Dr Kevin Chalut
The physical biology of pluripotency and differentiation
Laboratory: Cambridge Stem Cell Institute, Gleeson Building
Departmental Affiliation: Physics
Kevin Chalut is a biophysicist with a PhD in Physics from Duke University. Since 2011 he has been a Royal Society University Research Fellow. Kevin’s post-graduate background is in biotechnology and imaging, particularly with regards to detecting cancer and characterising stem cells. He is currently a group leader at both the Cavendish Laboratory and the Wellcome Trust-Medical Research Council Stem Cell Institute.
His work focuses on developing novel biotechnology to investigate physical states of cells such as mechanics and subcellular structure; in the last few years he has focused almost exclusively on the biophysics of embryos and embryonic stem cells. The ultimate goal of his laboratory is to discover physical mechanisms and their importance to pluripotency, differentiation and reprogramming.
Royal Society, Leverhulme Trust, MRC, BBSRC
(A) ES cells cultured on soft substrates (right) more effectively form pluripotent colonies than on stiff hydrogels or plastic, demonstrating the importance of controlling the mechanical microenvironment for ES cells.(B) Our lab investigates cell and nuclear shape, as mediated by forces in the nucleus and cytoskeleton. (C) We use biophysical techniques to apply mechanical stresses to ES cells in order to demonstrate the importance of mechanical forces in cell transitions, and the mechanisms by which mechanical forces lead to changes in gene expression. (D) We develop microfluidic techniques for single cell monitoring in order to better understand transitions through phases of pluripotency. Image Credits: Chibeza Agley (A), George Wylde (B) and Andrew Hodgson (D)
The transformation of a stem cell into a mature tissue cell consists of a progression of highly regulated steps. However, the process of differentiation, and how it is regulated, is not well understood, despite the importance both for comprehending embryonic development and for targeted stem cell therapies. Furthermore, differentiation has primarily been studied from a biochemical perspective, while mechanical aspects, despite their importance, have been largely overlooked. We are focused on illuminating biophysical aspects of transitions between states in ES cell differentiation and in embryonic development by utilising quantitative microscopy, microfabrication and microfluidic techniques. Biophysical aspects we focus on include cell mechanics and matrix signalling, where our work has demonstrated that the matrix environment is a potent regulator of transitions by controlling cell spreading and shape. Another biophysical aspect we study is how nuclear mechanics, as driven by chromatin and nuclear envelope structure, influence gene expression and transport of signalling molecules through nuclear pore complexes. We are also developing single cell microfluidic techniques to study transitions between states in ES cell differentiation. These techniques allow us to completely control the microenvironment and signalling environment of single ES cells, and retrieve samples at specific time points for downstream analysis or further experimentation. Our work will shed light on state transitions and differentiation in development, in particular how these transitions are mechanically regulated.
Chibeza Agley, Celine Labouesse, Christophe Verstreken, George Wylde, Ayaka Yanagida.
We are a biophysics and biotechnology laboratory devoted to discovering how physical processes drive the development of the mammalian embryo and the function of stem cells. Our central question is: What are the physical considerations giving rise to the unique biological properties of stem cells, and how is this important for self-renewal and differentiation? We are using microfluidics and advanced quantitative microscopy to study stem cell systems, and to deduce both how they thrive in the innately physical environment of the embryo and how they respond to controlled physical cues. Understanding the physical interplay between stem cells and their environment, both in the embryo and in culture, will help us formulate better strategies – based in Physics – to monitor and control stem cell function.
- Pagliara S, Franze K, McClain C, Wylde G, Fisher C, Franklin R, Kabla A, Keyser U, Chalut KJ. Auxetic nuclei in embryonic stem cells exiting pluripotency. Nature Materials, 2014, 13, 638-644. PMCID:PMC4283157
- Ekpenyong A, Man S, Achouri S, Bryant C, Guck J, Chalut KJ. Bacterial infection of macrophages induces decrease in refractive index. Journal of Biophotonics, 2013, 6(5), 393-397. PMID:22887897
- Chalut KJ, Höpfler M, Lautenschläger F, Martinez-Arias A, Guck J. Chromatin decondensation and nuclear softening accompany Nanog downregulation in embryonic stem cells. Biophysical Journal, 2012, 103, 2060-2070. PMCID:PMC3512036
- Chalut KJ, Ekpenyong A, Clegg W, Melhuish I, Guck J. Quantifying cellular differentiation by physical phenotype using digital holographic microscopy. Integrative Biology, 2012, 4, 280-284. PMID:22262315
- Chalut KJ, Ostrander J, Giacomelli M, Wax A. Light scattering measurements of subcellular structure provide noninvasive early detection of chemotherapy-induced apoptosis. Cancer Research, 2009, 69(3). PMCID:PMC2667891