Singapore – Scientists from the Institute of Medical Biology (IMB) of Agency for Science, Technology and Research (A*STAR), in Singapore, have discovered that the recently-identified hormone ELABELA is critical in promoting the growth of human embryonic stem cells (hESCs), suggesting its potential as a target for applications in tissue engineering and regenerative medicine. The study was done in collaboration with A*STAR’s Institute of Molecular and Cell Biology (IMCB) and Genome Institute of Singapore (GIS).
Clinical treatment has seen a paradigm shift towards regenerative medicine in the past decade, in which new cells can restore tissue and organ function by repairing or replacing malfunctioning cells and promoting repair. This departs radically from the past approach of removing damaged cells surgically and using pharmaceutical therapies to mitigate the symptoms, and eliminates the need for organ replacement. With the promising discovery of hESCs and induced pluripotent stem cells (iPSCs) as a way of generating new cells, regenerative medicine appears to be increasingly feasible. However, much remains unknown about the underlying mechanisms of hESCs, and as such, their widespread adoption in regenerative medicine still remains to be seen.
So far, only a few growth factors for hESCs have been discovered. In a ground-breaking study, IMB has now identified ELABELA as necessary for hESCs to self-renew and differentiate, making it a potential target to stimulate hESC growth, and ensuring its stability for use in regenerative medicine. It was found that genetically deleting ELABELA or inhibiting it with a neutralizing antibody resulted in compromised hESC growth, the loss of pluripotency, and increased cell death. This discovery points to a new role for the ELABELA hormone, which was previously known for its role in early blood vessel and heart development.
IMB’s scientists further discovered that ELABELA promotes hESC growth through activating the indispensable PI3K/AKT/mTORC1 pathway, known to regulate cell growth and viability, by promoting cell cycle progression and optimal protein translation. Prior to this, the PI3K/AKT pathway was known to be important for the growth of hESCs, but which endogenous growth factor was driving this effect was not clear.
By activating this pathway, ELABELA also protects the hESCs, and therefore presumably early human embryos, against the intrinsic cell death (apoptosis) pathway which is activated by a variety of cellular and environmental stresses. Given the high susceptibility of hESCs to spontaneous apoptosis and differentiation, ELABELA not only enhances their growth, but also performs the critical function of ensuring their survival.
In regenerative medicine, a key problem is ensuring the stability and survival of hESCs for future differentiation and transplantation. IMB’s discovery implies that clinicians and scientists can target and manipulate ELABELA in order to ensure optimal hESC growth during scale-up of cell production for clinical applications, thus making regenerative medicine cheaper and more accessible, and increasing the chances of successful cell replacement.
In addition, hESCs and human pre-implantation embryos are known to be very prone to stress. First author Dr Lena Ho conjectures, “Given ELABELA’s effectiveness in protecting them against cellular stress, our findings could have a profound effect on understanding how human pre-implantation embryos naturally survive after fertilization, with potential applications in fertility clinics.”
Corresponding author and IMB/IMCB Senior Principal Investigator Dr Bruno Reversade, whose team discovered ELABELA two years ago, said, “I foresee significant and immediate applications of our discovery, because ELA and its cell surface receptors are readily druggable and have tangible clinical indications.”
Professor Birgit Lane, Executive Director of IMB, stated, “This discovery underscores the continued importance of basic research in laying the foundation for clinical applications, and it is very gratifying to see such impact emerging from innovative research, with long-term translational potential for improving healthcare.”
Notes to Editor:
The research findings described in this media release can be found in the Cell Stem Cell Journal, under the title, “ELABELA Is an Endogenous Growth Factor Sustaining hESC Self-Renewal Via the PI3K/AKT Pathway” by Lena Ho1, Shawn Y.X. Tan1, Sheena Wee2, Yixuan Wu1, Sam J.C. Tan1, Navin B. Ramakrishna1, Serene C. Chng1, Srikanth Nama1, Iwona Sczerbineska3, Winston Chan3, Stuart Avery1, Norihiro Tsuneyoshi1, Huck Hui Ng3, Jayantha Gunaratne2, N. Ray Dunn1, Bruno Reversade1,2,4
1Institute of Medical Biology, Human Genetics and Embryology Laboratory, A*STAR, Singapore 138648
2Institute of Molecular and Cell Biology, A*STAR, Singapore 138673
3Genome Institute of Singapore, A*STAR, Singapore 138672
4Department of Pediatrics, National University of Singapore, Singapore 119260
Full text of the Cell Stem Cell paper can be accessed online from:
ANNEX A – About the Reversade Laboratory
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About A*STAR’s Institute of Medical Biology (IMB)
IMB is one of the Biomedical Sciences Institutes of the Agency for Science, Technology and Research (A*STAR). It was formed in 2007, with a mission to study mechanisms of human disease in order to discover new and effective therapeutic strategies for improved quality of life.
IMB has 22 research teams working in three primary focus areas - stem cells, genetic disease, and skin biology. The teams work closely with clinical collaborators as well as industry partners, to target the challenging interface between basic science and clinical medicine. IMB’s strategic research topics are targeted at translational research to understand the mechanisms of human disease so as to identify new strategies for disease amelioration, cure and eradication and to improve health and wellbeing. IMB hosts major strategic funding programs in rare genetic diseases and in skin biology, and in 2013, IMB became a founding institute of the Skin Research Institute of Singapore.
For more information about IMB, please visit www.imb.a-star.edu.sg.
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.
ANNEX – ABOUT THE REVERSADE LABORATORY
Dr Bruno Reversade, a human geneticist and embryologist holds a Senior Principal Investigator position at IMB and IMCB. He is the coordinating investigator on A*STAR’s strategic programme on rare genetic diseases. He is an adjunct professor of the Department of Paediatrics at the National University of Singapore. He is also a Fellow of the Branco Weiss Foundation based at ETH in Switzerland, and was the first recipient of the A*STAR Investigatorship, and the first EMBO Young Investigator based outside Europe.
For more information about Dr Reversade’s laboratory, visit www.reversade.com.
For more information about ELABELA, visit www.elabela.com.