<i>In Vivo</i> Intestinal Research Using Organoid Transplantation

Abstract

Our understanding of the biology of the intestinal epithelium has advanced since the establishment of an organoid culture system. Although organoids have enabled investigation of the mechanism of selfrenewal of human intestinal stem cells in vitro, it remains difficult to clarify the behavior of human normal and diseased intestinal epithelium in vivo. Recently, we developed a xenotransplantation system in which human intestinal organoids are engrafted onto epithelium-depleted mouse colons. This xenograft recapitulated the original tissue structures. Upon xenotransplantation, normal colon organoids developed normal colon crypt structures without tumorigenesis, whereas tumor-derived organoids formed colonic tumors resembling the original tumors. The non-tumorigenicity of human intestinal organoids highlights the safety of organoid-based regenerative medicine. As an example of regenerative medicine for short bowel syndrome, we devised a unique organ-repurposing approach to convert colons into small intestines by organoid transplantation. In this approach, the transplanted rat small intestinal organoids not only engrafted onto the rat colons but also remodeled the colon subepithelial structures into a small intestine-like conformation. Luminal flow accelerated the maturation of villi in the small intestine, which promoted the formation of a lymphovascular network mimicking lacteals. In this review, we provide an overview of recent advances in gastrointestinal organoid transplantation and share our understanding of human disease biology and regenerative medicine derived from these studies.

Human patient derived organoids: an emerging precision medicine model for gastrointestinal cancer research

“…In South Korea and Japan, intestinal organoids have been reported to be used in the clinical treatment of diseases such as ulcerative colitis or refractory Crohn’s disease. However, differences in genetic information between donors and recipients, immune rejection after transplantation, and the degree of benefit and risk to recipients also need to be accurately assessed after transplantation ( Sugimoto et al, 2022 ). At the same time, organ transplantation is also a moral test for donors.…”

Metabolic and Nutritional Issues after Lower Digestive Tract Surgery: The Important Role of the Dietitian in a Multidisciplinary Setting

“…The latter include a variety of tissue-engineered small intestines (TESIs). TESI approaches range from small intestinal submucosa grafts to intestinal tissue repurposing with either stem cells or organoid units, the latter of which appears extraordinarily promising [ 163 , 167 , 168 , 169 , 170 ].…”

Stem cell-derived intestinal organoids: a novel modality for IBD

“…In 2022, the same mouse-derived intestinal organoids were injected anally into UC mice by Tokyo Medical and Dental University (TMDU), Japan, to repair colitis, and these cultured organoids could precisely reach the location in the damaged intestinal epithelium and repair the damaged intestinal epithelium [ 148 ]. Subsequently, the TMDU research team announced the first successful transplantation of "organoids" into the intestinal mucosa of a patient with refractory UC [ 149 ]. The "organoid" is derived from the patient’s normal intestinal mucosa (including ISCs), and cultured in vitro in 3D to form 0.1–0.2 mm diameter "organoids", which are then endoscopically transplanted to the colon lesion site [ 148 , 149 ].…”

“…Subsequently, the TMDU research team announced the first successful transplantation of "organoids" into the intestinal mucosa of a patient with refractory UC [ 149 ]. The "organoid" is derived from the patient’s normal intestinal mucosa (including ISCs), and cultured in vitro in 3D to form 0.1–0.2 mm diameter "organoids", which are then endoscopically transplanted to the colon lesion site [ 148 , 149 ]. Periodic endoscopic observation of mucosal repair and improvement of colonic lesions was performed.…”