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Stem cell self-renewal and differentiation: hydrogelling together
One of the main barriers to stem cell therapy and regenerative medicine is the lack of a system which allows both self-renewal of stem cells and differentiation of the cells into specific cell types with specialised roles, in the same material environment. The culturing conditions required for self-renewal versus differentiation differ and up until now there has not been a system available that allows both processes to be carried out. In a new study published in PNAS, researchers from the University of Nottingham describe a hydrogel-based system with a simple chemical switch mechanism that overcomes these difficulties.

Regenerative medicine is a rapidly developing field underpinned by advances in biotechnology aimed at, for example, enhancing long-term survival of stem cells and their differentiation in vivo. In previous threads in this forum we have described new research in this field, for example the use of nanoparticles to deliver trophic factor mimetics to transplanted embryonic stem cells in animal models ( The current study addresses the issue of developing a practical, single system supporting both stem cell renewal and differentiation to specific cell types as a step towards mass production of fully differentiated tissues. The potential for this is of major importance in advancing regenerative medicine use in repair of human tissue and in maintenance of organ function win people with chronic or age-related diseases.

The researchers built on previous work in which they had used an alginate hydrogel system to promote self-renewal of stem cells. They introduced collagen into the alginate gel; collagen is used to make an extracellular matrix hydrogel which allows adhesion of stem cells and differentiation into specific cell types.

The innovation in this system was the introduction of a simple chemical switch, based on chelation of calcium ions, which resulted in conversion of the environment from alginate-dominated to collagen-dominated. On checking the cells after the switch by methods including confocal microscopy and PCR for biomarkers of stem cells or of differentiation, the researchers were able to confirm that the switch resulted in significant differentiation of the stem cells from the self-renewing profile observed in alginate-dominated hydrogel. The switch could be timed to generate cells of different stages in cell lineage and the efficiency of differentiation could be further improved by changes to the culture medium. The efficacy of the system was further confirmed by its use to generate terminally differentiated cardiomyocytes (heart cells).

Senior author on the paper, Prof. Kevin Shakesheff, said: “Our new combination of hydrogels is a first. It allows dense tissue structures to be produced from human pluripotent stem cells (HPSC) in a single step process never achieved before. The discovery has important implications for the future of manufacturing in regenerative medicine. This field of healthcare is a major priority for the UK and we are seeing increasing investment in future manufacturing processes to ensure we are ready to deliver real treatments to patients when HPSC products and treatments go to trial and become standard.”


Dixon, J.E., Shah, D.A., Rogers, C., Hall, S., Weston, N., Parmenter, C.D.J., McNally, D., Denning, C. and Shakesheff, K.M. (2014). Combined hydrogels that switch human pluripotent stem cells from self-renewal to differentiation. PNAS 2014 : 1319685111v1-201319685. Published online before print March 27, 2014, doi: 10.1073/pnas.1319685111; PNAS March 27, 2014

Press release: University of Nottingham; available at
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