Background: Current efforts to develop stem cell therapy as a novel treatment for neurointestinal diseases are limited by the unavailability of a model system to study cell transplantation in the human intestine. We propose that xenograft models support enteric nervous system (ENS) development in the fetal human intestine when transplanted into mice subcutaneously or intra-abdominally. Methods: Fetal human small and large intestine were grafted onto the small intestinal mesentery and into the subcutaneous tissue of immunodeficient mice for up to 4 months. Intestinal cytoarchitecture and ENS development were studied using immunohistochemistry. Key Results: In both abdominal and subcutaneous grafts, the intestine developed normally with formation of mature epithelial and mesenchymal layers. The ENS was patterned in two ganglionated plexuses containing enteric neurons and glia, including cholinergic and nitrergic neuronal subtypes. c-Kit-immunoreactive interstitial cells of Cajal were present in the gut wall. Conclusions & Inferences: Abdominal xenografts represent a novel model that supports the growth and development of fetal human intestine. This in vivo approach will be a useful method to study maturation of the ENS, the pathophysiology of neurointestinal diseases, and the long-term survival and functional differentiation of neuronal stem cells for the treatment of enteric neuropathies.
Bibliographical noteFunding Information:
We thank Dr. Vanda Lennon, MD, PhD (Mayo Clinic, Rochester, MN, USA) for the kind gift of Hu antibody.
Nandor Nagy was supported by a Bolyai Fellowship of the Hungarian Academy of Sciences. Allan M. Goldstein is supported by the National Institutes of Health (R01DK103785). Nahum Y. Shpigel, Allan M. Goldstein and Mike J. Gutnick were supported by BSF grant 2015157. The work leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2012-2017) under grant agreement no. 305564 as partners of the SysmedIBD research consortium (to Werner Muller, University of Manchester, United Kingdom). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
© 2017 John Wiley & Sons Ltd
- enteric nervous system
- enteric neuropathies
- fetal human intestine