Getting in shape - it's a matter of self-control

Living cells have an ‘in-built' system for controlling the length they grow to, according to research by scientists from the MRC Laboratory of Molecular and Cell Biology (LMCB) and the London Centre for Nanotechnology (LCN) at UCL, published in this week's PLoS Biology journal (November 16th). The work provides new insight into how cells respond to internal and environmental cues, paving the way for a greater understanding of animal development, disease development, and the ways in which we can engineer functional tissues.

The interdisciplinary team of researchers, led by Dr Buzz Baum and Dr Rachel McKendry, combined novel micropatterns, genetic tools, cutting edge microscopy and computational approaches to investigate how cells, the building blocks of life, control their physical shape in order to assemble into healthy, functional tissues.

The team pioneered lithographic methods traditionally associated with the microelectronic industry for use in biology. The printed patterns of ‘sticky' proteins - which cells like to adhere to - and blocked other areas of the surface with a non-adherent polymer film. This forced the cells to spread along controlled paths of different widths before the team measured the cells' shapes.

Surprisingly, UCL COMPLEX PhD student Remigio Picone revealed that cells spread to a reproducible length that is independent of the path width and cell size. The team's detailed analysis of the phenomenon suggests that living cells have an ‘in-built' length control system. In searching for the underlying molecular mechanism involved, the team identified a population of dynamic filaments, called microtubules, which grow in a polarised fashion and span from the centre of each cell to opposing ends. These microtubules serve as tracks for the transport of material from the nucleus to the cell periphery, enabling the cell to spread as they elongate. The reach of the microtubules is limited however, hence the limit to cell spreading observed.

"The data suggests that animal cells exhibit two distinct properties," says Dr Baum. "First, cells have flexible form that enables them to change in response to their environment. Second, they have an intrinsic ability to sense and change their shape, that enables them to work together to construct tissues with precise geometries. As with any successful team this combination of individual self-control and group cooperation may enable great things to be achieved, enabling cells to work together to construct and shape beautifully complex tissues with very well defined geometries.

"An important goal of future research will be to identify how these intrinsic cell length constraints and additional layers of regulation are altered during animal development and in disease states to give specific cells and tissues their characteristic forms."

"This work demonstrates the power of cross-disciplinary approaches to investigate the exquisite regulation of living systems," adds Dr Rachel McKendry, Reader in Biomedical Nanotechnology at the LCN, UCL. "By exploiting novel protein micro/nanopatterning technologies we have overcome the limitations of conventional tissue culture assays, where cells have random shapes and lack the spatially defined extrinsic cues found in-vivo. This exciting work could lead to a new paradigm of nanotools to study the mechanisms of animal development and scaffolds for tissue engineering."

The research was funded by the EPSRC COMPLEX doctoral training programme at UCL, Cancer Research UK, the Royal Society, Wellcome Trust, IRC in Nanotechnology (Cambridge, Bristol, UCL) and the EPSRC.

Length homeostasis in HeLa cells (f-actins in red and nucleus in blue) on patterned fibronectin lines (green). Scale bare 10µm

This paper "A Polarised Population of Dynamic Microtubes Mediates Homeostatic Length Control in Animal Cells" Remigio Picone, Xiaoyun Ren, Kenzo D. Ivanovitch, Jon D. W. Clarke, Rachel A. McKendry, Buzz Baum is published in PLoS Biology Vol 8 Issue 11

Notes for Editors:
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