Human pluripotent stem cell-derived organoids repair damaged bowel in vivo,Cell Stem Cell

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Human pluripotent stem cell-derived organoids repair damaged bowel in vivo
Cell Stem Cell ( IF 19.8 ) Pub Date : 2024-09-12 , DOI: 10.1016/j.stem.2024.08.009
Holly M Poling ₁ , Nambirajan Sundaram ₂ , Garrett W Fisher ₂ , Akaljot Singh ₂ , Joseph R Shiley ₃ , Kalpana Nattamai ₂ , Vinothini Govindarajah ₂ , Alexander R Cortez ₂ , Maksym O Krutko ₁ , Séverine Ménoret ₄ , Ignacio Anegon ₅ , Magdalena Kasendra ₂ , James M Wells ₆ , Christopher N Mayhew ₇ , Takanori Takebe ₈ , Maxime M Mahe ₉ , Michael A Helmrath ₂

Affiliation

Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH 45219, USA.
Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA.
Pluripotent Stem Cell Core, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA.
Nantes Université, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016 CNRS UMS 3556, Nantes 44035, France; INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes 44035, France.
Nantes Université, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016 CNRS UMS 3556, Nantes 44035, France.
Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA.
Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Pluripotent Stem Cell Core, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA.
Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA.
Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Nantes Université, Inserm, TENS UMR1235, The Enteric Nervous System in Gut and Brain Diseases, IMAD, Nantes 44035, France.

The fundamental goal of tissue engineering is to functionally restore or improve damaged tissues or organs. Here we address this in the small bowel using an in vivo xenograft preclinical acute damage model. We investigated the therapeutic capacity of human intestinal organoids (HIOs), which are generated from human pluripotent stem cells (hPSCs), to repair damaged small bowel. We hypothesized that the HIO’s cellular complexity would allow it to sustain transmural engraftment. To test this, we developed a rodent injury model where, through luminal delivery, we demonstrated that fragmented HIOs engraft, proliferate, and persist throughout the bowel following repair. Not only was restitution of the mucosal layer observed, but significant incorporation was also observed in the muscularis and vascular endothelium. Further analysis characterized sustained cell type presence within the regenerated regions, retention of proximal regionalization, and the neo-epithelia’s function. These findings demonstrate the therapeutic importance of mesenchyme for intestinal injury repair.

中文翻译：

人类多能干细胞衍生的类器官修复体内受损的肠道

组织工程的基本目标是在功能上恢复或改善受损的组织或器官。在这里，我们使用体内异种移植临床前急性损伤模型在小肠中解决这个问题。我们研究了由人类多能干细胞 (hPSC) 产生的人类肠道类器官 (HIO) 修复受损小肠的治疗能力。我们假设 HIO 的细胞复杂性使其能够维持透壁植入。为了测试这一点，我们开发了一种啮齿动物损伤模型，通过腔内递送，我们证明了碎片化的 HIO 在修复后植入、增殖并持续存在于整个肠道中。不仅观察到粘膜层的恢复，而且还在肌层和血管内皮中观察到显着的合并。进一步的分析表征了再生区域内存在的持续细胞类型、近端区域化的保留以及新上皮的功能。这些发现证明了间充质对于肠道损伤修复的治疗重要性。

更新日期：2024-09-12

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