Dr. David Hay is a Principal Investigator at the University of Edinburgh's MRC Centre for Regenerative Medicine. David has worked in the field of stem cell biology and differentiation over the last decade. His work has highlighted the important role that cell physiology and chemical biology plays in the generation of predictive and drug-inducible human hepatocytes from pluripotent stem cells. The impact of this work has led to a number of publications and regular appearances at high profile international conferences.
Most recently, David and his colleagues spun out a company from the University of Edinburgh, FibromEd, whose focus is to reduce the cost of human drug attrition.
1. Tell us about yourself:
I have a PhD from the University of St Andrews, and now I'm the Principal Investigator at the University of Edinburgh's MRC Centre for Regenerative Medicine. For the last decade, I've worked in the field of pluripotent stem cell biology and hepatocyte derivation.
My work is focussed on human stem cell differentiation. We're interested in developing predictive human models and new medical devices. We have developed a robust stem cell differentiation process which generates high fidelity human hepatocytes. More recently, we have combined our approach with materials chemistry to deliver a more functional and stable in vitro system. This work has led to a University of Edinburgh spin out company, FibromEd, which focuses on developing novel tools for research and industry.
On PSC Research
1. What do you consider to be the most important advance(s) in stem cell research over the past 5 years?
Given our focus on cell based modelling, I would say the most important advances in our field are:
a. Generation of human iPSCs from somatic cells permits selectable genotype.
b. Generation of efficient differentiation processes and disease models that recapitulate human physiology.
c. Demonstration that materials chemistry has an important role to play in the maintenance and differentiation of stem cells.
2. What advances do you hope the field will achieve in the next 5 years?
I hope that in the next five years that we will gain a better understanding of human physiology using stem cell derived somatic cells as models. Moving on from this I can envisage the development of gold standard models that allow the identification and development of safer and more efficacious medicines.
3. How challenging was it for you to produce a robust and reproducible differentiation protocol to generate end-stage terminally differentiated hepatocytes from hPSCs?
We generated a number of differentiation procedures to get to where we are today. The earliest prototypes relied heavily on chemical additives to drive cell commitment. While this was efficient, the breakthrough came with the addition of key developmental factors to drive cell commitment. This not only improved the efficiency of our process, but cell function was substantially improved in vitro and in vivo (Hay et al, 2008, Proc Nat Acad Sciences, 105, 12301-12306). Additionally, these studies served as the blue print to efficiently deliver iPSC-derived hepatocytes from different genetic backgrounds (Sullivan et al, 2010, Hepatology, 51(1):329-35). A further breakthrough came using synthetic polymer surfaces to stabilize and improve stem cell-derived hepatocyte biology (Hay et al, 2011, Stem Cell Research, 6: 92-101) to the point where the cell based assays are now suitable for industrial screening.
4. Some recent studies have revealed important small molecules that can replace growth factors within expansion and differentiation of hPSCs. How do you foresee the effect of such small molecules, and what is your view of their long-term effect on culture systems and the cells themselves?
I think the use of small molecules which accurately mimic growth factor action has a very important role to play in stem cell scale up and differentiation. Such approaches have the potential to provide defined cell culture conditions, which will lead to improvements in biological modelling and deliver affordable research and clinical grade somatic cells. However, one must be careful and thoroughly examine any potential off-target effects and/or cellular stresses. Therefore, I think more detailed studies are required to assess the long-term effects of chemical addition on cell stability. We are working toward this goal at the University of Edinburgh and FibromEd Limited.
1. What has your experience been in working with mTeSR™1?
We were aware that we needed to move away from murine embryonic fibroblast conditioned medium (MEF-CM) to a quality assured and serum free stem cell maintenance system. Moreover, we required a growth medium which consistently supported manufacture at larger scale.
So we started using mTeSR™1 four years ago for our routine experimentation and scale-up of our differentiation process. mTeSR™1 has enabled our research by providing more defined conditions and less batch-to-batch variation that was observed with MEF-CM. mTeSR™1 has also permitted rapid scale up in a serum-free environment, enabling larger experiments to be routinely carried out in the lab. We have used mTeSR™1 successfully and have been able to maintain hESC populations for over 40 passages with stable karyotype.
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