未经证实:溃疡性结肠炎(UC)是一种以反复缓解和复发为特征的炎症性肠病。免疫抑制药物促进了许多UC患者缓解的诱导和维持。然而,免疫抑制药物不能直接修复受损的肠粘膜,并且不足以预防复发。因此,新的治疗方法修复受损的上皮在UC已经尝试通过移植的肠道器官,可以通过嵌入基质胶而分化为粘膜,从患者来源的肠道干细胞产生。方法,然而,提出了产生足够的细胞用于UC治疗的挑战,患者来源的细胞可能已经获得了病理变化。相比之下,从健康个体产生的人诱导多能干细胞(iPS)无限增殖并且可以分化成靶细胞。最近开发的人iPS细胞衍生的肠道类器官(HIOs)旨在产生与成人肠道非常相似的类器官。然而,迄今为止,没有研究报告将HIOs注射到体内炎症模型中,目前尚不清楚HIOs是否具有与成人肠道非常相似的细胞或与肠道干细胞保持更好的结肠炎组织修复能力。
UNASSIGNED:我们通过悬浮培养,有和没有小分子化合物,产生了两种类型的HIO:主要包括更多的肠干细胞[HIO(A)]和主要包括更多的肠上皮细胞和分泌细胞[HIO(B)]。我们检查了所产生的HIO是否在体内移植,并比较了它们加速受损组织恢复的能力。
UNASSIGNED:研究结果表明,HIOs表达肠道特异性标志物,例如尾型同源盒2(CDX2)和绒毛蛋白,和HIOs移植在小鼠的肾胶囊下。然后,我们将HIO注射到结肠炎模型小鼠中,发现注射HIO(A)的小鼠的体重和临床评分比假手术组的小鼠更早恢复。Further,HIO(A)组结肠组织中粘液的产生以及细胞增殖标志物和紧密连接蛋白的表达恢复到与健康小鼠相似的水平。然而,HIO(A)和HIO(B)均不能移植到结肠中。
UNASSIGNED:有效的细胞疗法应通过植入损伤部位直接修复组织。然而,本研究中观察到的影响无移植移植组织修复率的类器官性质差异应被视为开发使用iPS衍生类器官的再生医学时的重要考虑因素.
UNASSIGNED: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by repeated remissions and relapses. Immunosuppressive drugs have facilitated the induction and maintenance of remission in many patients with UC. However, immunosuppressive drugs cannot directly repair impaired intestinal mucosa and are insufficient for preventing relapse. Therefore, new treatment approaches to repair the damaged epithelium in UC have been attempted through the transplantation of intestinal organoids, which can be differentiated into mucosa by embedding in Matrigel, generated from patient-derived intestinal stem cells. The method, however, poses the challenge of yielding sufficient cells for UC therapy, and patient-derived cells might already have acquired pathological changes. In contrast, human induced pluripotent stem (iPS) cells generated from healthy individuals are infinitely proliferated and can be differentiated into target cells. Recently developed human iPS cell-derived intestinal organoids (HIOs) aim to generate organoids that closely resemble the adult intestine. However, no study till date has reported HIOs injected into in vivo inflammatory models, and it remains unclear whether HIOs with cells that closely resemble the adult intestine or with intestinal stem cells retain the better ability to repair tissue in colitis.
UNASSIGNED: We generated two types of HIOs via suspension culture with and without small-molecule compounds: HIOs that include predominantly more intestinal stem cells [HIO (A)] and those that include predominantly more intestinal epithelial and secretory cells [HIO (B)]. We examined whether the generated HIOs engrafted in vivo and compared their ability to accelerate recovery of the damaged tissue.
UNASSIGNED: Findings showed that the HIOs expressed intestinal-specific markers such as caudal-type homeobox 2 (CDX2) and villin, and HIOs engrafted under the kidney capsules of mice. We then injected HIOs into colitis-model mice and found that the weight and clinical score of the mice injected with HIO (A) recovered earlier than that of the mice in the sham group. Further, the production of mucus and the expression of cell proliferation markers and tight junction proteins in the colon tissues of the HIO (A) group were restored to levels similar to those observed in healthy mice. However, neither HIO (A) nor HIO (B) could be engrafted into the colon.
UNASSIGNED: Effective cell therapy should directly repair tissue by engraftment at the site of injury. However, the difference in organoid property impacting the rate of tissue repair in transplantation without engraftment observed in the current study should be considered a critical consideration in the development of regenerative medicine using iPS-derived organoids.