Paneth cells in the developing gut: when do they arise and when are they immune competent?

Abstract

Background:Little is known about the perinatal development of Paneth cells (PCs) during gestation and the relation with necrotizing enterocolitis (NEC). We aimed to investigate when PCs arise and when they become immune competent during gestation. Methods: We included 57 samples of ileum tissue of fetuses/ infants with a gestional age (GA) between 9 and 40 wk taken as part of a standard autopsy procedure. Hematoxylin-eosin staining and anti-human defensin 5 immunohistochemistry were performed. We performed a semi-quantitative assessment of (immune-competent) PC numbers per 10 crypts per tissue section per GA. results: The number of PCs and the number of immunecompetent PCs increased with increasing GA (Spearman's ρ = 0.41, P = 0.002 and ρ = 0.61, P < 0.001, respectively). Whereas significantly higher PC numbers were observed after 37 wk gestation (median 7, range 0-12) compared to preterm infants (median 0, range 0-15; P = 0.002), we counted higher numbers of immune-competent PCs already in infants with GA above 29 wk (median 6, range 0-18) compared to infants with GA under 29 wk (median 2, range 0-9; P < 0.001). conclusion: The significant increase of immune-competent PCs starting from a GA of 29 wk mimics the rise in incidence of NEC during a similar postmenstrual age in preterm infants.P aneth cells (PCs) are specialized epithelial immune cells located in the base of the crypts of Lieberkühn located in the small intestine (1,2). PCs can be seen in the gut by the first trimester and are thought to mature during gestation (1,2). PCs protect the intestinal stem cells from pathogens by stimulating stem cell differentiation, shaping the intestinal microbiota, and assist in reparation of the gut (2). To this end, they secrete (among other things) human α-defensins (HD5/HD6) (3). These defensins protect the intestinal mucosa against bacterial invasion, and are thought to be associated with initiating and adapting immunity (3). How PCs develop after the first trimester and when PCs become immune competent remains uncertain.PCs are thought to play a role in the development of NEC, a common and devastating disease most commonly observed in preterm infants (4-6). NEC involves the preterm intestine and has a complex pathophysiology in which bacterial invasion and an excessive inflammatory response is an important contributing factor (5,6). Unfortunately, the exact pathophysiology is incompletely understood.It has been hypothesized that maturation of immune-competent PCs is crucial for NEC development (4,(6)(7)(8). In the preterm gut, PCs secrete defensins that might contribute to an excessive inflammatory response as observed in NEC (4). This hypothesis is derived from the observation that extremely-low-birth-weight human infants generally have the longest interval before the onset of NEC-with a peak incidence at the postmenstrual age of 29-33 wk (4,6-8). Despite the possible role for PC-maturation in the pathophysiology of NEC, little is known about PC-maturation and functioning in the immature intestine. Therefore, we ...

Paneth cell disruption-induced necrotizing enterocolitis requires live bacteria and occurs independent of TLR4 signaling

“…While intestinal stem cells grow better in the presence of Paneth cells (Sato et al, 2009, 2011), ablation of Paneth cells in intestinal organoids has been shown to have no effect on the number or functional of stem cells (Durand et al, 2012; Kim et al, 2012). However, understanding the role of Paneth cells in the immature intestine is much more complex than in adult tissue as the developing intestine contains fewer Paneth cells and those that are present may not function as well as those contained in mature intestine (Heida et al, 2016). Thus, understanding the effects of Paneth cell disruption in the immature intestine may be of critical importance to understanding injury and repair mechanisms.…”

“…This is extremely clinically relevant. Infants most often develop NEC between 27 and 34 weeks corrected gestation (Yee et al, 2012; Stoll et al, 2015), an age when the infant's intestinal tract has a relatively hyper-reactive immune response (Neal et al, 2013; Yazji et al, 2013; Lu et al, 2014; Nino et al, 2016), possesses an immature intestinal flora that has an increased composition of potentially pathogenic bacteria (Elgin et al, 2016), and contains an immature cohort of protective Paneth cells (Heida et al, 2016). In this mileau, based on the data we have presented, we propose that disruption of Paneth cell biology through inflammation (Brown et al, 2014) or other mechanisms can be the initiating factor that leads to a critical imbalance of the host-microbe axis that eventually ends in tissue damage and NEC.…”

Pathogenesis of NEC: Role of the innate and adaptive immune response

“…Significant HD5 expression can be detected at above 29 weeks 201 . Premature infants have been shown to have fewer Paneth cells with decreased function 191,199,201,202 . Multiple animal studies implicate the importance of Paneth cells in NEC pathogenesis 203,204 .…”

hPSC-derived lung and intestinal organoids as models of human fetal tissue

“…For instance, the postnatal mouse intestine continues to develop for two weeks after birth before the crypt domains are properly formed, and before Paneth cells differentiate (Kim et al, 2012). In contrast, human studies have indicated that crypts and Paneth cells are present by the third trimester of gestation (Heida et al, 2016). Similarly, there are intrinsic differences between humans and mice within lung tissue as well.…”