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Dr Jim Ralphs  -  PhD


Cellular control of extracellular matrix secretion and organisation in connective   tissues
Fluorescent imaging.

Fig 1 Gap junctions (red) on cell processes linking tendon cells in vivo (green).

Actin stress fibres

Fig 2 Actin stress fibres (green) running longitudinally in tendon cells

The function of connective tissues depends on the organisation of their collagen fibres, arranged in parallel fibres, in parallel sheets (lamellae; annulus fibrosus, cornea, bone), or with more complex or random, orientation (cartilage, dermis, loose connective tissue).

My research is on roles of the cytoskeleton and cell-cell interactions in control of secretion and orientation of the extracellular matrix in fibrous connective tissues.

In tendons, longitudinal rows of fibroblasts are embedded between parallel collagen fibre bundles. Along a row, cells are connected by gap junctions made of connexins 43 and 32, and by adherens junctions. The adherens junctions link short lengths of actin stress fibres end to end from cell to cell along the cell row.

Embryonic Annulus

Fig 3 Oriented cells of the embryonic annulus fibrosus

Actin stress fibres

Fig 4 Actin stress fibres controlling cell and matrix orientation in embryonic annulus

Gap junctions modulate cell response to load: antisense downregulation of of connexin 43 enhances, and connexin 32 depresses, matrix secretion. Adherens junction and stress fibre components are upregulated by load suggesting that cells may bind together more strongly; cell-cell junctions involving cadherins could also be involved in mechanosensation and thus initiation of load responses.

The annulus fibrosus consists of concentric collagenous lamellae linking vertebral bodies in the spine. In successive lamellae collagen fibres are tilted, forming a radial ply structure. The cornea has a similar organisation, although with thinner, more numerous lamellae In the annulus, oriented matrix deposition is preceded by orientation of fibroblasts into parallel sheets, with the long axis of the fibroblasts in each layer showing the same alternating angle as the collagen in the lamellae. The orientation process is associated with cadherin based cell-cell interactions, some gap junction expression and the development of prominent longitudinal actin stress fibres in the fibroblasts. In new studies, we are investigating possible associations between the collagen secretory pathway and prominent actin fibres in corneaL stromal fibroblasts, and early stage interactions between connective tissue cells.

Current Sources of Funding

Medlink/Health Technology Devices Programme:

Mesenchymal progenitor cells in allogeneic orthopaedic tissue engineering
(with Prof CW Archer and Smith and Nephew plc, York)
£509,566
2003-2006

BBSRC:

Developmental dynamics, cell-cell and cell-matrix interactions in the avian corneal stroma
(with Dr AJ Quantock and Prof B Caterson)
£310,000
2004-2007

BBSRC:

Progression of animal cell interactions and intra-cellular processes triggered on contact in ultrasound standing wave traps
(with Prof WT Coakley and Prof CW Archer )
£407,000, 2005-8.

Affiliated Staff

Dr Anthony Hayes
Dr Kirsty Richardson

Postgraduate Research Students

Miss Ewa Czekanska