Inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are characterized by relapsing phases of intestinal inflammation and phases of remission. Besides other potential risk factors, a dysregulated immune response is considered a major cause. [1] Of note, the risk for cardiovascular (CV) disease is increased in IBD patients particularly during inflammatory flares and even in the absence of traditional risk factors, indicating a dominant role of systemic inflammation in driving CV events. The bone marrow (BM) niche, containing hematopoietic and mesenchymal stem cells (HSC, MSC), regulates hematopoiesis and controls their trafficking, quiescence, and differentiation. [2] However, it is yet unknown whether and how the BM niche remodels in chronic colitis, thus impacting the inflammatory response.
We hypothesize that repeated DSS-induced inflammation remodels the BM niche in a site- and time-dependent manner, altering vascular structure and in turn influencing HSC trafficking and lineage decisions, which may contribute to enhanced atherosclerosis.
Male 5–8-week-old C57BL/6J wild-type and apolipoprotein E-deficient (Apoe-KO) mice underwent one to five cycles of dextran sodium sulfate (DSS, 2%) or respective control treatment followed by 2-week washouts, mimicking relapsing phases of IBD. HSC and mature leukocyte populations in the BM of femur, tibia, sternum, and vertebrae were quantified by flow cytometry. For histology, we quantified sinusoidal endothelium identified by endomucin and basement membranes marked by laminin. Aortic atherosclerotic plaque burden was determined in Apoe-KO mice by en face Oil Red O staining of the aorta.
Chronic colitis was confirmed by assessing body-weight loss, an increased colon weight-to-length ratio, and histological evidence of inflammation and epithelial damage in the colon. Flow cytometry across different hematopoietically active skeletal sites showed that HSCs expanded after three DSS cycles together with myeloid skewing. Among the hematopoietic niches, the femur showed the strongest increase in immune-cell numbers in response to DSS treatment. In line with increased immune cell release in the circulation, femoral sections revealed an increased number of sinusoids in the metaphysis after three cycles. Staining of laminin showed no significant differences thus pointing towards vascular remodeling or activation rather than angiogenesis.
Our findings indicate that repetitive cycles of experimental colitis result in remodeling of the BM niche, characterized by an expansion in the number of sinusoids, which may enhance cell effluxfrom the BM and which might be associated with accelerated atherogenesis under hypercholesterolemia.
References:
- Baumgart, D. C. & Carding, S. R. Inflammatory bowel disease: cause and immunobiology. The Lancet 369 1627-1640 (2007).
- Mercier, F. E., Ragu, C., & Scadden, D. T. The bone marrow at the crossroads of blood and immunity. Nature Reviews Immunology, 12(1), 49–60 (2012).
