Organoid Transplantation: New Avenues to Treat Short Bowel Syndrome

GENTILINI, MARÍA VIRGINIA; RUMBO, MARTÍN; GONDOLESI, GABRIEL E.

TRANSPLANTATION

LIPPINCOTT WILLIAMS & WILKINS

Año: 2021 vol. 105 p. 2130 - 2131

0041-1337

Short-bowel syndrome (SBS) is a rare and devastating malabsorptive disorder most frequently caused by massive surgical resection of the small intestine. The condition requires chronic parenteral nutrition with frequent, costly, and often long-term hospitalizations1. In pediatric patients, SBS is usually due to congenital malformations (e. g., gastroschisis, intestinal atresia, malrotation) or necrotizing enterocolitis. In adults, SBS can result mainly from surgical complications, mechanical or vascular ischemia because of inflammation or trauma2. The estimated prevalence varies from 1.4 to 30 cases/million3,4. Morbidity and mortality remain high, ranging from 30% to 50%1.Over the last sixty years, the management of SBS patients has drastically changed, with parenteral nutrition (PN) becoming the current standard of care. Long-term life-threating complications (infection, catheter malfunction, thrombosis, and metabolic derangements), however, are observed as consequence. Despite the use of PN, all patients require evaluation by a multidisciplinary team to assess alternatives for achieving intestinal rehabilitation. Surgery 2,5,6 including Bianchi´s procedure7, serial transverse enteroplasty8, or autologous gastrointestinal reconstruction surgery9 in addition to the application with with enterohormone analogues have been therapeutic approaches10,11. When all those strategies fail, intestinal transplant appears as the last resort.Nevertheless, the shortage of donor organs (mainly for the pediatric population) and the higher incidence of rejection-related graft loss, underscore the need for innovative treatment strategies.The concept of using autologous tissue to develop a new intestine has been a goal for many years representing a promising approach, although until now fraught with technical limitations.Regenerative-medicine approaches to lengthen the remaining functioning intestine have been tried. Techniques evolved from culturing individual intestinal cells to the report by Sato et al12 describing the generation of intestinal organoids in vitro from Lgr5+ stem cells, a game-changing work on its own. Since then, intestinal organoids as tissue sources for regenerative therapies have been explored and fascinating advances in understanding intestinal epithelial biology have been reported. The need for developing different scaffolds or matrices as support for stem cells to reconstitute the tube-like anatomy of the intestine has become clear. Finally, the physical requirement for fluid circulation along the luminal compartment of these devices has been appreciated as a critical piece to establish proper functionality of the regenerated intestinal tissue13. The complete regeneration of other components of the intestinal anatomy, however, including micro- and macrocirculation as well as the lymphatic network critical for lipid absorption has remained challenging.The recent work by Sugimoto and co-workers published in Nature represents another game changing milestone14. This work has overcome most of the previously mentioned impediments in a single model, combining the use of ileal epithelial organoids to populate a segment of the colon permissive for organoid engraftment to generate a fully functional small-intestinalized colon (SIC). The remarkable aspect of the techniques proposed by Sugimoto et al. involve the combinatorial in-vivo engraftment and surgical interposition to achieve the development of a subepithelial lymphatic structure specific to the small intestine during the SIC generation, showing that epithelial overlay by small intestinal organoids can direct the formation of small intestinal structures in the colon. Furthermore, the authors demonstrated the feasibility of their approach as a treatment intervention using the SIC as an autologous graft transposed in the small intestine with functional in-vivo features, demonstrating the amelioration of the intestinal failure in a rat-SBS model.Using their xenotransplantation method with human-small-intestine organoids transplanted onto the colorectal surface of immunodeficient mice15, the authors have been able to show that the small-intestine organoids had an organ-remodeling capability which can properly reconstitute the small-intestine epithelium, preserving the absorption functionality in a heterotopic environment. The spontaneous formation of villus-like structures from xenotransplanted human-ileum organoids suggests that epithelium-autonomous programs instructed villus morphogenesis. Several elements are involved in this process. As in their previous reports13, the authors demonstrated that mechanical stimulation facilitated the formation of villus-like structures from a monolayer of duodenum and ileum organoids, but not from colon organoids.To investigate whether the SIC can substitute the function of the small intestine, the authors developed a rat-SBS model and established an initial rat-SIC model converting the colonic epithelium with syngeneic rat-ileum organoids. Notably, the transplanted organoids maintained their original tissue identity after transplantation substantiating the dependency of villus maturation on endoluminal flow and the specificity of the organoid anatomy as this process did not occur when they repopulated colonic epithelium with colon-derived organoids. Thus, Sugimoto et al demonstrated, for the first time, that organoids could rebuild the histologic architecture of their origin, regardless of the anatomic mismatch of epithelial and subepithelial tissues. Subsequently, they established the rat-SBS model by total jejunoileal resection and interposed the organoid-transplanted colon between jejunum and the ileocolic valve. All rats with colon-organoid-transplants became moribund within two weeks. In contrast, rats that received ileum-organoid transplants demonstrated a more stable body weight and significantly improved survival rates. We need to emphasize that the SIC maintained neuronal circuitry and intact autonomic innervation of the muscle layers, suggesting that the engineered colon acquired functions of the small intestine in vivo.The involvement of microbiota for the adaptation after SBS has been demonstrated clinically16. Exploring the bacterial composition in fecal samples, the authors found that SIC treatment, but not the transplantation of the colon organoid, affected microbiota composition. These results underscore the functional role of the small-intestinal epithelium in shaping the gut microbiota. Further investigations need to determine the impact of organoid transplantation on changes of the microbiota including effects on nutrition and immunity.The work by Sugimoto provides fascinating insights into the potential interplay between translational research and future regenerative medicine approaches to treat a complex human condition of the small intestine. Several issues remain to be answered prior to a clinical application, including the amount of organoids necessary to achieve functional restauration in humans, biomarkers that could be used to predict successful organoid engraftment, the specific clinical condition that could be targeted first and what immunosuppression will be needed if using heterologous organoids.In conclusion, this study combines tissue engineering, organoid technology, microsurgery, biophysical methodology, and a rat-SBS model, demonstrating the power of a multidisciplinary approach to improve severe SBS through engrafting small intestinal organoids.