EMBARGOED UNTIL 0000H Singapore Standard Time, 19 JULY / 1200 Eastern Standard Time, 18 JULY 2017
REPROGRAMMING IMACS — BUT NOT THE KIND YOU THINK
A new method that leads to the formation of specialized tissue cells could improve the understanding of neurodegenerative diseases, inflammatory diseases and cancer.
Macrophages are specialized cells involved in tissue development, repair and immunity. Macrophage communities in several types of tissues are derived from ‘yolk-sac precursor cells’, named primitive macrophages, planted there during early embryonic development. Isolating these precursor cells in sufficient numbers to study them has proven challenging.
An international team of researchers has found a breakthrough solution to this problem – developing a revolutionary protocol to induce the formation of primitive macrophages that are very similar to those derived from the yolk-sac. This will enable scientists to study primitive macrophage-derived cells in vivo, which is a critical step in advancing our understanding of various inflammatory diseases, cancer, and neurodegenerative diseases such as Alzheimer’s disease. The study was led by Dr Florent Ginhoux from the Singapore Immunology Network (SIgN), a research institute under Singapore’s Agency for Science, Technology and Research (A*STAR), together with Japan’s Kyoto Pharmaceutical University.
The team started with induced pluripotent stem cells (iPSCs): adult cells that are reprogrammed into an embryonic state, and are then directed to develop into any type of cell. By modifying currently available strategies, they were able to induce the formation of iPSC-derived primitive macrophages (iMacs) that are genetically, physically, and functionally similar to primitive yolk-sac-derived macrophages.
When they cultured iMacs with iPSC-derived neurons (nerve cells present in the brain), or transferred them into mouse brains, the iMacs developed into microglia, the resident macrophages of the central nervous system. The team also grafted the iMacs into the lungs of mutant mice with pulmonary alveolar proteinosis (PAP), a rare genetic lung disease. The iMacs matured into specialized lung macrophages that cured the disease, suggesting that iMacs could be used for cellular therapy treatment for various diseases.
The team also successfully developed iMacs from iPSCs derived from a patient with familial Mediterranean fever, a genetic disease characterized by recurrent fever and painful inflammation of the abdomen, chest and joints. The iMacs showed an excessive inflammatory response similar to that present in diseased individuals and can be used now as a cellular model to study the disease.
The new protocol, which has been patented by A*STAR, also yields a larger number of macrophages that more accurately represent their natural development in the body than previous methods.
The results demonstrate that the new protocol “could help to overcome the limitations placed on research into certain rare-disease entities by the lack of an adequate supply of disease-specific primary cells, and they might facilitate the development of novel therapeutic approaches, in particular for patients with PAP,” write the researchers in their recently-published study in the journal Immunity.
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Email: [email protected]
About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that spearheads economic oriented research to advance scientific discovery and develop innovative technology. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit society.
As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by contributing to societal benefits such as improving outcomes in healthcare, urban living, and sustainability.
We play a key role in nurturing and developing a diversity of talent and leaders in our Agency and Research Institutes, the wider research community and industry. A*STAR oversees 18 biomedical sciences and physical sciences and engineering research entities primarily located in Biopolis and Fusionopolis.
For more information on A*STAR, please visit www.a-star.edu.sg.
About A*STAR’s Singapore Immunology Network (SIgN)
The Singapore Immunology Network (SIgN), officially inaugurated on 10 February 2006, is a research consortium under the Agency for Science, Technology and Research (A*STAR)’s Biomedical Research Council. The mandate of SIgN is to advance human immunology research and participate in international efforts to combat major health problems. Since its launch, SIgN has grown rapidly and currently includes 200 scientists from 25 different countries around the world working under 18 renowned Principal Investigators. At SIgN, researchers investigate immunity during infection and various inflammatory conditions including cancer and are supported by cutting edge technological research platforms and core services.
Through this, SIgN aims to build a strong platform in basic human immunology research for better translation of research findings into clinical applications. SIgN also sets out to establish productive links with local and international institutions, and encourage the exchange of ideas and expertise between academic, industrial and clinical partners and thus contribute to a vibrant research environment in Singapore.
For more information about SIgN, please visit www.a-star.edu.sg/sign.
About Kyoto Pharmaceutical University
Kyoto Pharmaceutical University was originally established as a private German school founded by young scholars trained by the German educator Rudolf Lehmann with the goal of teaching Western medicine and pharmaceutics in the German language. The University is the second oldest private pharmacy school in Japan with a long history and tradition; we celebrated our 130th anniversary in 2014. As expressed in our motto “Philosophia et Praktikos,” the founding principles of the University are to be independent and self-reliant, to commit to lifelong learning, and to put the lessons into practice. Over the years, more than 22,000 graduates have pursued careers in the pharmaceutical industry, hospitals, pharmacies, universities, and government agencies, where they have been recognized for excellence.
For more information, please visit https://www.kyoto-phu.ac.jp/english/
NOTES FOR EDITOR:
The research findings described in this scientific advisory can be found in the 18th July 2017 online issue of the scientific journal Immunity, under the title, "Induced pluripotent stem cell-derived primitive macrophages provide a platform to model tissue-resident macrophage differentiation and function" by Kazuyuki Takata,1,2,11 Tatsuya Kozaki,1,11 Christopher Zhe Wei Lee,1,12 Morgane Sonia Thion, 3,12 Masayuki Otsuka,1 Shawn Lim,1 Kagistia Hana Utami,4 Kerem Fidan,5 Dong Shin Park,1 Benoit Malleret,1,6 Svetoslav Chakarov,1 Peter See,1 Donovan Low,1 Gillian Low,1 Marta Garcia-Miralles,4 Ruizhu Zeng,4 Jinqiu Zhang,4 Chi Ching Goh,1 Ahmet Gul,7 Sandra Hubert,1 Bernett Lee,1 Jinmiao Chen,1 Ivy Low,1 Nurhidaya Binte Shadan,1 Josephine Lum,1 Tay Seok Wei,1 Esther Mok,1 Shohei Kawanishi,2 Yoshihisa Kitamura,2,12 Anis Larbi,1 Michael Poidinger,1 Laurent Renia,1 Lai Guan Ng,1 Yochai Wolf,8 Steffen Jung,8 Tamer O¨ nder,5 Evan Newell,1 Tara Huber,9 Eishi Ashihara,2 Sonia Garel,3 Mahmoud A. Pouladi,4,10 and Florent Ginhoux1,14
1 Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
2 Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
3 Ecole Normale Supe´ rieure, PSL Research University, Institut de Biologie de l’ENS (IBENS), INSERM, U1024, CNRS, UMR8197,
F-75005 Paris, France
4 Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore 138648, Singapore
5 School of Medicine, Koc¸ University, Istanbul 34450, Turkey
6 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System
7 Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey
8 Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
9 Stem Cell and Developmental Biology Department, Genome Institute of Singapore, Agency for Science, Technology and Research,
Singapore, 138672, Singapore
10 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
11 These authors equally contributed to the work
12 These authors equally contributed to the work
13 Present address: Department of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu 525-8577, Japan
14 Lead contact
Correspondence should be addressed to Florent Ginhoux ([email protected])
After lifting of the embargo, full text of the article can be accessed from: www.cell.com/immunity/fulltext/S1074-7613(17)30277-7