Gastroschisis in the rat model is associated with a delayed maturation of intestinal pacemaker cells and smooth
P Midrio1, M S Faussone-Pellegrini, M G Vannucchi
1Children's Institute for Surgical Science, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Insights
Gastroschisis delays intestinal pacemaker (ICC) and smooth muscle cell (SMC) development in rat fetuses. This impaired cell differentiation may explain the gastrointestinal dysmotility observed in newborns with gastroschisis.
Area of Science:
- Gastroenterology
- Developmental Biology
- Neonatal Surgery
Background:
- Peristalsis generation relies on a functional pacemaker system within the gastrointestinal tract.
- Interstitial cells of Cajal (ICC), identified by c-kit protein expression, are the primary intestinal pacemakers.
- Gastroschisis, a congenital defect, is associated with severe neonatal gastrointestinal dysmotility, yet the underlying cellular mechanisms remain poorly understood.
Purpose of the Study:
- To investigate the morphology and differentiation of intestinal smooth muscle cells (SMC) and interstitial cells of Cajal (ICC) in a rat model of gastroschisis.
- To determine if gastroschisis impacts the development of the cellular components responsible for intestinal motility.
Main Methods:
- Surgical creation of gastroschisis in rat fetuses at 18.5 days gestation, with control groups undergoing manipulation only.
- Harvesting of small intestine at 21.5 days gestation for analysis.
- Histological examination using Hematoxylin & Eosin (H&E), immunohistochemistry for c-kit and alpha-smooth muscle antibody (alpha-SMA), and transmission electron microscopy (TEM).
Main Results:
- Control fetuses showed developing SMC and ICC with increasing c-kit and alpha-SMA expression.
- Gastroschisis fetuses exhibited a significant lack of differentiated ICC and reduced c-kit/alpha-SMA expression in SMC.
- The severity of cellular damage in gastroschisis correlated with the degree of impaired SMC and ICC differentiation, with less damaged areas showing immature ICC.
Conclusions:
- Intestinal smooth muscle cell and interstitial cell of Cajal differentiation is significantly delayed in rat fetuses with gastroschisis.
- The degree of delay in cell differentiation is most pronounced in the most severely affected intestinal segments.
- These findings provide a cellular basis for understanding the delayed onset of peristalsis and variable recovery patterns in human infants with gastroschisis.
Background:
A pacemaker system is required for peristalsis generation. The interstitial cells of Cajal (ICC) are considered the intestinal pacemaker, and are identified by expression of the c-kit gene--encoded protein. Gastroschisis is characterized by a severe gastrointestinal dysmotility in newborns. In spite of this clinical picture, few studies have focused on smooth muscle cells (SMC) morphology and none on ICC. Therefore, their morphology has been studied in fetuses at term in the rat model of gastroschisis.
Methods:
At 18.5 day's gestation (E18.5), 10 rat fetuses were killed, 10 underwent surgical creation of gastroschisis, and 10 underwent manipulation only. The small intestine of the latter 2 groups was harvested at E21.5. Specimens were processed for H&E, c-kit and actin (alpha smooth muscle antibody [alpha-SMA]) immunohistochemistry, and transmission electron microscopy (TEM).
Results:
In the controls, SMC were c-kit+ and alpha-SMA+, with labeling intensity increasing by age. At E21.5, some cells around the Auerbach's plexus were more intensely c-kit+, and differentiating ICC were seen under TEM at this level. Gastroschisis fetuses had no c-kit+ cells referable to ICC. In the more damaged loops, SMC were very faintly c-kit+ and alpha-SMA+. Under TEM, there were few differentiated SMC and no presumptive ICC. In the less-damaged loops, SMC were faintly c-kit+ and alpha-SMA+ and had ultrastructural features intermediate between those of E18.5 and E21.5 controls; ICC were very immature.
Conclusions:
ICC and SMC differentiation is delayed in gastroschisis with the most damaged loops showing the most incomplete picture. These findings might help in understanding the delayed onset of peristalsis and the variable time-course of the recover seen in babies affected by gastroschisis.
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