Abstract
C3a is important in the regulation of the immune response as well as in the development of organ inflammation and injury. Furthermore, C3a contributes to liver regeneration but its role in intestinal stem cell function has not been studied. We hypothesized that C3a is important for intestinal repair and regeneration. Intestinal organoid formation, a measure of stem cell capacity, was significantly limited in C3-deficient and C3a receptor (C3aR) 1-deficient mice while C3a promoted the growth of organoids from normal mice by supporting Wnt-signaling but not from C3aR1-deficient mice. Similarly, the presence of C3a in media enhanced the expression of the intestinal stem cell marker leucine-rich repeat G-protein-coupled receptor 5 (Lgr5) and of the cell proliferation marker Ki67 in organoids formed from C3-deficient but not from C3aR1-deficient mice. Using Lgr5.egfp mice we showed significant expression of C3 in Lgr5+ intestinal stem cells whereas C3aR1 was expressed on the surface of various intestinal cells. C3 and C3aR1 expression was induced in intestinal crypts in response to ischemia/reperfusion injury. Finally, C3aR1-deficient mice displayed ischemia/reperfusion injury comparable to control mice. These data suggest that C3a through interaction with C3aR1 enhances stem cell expansion and organoid formation and as such may have a role in intestinal regeneration.
Highlights
Intestinal stem cells, known as crypt base columnar cells, have been recognized as responsible for intestinal regeneration a vital process for the homeostatic self-renewal and the response to catastrophic exogenous insults, including irradiation, exposure to food toxins and ischemia/ reperfusion [1]
C3a is a key modulator of the inflammatory response to infectious and non-infectious insults [16] and promotes organ regeneration [17] yet it is unknown whether it is involved in intestinal stem cell function and organoid formation
Tissue injury is accompanied by inflammation and it is reasonable to consider that inflammation-defined molecules drive the regeneration machinery to maintain intestinal homeostasis [21]
Summary
Intestinal stem cells, known as crypt base columnar cells, have been recognized as responsible for intestinal regeneration a vital process for the homeostatic self-renewal and the response to catastrophic exogenous insults, including irradiation, exposure to food toxins and ischemia/ reperfusion [1]. Lgr is a target of the Wnt signaling pathway and Wnt agonists, like R-spondin 1, expand Lgr5+ cells and accelerate intestinal recovery after irradiation [3]. IL-22 supports intestinal regeneration by enhancing the phosphorylation of STAT3 [4], whereas it has been proposed that additional inflammatory signals may be involved in intestinal regeneration. It has been shown that C3a and C5a are critical in liver tissue regeneration after exposure to carbon tetrachloride or partial hepatectomy by promoting hepatocyte proliferation [5, 6] and in retina tissue regeneration [7]. C3a promotes neurogenesis in mice subjected to ischemic brain injury [8] and C3 deficiency decreased the number of cardiac stem/progenitor cells in the infarct
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