Transplantation of Human Intestine Into the Mouse: A Novel Platform for Study of Inflammatory Enterocutaneous Fistulas

NF-kappa-B activation unveils the presence of inflammatory hotspots in human gut xenografts

“…Mice were allowed to recover and 2-3 weeks thereafter were subjected to intravital whole body bioluminescence imaging before and after systemic IP injection of LPS ( Figure 2) or human TNFα (Figure 3) and intraluminal challenge with wildtype (WT) or T3SS-defective mutant enteropathogenic E. coli (EPEC) bacteria (Figure 4). We have previously demonstrated activation of acute inflammation in human gut xenografts following systemic LPS (Bruckner et al, 2019) or intraluminal EPEC infection (Nissim-Eliraz et al, 2017). While the tacit assumption is that gut inflammation is homogeneous, we surprisingly observed one to two foci of luminescence activity in all xenografts following challenge with similar time course for LPS and TNFα and somewhat longer activity following luminal bacterial challenge.…”

“…In this, the experimental platform is similar to other examples of development of human tissues (lung, skin and liver) subcutaneously transplanted into SCID mice (Gaska and Ploss, 2015;Wahl et al, 2019). Furthermore, we have shown that many human innate and adaptive components of immune system, which have been shown to be already active in fetal gut at the time of transplantation (Rechavi et al, 2015;Li et al, 2018;Li et al, 2019;Schreurs et al, 2019;Stras et al, 2019), are present and active in the mature xenograft (Bruckner et al, 2019;Goldberg et al, 2019).…”

“…While ectopic and not functional, these gut implants develop characteristic structures of the human gut with extensive vasculature and their structural features are highly similar to those of normal human gut, including mucosal villous epithelium, crypt structures, blood vessels and enteric nervous system. We and others have previously shown that virtually all the cell types that are present in the normal human gut are also present in these xenografts (Savidge et al, 1995;Savidge et al, 2001;Golan et al, 2009;Golan et al, 2011;Nissim-Eliraz et al, 2017;Nagy et al, 2018;Bruckner et al, 2019). Moreover, the general architecture of the gut appears normal, and the tissue is well-vascularized by a human capillary system that anastomoses to the circulatory system of the murine host.…”

“…We have examined the activation of NF-B in segments of human fetal gut transplanted and developing in a subcutaneous, sterile environment in SCID mice. The experimental model system we have used was first reported by Winter et al in 1991(Winter et al, 1991 and refined in our laboratories for study of the human enteric nervous system (Nagy et al, 2018), human-specific pathogens (Golan et al, 2009;Golan et al, 2011) and inflammatory bowel diseases (IBD) (Canavan et al, 2016;Bruckner et al, 2019;Goldberg et al, 2019). Fetal gut was obtained after informed consent from pregnancy terminations performed legally at 12-18 weeks gestational age and transplanted subcutaneously in mature SCID mice.…”

“…This model system was extensively described by us (Golan et al, 2009;Golan et al, 2011;Canavan et al, 2016;Nissim-Eliraz et al, 2017;Nagy et al, 2018;Bruckner et al, 2019;Goldberg et al, 2019). C.B-17/IcrHsd-Prkdc scid (abbreviated as SCID) mice were purchased from Harlan Biotech Israel (Rehovot, Israel).…”