Cells respond to a diverse range of cues within their environment, from soluble factors and physical forces to the different facets of the extracellular matrix and the activity of nearby cells. This signaling is bidirectional, with cells themselves generating physical forces, making or breaking the extracellular matrix and impacting surrounding cells. All of these factors, termed biophysical cues, orchestrate cellular processes throughout the life cycle. Ensuring the appropriate biophysical cues are enforced at the right time and place is particularly important in guiding the fate of stem cells. Understanding this process is key to translating stem cell research into clinical applications. With this in mind, Stem Cell Research & Therapy brings together a collection of articles addressing ‘Physical influences on stem cells’, edited by Gordana Vunjak-Novakovic from Columbia University, USA, and summarized here.

Gordana Vunjak-Novakovic, Professor, Columbia University, USA.

Vunjak-Novakovic obtained her PhD degree in chemical engineering at the University of Belgrade, Serbia, where she went on to pursue her research career, ultimately leading to a professorship. She then moved to the USA to join the Harvard-MIT Division for Health Sciences and Technology, during which time she was appointed a Fulbright Fellow and cultivated her interest in tissue engineering and emerging technologies to treat human disease and injury. In 2005, Vunjak-Novakovic joined Columbia University, USA, where her laboratory is now established. Her research interests focus on engineering functional tissues for use as models of disease, regenerative medicine and stem cells.

Vunjak-Novakovic explains more about where this area of research currently stands, touching upon stem cell culture and tissue engineering, and goes on to discuss what the future may hold.


How has the development of new technology advanced investigations into how physical cues regulate stem cells?

In the body, cells are surrounded by other cells, embedded in extracellular matrix, and exchanging nutrients, oxygen and metabolites by capillary networks whose density is dependent on the local metabolic needs. In this three-dimensional environment, cellular processes are mediated by a variety of molecular, structural, hydrodynamic, mechanical, and electrical cues and their spatial and temporal levels and combinations. In contrast, traditional Petri dish cultures contain cells attached to plastic and bathing in culture medium that is periodically refreshed. Between medium changes, nutrients are depleted and the metabolites and cell-secreted factors accumulate, to be reset to the initial conditions once the medium has been changed. Clearly, these conditions are far from those cells encounter in vivo.

Tissue engineering approaches have fundamentally changed this situation by providing biologically inspired engineering designs. Cells are cultured in three-dimensional settings, in biomaterial scaffolds that serve as structural and informational templates for cell attachment and tissue formation. Bioreactors are used to provide environmental control, enhance exchange of nutrients and metabolites using in vivo-like mechanisms, and introduce tissue-specific physical signals. Tissue engineering, a discipline driven by the needs of regenerative medicine, is now offering bioengineered niches of high biological fidelity for studies of stem cells.


What advances has stem cell research seen in the  last ten years and where is the field going?

While progress in stem cell research has been rapid and gratifying, we certainly have more questions than answers. The derivation of human embryonic stem cell lines, reported just 15 years ago by James Thomson gave a huge stimulus to the whole field because of the potential of these cells to grow in culture without limit and to give rise to any cell type in the human body. A ‘perfect’ model for studies of human development became available. Nine years later, Yamanaka and Thomson both showed that adult human skin cells can be converted into so-called induced pluripotent stem cells (iPS cells) that closely resemble human embryonic stem cells. These cells enabled unprecedented advances in basic research on the function of the human body, drug testing, study of disease, and regenerative medicine, as they can be derived from any individual and directed into practically any cell type. As iPS cells are derived using increasingly improving methods, we are yet to learn how to fully utilize their biological potential, and how to apply regulatory factors – biological and physical – to regulate their fate, direct them to differentiate into specific cell lineages, and assemble into functional tissues. Much of the current effort is dedicated to studies of adult stem cells residing in their niches in various organs in the body, and in exploring ways to mobilize these cells to regenerate lost and damaged tissues in the body.


How do you think stem cell culture will change in the future?

We now have the ability to provide in vitro settings for stem cell culture that mimic many aspects of the actual in vivo environment of the cell: three-dimensional context, the presence of other cells of the same and different types, extracellular matrix, soluble and immobilized molecular factors, and physical signals. This new generation of culture systems, developed using methods of tissue engineering, allows us to study cells under conditions of high biological fidelity, while having control over environmental factors and insight into cellular responses. We also have the ability to generate spatial gradients of multiple factors, known to drive developmental processes, tissue formation and the establishment of boundaries. Finally, stem cell culture today can include the application of temporal sequences of molecular and physical factors, such as controlled release of growth factors or dynamic changes in fluid shear, stretch or electrical potentials. The future prospects are unlimited, and will likely evolve around complex biological questions explored by studying cells under conditions predictive of whole body physiology.


What are the most exciting studies that are currently going on in the biophysical regulation of stem cells as relates to tissue engineering?

With recent major advances in stem cell biology, tissue engineering is becoming increasingly oriented towards biologically inspired in vitro cellular microenvironments designed to guide stem cell growth, differentiation and functional assembly. Many exciting developments are now in progress, by combining biological principles and engineering designs. Functional tissues, such as living human bone, are being grown in the lab, from different kinds of stem cells, into different clinical shapes and sizes. These studies are being advanced through large animal studies towards clinical applications.

Bioengineering of whole organs, such as lung and heart, is being approached by using the native organ as a ‘scaffold’ for stem cells regulated to drive regeneration of native tissue structure. In parallel, human microtissues made from iPS cells and connected to each other on microfluidic platforms, are used to investigate physiology, and test the safety and efficacy of drugs for any specific patient or state of disease. Incorporation of fluorescent labels attached to specific promoters in these cells allow us to study cellular processes as they happen, in real time.

Collectively, these and many other ongoing efforts are accelerating stem cell research and the utilization of the enormous potential of stem cells in new therapeutic modalities.


What would make the perfect scaffold for tissue engineering?

A ‘perfect’ scaffold for engineering a specific tissue would be the one resembling the native extracellular matrix of that same tissue: its molecular composition, architecture, and mechanical properties. This way, the regulation of cell behavior by the scaffold would be similar to that provided by the native extracellular matrix. In most tissues, the properties are anisotropic – the composition, structure and mechanical features are different in different directions, and these features should ideally be reproduced when designing a scaffold. Such advanced scaffolds will be most effective in supporting regeneration of native-like tissue structures. Scaffolds should also biodegrade at an adequate kinetic rate – similar to the rate of tissue formation, as it serves as a temporary template for the new tissue and should be completely resorbed over time. These multiple and complex requirements are being met by a new generation of specialized scaffolds that are either derived from native tissues (by completely removing cellular material) or synthesized from biocompatible materials. Roughly the same principles for scaffold selection and design apply to our needs in in vitro cell culture and in vivo tissue regeneration.


What do you think will be feasible in tissue engineering in the next ten years?

This is not easy to tell. In regenerative medicine, the progress has been enormous, while many questions remain as well as the need to demonstrate the safety and functionality of engineered tissues in the long term and in patients of various ages and disease states. In our aging population, addressing the needs of older individuals and tissue-engineered modalities in patients with systemic diseases (such as cardiovascular disease or diabetes) are increasingly important. Tissue engineering has been most successful with organs that are thin, simple and have structural rather than metabolic function. With advances in methods to generate vascular networks perfusable with blood, the prospects of engineering large tissues and sustaining their viability are rapidly improving. Also, new scaffold designs, with gradients and interfaces, are leading to the regeneration of more complex and functional tissues. Among many directions now pursued, the microphysiological ‘organs on a chip’ platforms utilizing microtissues made from human iPS cells are very close to commercial utilization in development and testing of drugs.


What sort of impact will tissue engineering research have on other fields?

We are already experiencing major impacts on cell biology, regenerative medicine, materials science, the pharmaceutical industry, and also the way we train the next generation of scientists/bioengineers/clinicians for work with stem cells. More sophisticated and better controlled tissue engineering systems allow us to address more sophisticated biological questions, and even more importantly, to ask new questions that will drive future developments in stem cell research. Tissue engineering will expand the options for overcoming disease and the failure of our organs, and help us live longer and better lives, by offering tissues for transplantation, methods to induce and guide tissue regeneration in the body, and new technologies for drug development. Finally, this exciting work at the interface of several disciplines is inspiring new approaches to education and training, which are increasingly focused on teaching concepts and critical thinking. Stem cell research is certainly one of the most exciting areas of human endeavor and certainly an area of high impact on our life.


More about the researcher(s)

  • Gordana Vunjak-Novakovic, Professor, Columbia University, USA.

    Gordana Vunjak-Novakovic

    Gordana Vunjak-Novakovic obtained her PhD degree in chemical engineering at the University of Belgrade, Serbia, where she went on to pursue her research career leading to a professorship. She then moved to the USA to join the Harvard-MIT Division for Health Sciences and Technology, during which time she was appointed a Fulbright Fellow and cultivated… Read more »

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