Abstract
Intestinal failure is a rare life‐threatening condition that results in the inability to maintain normal growth and hydration status by enteral nutrition alone. Although parenteral nutrition and whole organ allogeneic transplantation have improved the survival of these patients, current therapies are associated with a high risk for morbidity and mortality. Development of methods to propagate adult human intestinal stem cells (ISCs) and pluripotent stem cells raises the possibility of using stem cell‐based therapy for patients with monogenic and polygenic forms of intestinal failure. Organoids have demonstrated the capacity to proliferate indefinitely and differentiate into the various cellular lineages of the gut. Genome‐editing techniques, including the overexpression of the corrected form of the defective gene, or the use of CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to selectively correct the monogenic disease‐causing variant within the stem cell, make autologous ISC transplantation a feasible approach. However, numerous techniques still need to be further optimized, including more robust ex vivo ISC expansion, native ISC ablation, and engraftment protocols. Large‐animal models can to be used to develop such techniques and protocols and to establish the safety of autologous ISC transplantation because outcomes in such models can be extrapolated more readily to humans. Stem Cells Translational Medicine 2017;6:666–676
Highlights
Intestinal failure (IF) is a rare multifactorial clinical condition that results in patients’ inability to sustain normal growth and nutritional and hydration status without the use of parenteral nutrition (PN) [1, 2]
Transplanted murine fetal small bowel spheroids can be engrafted into adult colon and differentiate into colonic epithelium [20], whereas adult small bowel enteroids engrafted into adult colon retain features of the small bowel [19]. These findings suggest that fetal intestinal epithelium have a plastic character that differentiate according to niche-specific signals
intestinal stem cells (ISCs) may be isolated from crypts by fluorescence-activated cell sorting (FACS) or can be expanded in vitro by using elevated canonical Wnt signaling that promotes the relative abundance of ISCs
Summary
Intestinal failure (IF) is a rare multifactorial clinical condition that results in patients’ inability to sustain normal growth and nutritional and hydration status without the use of parenteral nutrition (PN) [1, 2]. The first functional restoration experiments have been performed in ISCs derived from patients with cystic fibrosis using CRISPR (clustered regularly interspaced short palindromic repeat)/Cas genome editing [17] This corrected disease-causing mutation indicated the therapeutic potential of combining reconstituted intestinal enteroids and genome editing technology. Various acute and chronic injuries resulting in the loss of the rapidly dividing CBCCs include radiation exposure, enteric infection, rejection, and inflammation; the surviving progenitor and/or quiescent differentiated populations are thought to revert back to the vacant stem cell niche at the crypt base, where they quickly regain ISC identity and restore epithelial renewal (Fig. 2B) [33, 38,39,40]. Lrig is highly expressed by most crypt cells and controls ISC homeostasis by negative regulation of ErbB signaling; its removal leads to expansion of the proliferative compartment [35, 59]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
