Regius Professor of Physiology
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The University of Aberdeen
Professor Colin D. McCaig, Regius Professor of Physiology, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland
After gaining a first class BSc (Hons) in Physiology from the University of Edinburgh, Colin McCaig went on to complete his PhD in Physiology at the University of Glasgow. He then worked abroad as a Postdoctoral fellow in the USA and New Zealand. In 1983 he was awarded a prestigious Beit Memorial Research Fellowship at the University of Edinburgh, and moved to Aberdeen in 1988 as a Wellcome Trust University Award Lecturer.
Colin McCaig is Regius Professor of Physiology. He was Head of the Department of Biomedical Sciences for five years and Head of the School of Medical Sciences for 12 years during which time research and teaching regularly were rated as excellent.
He and his colleagues Professor Min Zhao and Drs. Iain Gibson, Ann Rajnicek, Bing Song and Jin Pu are interested in the controls of directed cell motility and directed cell division. One particular interest is in the role played by small physiological electrical fields in the development and regeneration of many tissues.
Two recent review articles present an overview of this groups work.
McCaig, C.D., Rajnicek, A.M., Song, B. & Zhao, M. (2002). Has electrical growth cone guidance found its potential? Trends in Neurosciences 25, 354-359.
McCaig, C.D. Rajnicek, A.M., Song, B.& Zhao, M. (2005). Controlling cell behaviour electrically: Current views and future potential. Physiological Reviews 85, 943-978.
Steady, direct current extracellular electrical fields are present in places where cells grow, divide and migrate during development and are found also after a wound, when tissue regeneration is required. We have used tissue culture to mimic the effects of these small dc electrical fields and have shown that a wide variety of cell types shows robust but subtly differing responses when grown in the presence of the sort of fields they would experience in the animal. Migration of neuronal cell bodies, neuronal growth cones, corneal epithelial cells, lens epithelial cells, vascular endothelial cells, human neutrophils and of the social amoeba Dictyostelium discoideum are all directed strongly by a physiological electrical field. Importantly, different cell types migrate in different directions and for lens epithelial cells and neuronal growth cones the direction of migration can switch as a function of EF strength. How this switch is activated is unclear.
Our group also studies these issues at a tissue and whole animal level, using monolayer cultures with scratch wounds and excised whole tissues to study the movements of cells in 3-dimensions. In addition we are using genetically modified mice to study the signalling mechanisms underpinning electrically-enhanced and directed wound healing.
Our work has led to a growing recognition of the important roles played by physiological electrical fields in cell growth, division and migration (see Research Roundup article J Cell Biol. 159, 14 2002). Our work has also formed the basis for human clinical trials carried out by colleagues in the US who have used direct current electrical stimulation for the first time to attempt to repair damage to the spinal cord:
see http://www.vet.purdue.edu/cpr/ Center for Paralysis Research website and J. Neurosurgery Spine 2, 3-10 (2005)
This work has featured recently in several national newspaper articles including The Observer: Spine doctors raise hope of electric cure. Robin McKie, science editor, May 29 2005 http://observer.guardian.co.uk/uk_news/story/0,,1494933,00.html
Examples of our work in directing nerve growth in directing epithelial cell migration and wound healing and in orienting the axis of epithelial cell division are shown (make link to a new page).
Several videos illustrating aspects of our work can be accessed at the following addresses:
1. neuronal growth cones turn cathodally in a physiological EF http://www.abdn.ac.uk/~bms024/growthcone
2. corneal epithelial cells migrate cathodally in vitro and move cathodally to close a wound in vivo http://www.abdn.ac.uk/~bms024/CEC.html; user name: user1, password imsbms), (Rajnicek).
3. closure of wounds in monolayer sheets of corneal epithelial cells is driven by a physiological EF and depends on EF polarity: http://www.abdn.ac.uk/~bms024/private/shortVersion (username: user1, password: imsbms), (Pu & Zhao).
4. a rat breast cancer cell line (MTln3) transfected with EGFR-GFP, which migrates anodally ( http://www.abdn.ac.uk/~bms024/private/MTln.html user name: user1, password: imsbms; EF [150mV/mm] vector is horizontal with anode to the left), (Zhao).
5. human neutrophils migrate cathodally http://www.abdn.ac.uk/~bms024/private/neutrophil, (username: user1, password: imsbms), (Zhao).
Figure 1. Nerve sprouting is directed towards a wound edge in the rat cornea.
Nerves are labelled in yellow against a propidium iodide stained background in red.
The wound edge is at the bottom of each panel. Scale bar = 100mm.
A. Control cornea 16h post wound, nerves have sprouted but are not yet oriented towards the wound edge.
B. Control nerves 24h post wound, nerve growth is strongly directed towards the wound edge.
C. A wound in the cornea creates a naturally occurring electrical field with the wound bed acting as a cathode [Song et al Proc Natl Acad Sci USA 99, 13577-13582(2002)]. Enhancing this EF with prostaglandin E2 or
D. with aminophlline induced wound directed nerve sprouting at 16h which was more directly oriented towards the wound edge [Song et al (2004). J.Neuroscience). J.Cell Sci. 117, 4681-4690 (+ news and views and journal cover illustration).].
Figure 2: Single corneal epithelial cells migrate cathodally in a physiological EF.
A wound in the cornea creates a naturally occurring electrical field with the wound bed acting as a cathode [Song et al Proc Natl Acad Sci USA 99, 13577-13582(2002)].
The mechanism of EF-directed epithelial cell migration involves cathodal activation of the EGF receptor, with downstream activation and phosphorylation of enzymes in the MAP kinase signaling pathway (FASEB. J. 16, 857-859 and 10.1096/fj.01-0811fje).
Here a probe for dual phosphorylated ERK 1/2 has been used and the colour and height coding indicate greater activation at the leading cathodal-facing edge.
Figure 3: Corneal wounds in rat generate a DC wound-induced electrical field (EF).
This EF controls wound healing.
The corneal epithelium transports sodium ions in and chloride ions out and this creates a trans-corneal potential difference (TCPD). At a wound the TCPD collapses, but it is maintained at normal levels around 1mm back from the wound edge [see Song et al Proc Natl Acad Sci USA 99, 13577-13582(2002)]. This creates a steady DC EF which persists until the epithelium re-seals.
The TCPD and the EF can be manipulated pharmacologically.
Increasing the EF with PGE2 or aminophylline enhanced wound healing.
Reducing the EF with ouabain inhibited wound healing.
Figure 4: The axis of cell division is oriented by a physiological electrical field.
a) In culture corneal epithelial cells divide with an axis of division that is oriented randomly.
b) Cultured in a physiological EF the cleavage plane (phase bright) forms perpendicular to the EF vector [see Zhao et al (1999) Proc. Natl. Acad. Sci.USA. 96, 4942-4946].
c) Near a corneal wound edge (at left margin) the axis of cell division also is oriented. The naturally occurring EF induced at the wound controls this. The vector of this EF runs horizontally with the cathode at the wound (left margin). Mitotic spindles are stained green with a fluorescent antibody to a-tubulin and the actin cytoskeleton is stained with rhodamine phalloidin (red). The spindle axis is outlined with yellow arrows. In corneas treated with ouabain, which inhibits the EF, oriented cell division is prevented [Song et al Proc Natl Acad Sci USA 99, 13577-13582(2002)].
d) By contrast to c), in corneas treated with aminophylline to enhance the natural wound-induced EF, the axis of cell division lies much more along the EF vector horizontally.