2016 Fiscal Year Annual Research Report
Mechanism of autoinflammation in chronic granulomatous disease: the molecular crosstalk between innate immune cells and gastrointestinal environments
| Project/Area Number |
15K20949
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| Research Institution | The University of Tokyo |
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Principal Investigator |
頼 貞儀 東京大学, 医科学研究所, 特任助教 (30739925)
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| Project Period (FY) |
2015-04-01 – 2017-03-31
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| Keywords | 慢性肉芽腫 / autoinflammation / intestine organoid |
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| Outline of Annual Research Achievements |
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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[Journal Article] An All-Recombinant Protein-Based Culture System Specifically Identifies Hematopoietic Stem Cell Maintenance Factors.2017
Author(s)
Ieyasu A, Ishida R, Kimura T, Morita M, Wilkinson AC, Sudo K, Nishimura T, Ohehara J, Tajima Y, Lai CY, Otsu M, Nakamura Y, Ema H, Nakauchi H, Yamazaki S.
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Journal Title
Stem Cell Reports
Volume: 8
Pages: 500-508
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Pre-Transplantation Blockade of TNF-α-Mediated Oxygen Species Accumulation Protects Hematopoietic Stem Cells.2016
Author(s)
Ishida T, Suzuki S, Lai CY, Yamazaki S, Kakuta S, Iwakura Y, Nojima M, Takeuchi Y, Higashihara M, Nakauchi H, Otsu M.
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Journal Title
Stem Cells
Volume: 35
Pages: 989-1002
DOI
Peer Reviewed / Open Access / Int'l Joint Research
