Cay Kielty, BSc PhD FMedSci
The extracellular matrix-rich cellular microenvironment provides support for cells and stores growth factors. My group studies how cells assemble matrix, and how it regulates cell fate.
The scientific story
How cells assemble matrix: My focus is fibrillin microfibrils which are essential structural components of elastic fibres. The importance of microfibrils and elastic fibres is underlined by severe disorders such as Marfan syndrome caused by mutations in fibrillin-1, and cutis laxa caused by mutations in elastin and some fibulins. We study how cells assemble microfibrils and elastic fibres, and how they store latent TGFbeta and control its bioavailability. Current interests are to define how cells direct the assembly of individual microfibrils and tissue microfibril arrays, and how certain ADAMTS(L) molecules influence this process.
Fibrillin microfibril arrays deposited by human pigmented retinal epithelial cells (A. Godwin, Kielty lab)
How matrix regulates cell fate: Using human mesenchymal stromal cells (MSCs), we are studying how the matrix-rich microenvironment regulates both their differentiation potential and their inflammatory secretome. Using 3D cultures, we have shown that fibronectin activation of alpha5beta1 integrin enhances PDGF receptor signals; blocking this receptor crosstalk induces a ‘mesendodermal’ state and in vivo neovascularisation potential. We have used quantitative proteomics to define the cell-matrix interface of mesenchymal progenitor cells (including MSCs), which has identified many new cell surface markers of multipotent cells. Our current focus is to define signalling crosstalk regulated by matrix/integrin and cytokine receptors.
siRNA of novel MSC markers changes cell shape and focal adhesions (Holley R et al, 2014)
Translational activities: I am a partner on the UK Regenerative Medicine Platform (UKRMP) Hub ‘Engineering and exploiting the stem cell niche’. We are defining microenvironmental (niche) matrix molecules that influence endothelial differentiation, and how Notch and matrix/integrin signals intersect. I also have UKRMP support for a recombinant matrix platform to underpin niche bioengineering (with Hub colleagues). I am Director of our new £4.4m EPSRC & MRC Centre for Doctoral Training in Regenerative Medicine (http://www.regenmedcdt.manchester.ac.uk/), and co- lead a Network for Regenerative Medicine of the University of Manchester Research Institute.
Recent key publications
Baldwin, A.K., Cain, S.A., Lennon, R., Godwin, A., Merry, C.L.R. and Kielty, C.M. (2014). Epithelial-mesenchymal status influences how cells deposit fibrillin microfibrils. J Cell Sci. 127, 158–171. PMC
Ball, S.G., Worthington, J.J., Canfield, A.E., Merry, C.L.R. and Kielty, C.M. (2014). Mesenchymal stromal cells: inhibiting PDGF receptors or depleting fibronectin induces mesodermal progenitors with endothelial potential. Stem Cells. 32, 694-705. PubMed
Banka, S., Cain, S.A., Carim, S., Daly, S.B., Urquhart, J.E., Erdem, G., Harris, J., Bottomley, M., Donnai, D., Kerr, B., Kingston, H., Superti-Furga, A., Unger, S., Ennis, H., Worthington, J., Herrick, A.L., Merry, C.L., Yue, W.W., Kielty, C.M. and Newman, W.G. (2014). Leri's pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis. Ann Rheum Dis. in press.
Cain, S.A., McGovern, A., Baldwin, A.K., Baldock, C. Kielty, C.M. (2012). Fibrillin-1 mutations causing Weill-Marchesani syndrome and Acromicric and Geleophysic Dysplasias disrupt HS interactions. PLoS One, 7:e48634. doi: 10.1371/journal.pone.0048634. PubMed