| 研究実績の概要 |
Chronic granulomatous disease (CGD) is commonly known as a phagocyte disorder but it is also characterized by autoinflammation in the gastrointestinal tract, where innate lymphoid cells (ILCs) reside. During the first year, we clarified that the hematopoietic stem and progenitor cells (HSPCs), the origin of ILCs, in CGD mice are comparable to wild-type control suggesting that differentiation of progenitor cells remain unaffected. To model the gastrointestinal tract, induced pluripotent stem (iPS) cells were generated from CGD patients. Human derived intestinal organoids (HIOs) were generated as follows; step 1) endoderm induction: iPS cell treatment with activing A, step 2) pattering to mid- and hindgut tissue: treat the endoderm inducted cells with FGF4 and WNT3a, step 3) 3D culture phase: culture the 3D spheroids formed in step 2 with intestinal growth factors. The resulting HIOs showed villus-like structures with microscopic brush borders as well as crypt-like structures that resembled normal morphology of human intestines. Moreover, those HIOs proliferate and could be expanded more than 4 months suggesting the maintenance of the self-renewable capacity of human intestinal stem cells. To date, this is the first successful attempt at generating intestinal tissue from CGD-iPS cells. This is of critical importance due to the difficulty in obtaining patient's samples and existing discrepancies between mouse and human cells. Here, we established a new platform for studying human gastrointestinal system in vitro and the pathphysiology of CGD colitis.
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