediated by cytokine production, and targeted anticytokine therapy is the current standard for IBD treatment. The cytokine profile from CD patient–derived mesenteric ADSCs and fat tissue was significantly different from that of these patients’ disease-free counterparts. The authors hypothesized that mesenteric ADSCs release adipokines in response to disease-associated signals; this release of adipokines results from differential gene expression of mesenteric ADSCs in CD versus control patients. To test this hypothesis, conditioned media from CD patient–derived ADSCs was used to study gene expression in colonic intestinal epithelial cells in vitro and in mice with experimental colitis in vivo.

Using the Human LncRNA Expression Microarray V4.0, expression of 20,730 protein-coding mRNA targets was analysed, and 992 mRNA transcripts were found to be differentially (less than or equal to twofold change) expressed in CD patient–derived ADSCs, compared with control patient–derived ADSCs. Subsequent pathway analysis suggested activation of cellular growth and proliferation pathways with caspase 8 and p42/44 as top predicted networks that are differentially regulated in CD patient–derived ADSCs with respect to those of control patients.

The investigators treated intestinal epithelial cells – specifically, NCM460 – with conditioned 233 media from the same CD or control patient–derived ADSCs; subsequent microarray profiling using the GeneChip Human Gene ST Array showed increased expression of interleukin-17A, CCL23, and VEGFA. Ingenuity Pathway Analysis of mRNA expression indicated convergence in injury and inflammation pathways with the SERPINE1 gene, which suggests it’s the central regulator of the differential gene expression network.

In vivo, mice with active dextran sulfate sodium (DSS) colitis that were treated with daily injections of conditioned media from CD patients showed attenuation of colitis as compared with mice treated with vehicle or conditioned media from control patients. Furthermore, the mRNA expression of proinflammatory cytokines was reduced with increased proliferative response (as measured by Ki67 expression) in intestinal epithelial cells in the dextran sulfate sodium–treated mice receiving media from CD patients, compared with that in mice receiving media from control patients or vehicle-treated mice.

Cell proliferation was studied in real time (during a period of 120 hours) using the xCELLigence platform. The authors suggested that mesenteric adipose tissue–derived mediators may regulate proliferative responses in intestinal epithelial cells during intestinal inflammation, as observed by enhanced cell-doubling time in conditioned media from CD patient–derived ADSCs.

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