TY  - JOUR
AB  - Extracellular matrices (ECMs) in the intervertebral disc (IVD), lung and artery are thought to undergo age-dependant accumulation of damage by chronic exposure to mechanisms such as reactive oxygen species, proteases and glycation. It is unknown whether this damage accumulation is species-dependant (via differing lifespans and hence cumulative exposures) or whether it can influence the progression of age-related diseases such as atherosclerosis. Peptide location fingerprinting (PLF) is a new proteomic analysis method, capable of the non-targeted identification of structure-associated changes within proteins. Here we applied PLF to publicly available ageing human IVD (outer annulus fibrosus), ageing mouse lung and human arterial atherosclerosis datasets and bioinformatically identified novel target proteins alongside common age-associated differences within protein structures which were conserved between three ECM-rich organs, two species, three IVD tissue regions, sexes and in an age-related disease. We identify peptide yield differences across protein structures which coincide with biological regions, potentially reflecting the functional consequences of ageing or atherosclerosis for macromolecular assemblies (collagen VI), enzyme/inhibitor activity (alpha-2 macroglobulin), activation states (complement C3) and interaction states (laminins, perlecan, fibronectin, filamin-A, collagen XIV and apolipoprotein-B). Furthermore, we show that alpha-2 macroglobulin and collagen XIV exhibit possible shared structural consequences in IVD ageing and arterial atherosclerosis, providing novel links between an age-related disease and intrinsic ageing. Crucially, we also demonstrate that fibronectin, laminin beta chains and filamin-A all exhibit conserved age-associated structural differences between mouse lung and human IVD, providing evidence that ECM, and their associating proteins, may be subjected to potentially similar mechanisms or consequences of ageing across both species, irrespective of differences in lifespan and tissue function.
AU  - Eckersley, A.*
AU  - Ozols, M.*
AU  - Chen, P.*
AU  - Tam, V.*
AU  - Ward, L.J.*
AU  - Hoyland, J.A.*
AU  - Trafford, A.*
AU  - Yuan, X.M.*
AU  - Schiller, H. B.
AU  - Chan, D.*
AU  - Sherratt, M.J.*
C1  - 65482
C2  - 52315
SP  - 108-137
TI  - Peptide location fingerprinting identifies species- and tissue-conserved structural remodelling of proteins as a consequence of ageing and disease.
JO  - Matrix biol.
VL  - 114
PY  - 2022
SN  - 0945-053X
ER  - 

TY  - JOUR
AB  - Deep and voluminous skin wounds are repaired with scars, by mobilization of fibroblasts and extracellular matrix from fascia, deep below the skin. The molecular trigger of this novel repair mechanism is incompletely understood. Here we reveal that the gap junction alpha-1 protein (Connexin43, Cx43) is the key to patch repair of deep wounds. By combining full-thickness wound models with fibroblast lineage specific transgenic lines, we show Cx43 expression is substantially upregulated in specialized fibroblasts of the fascia deep beneath the skin that are responsible for scar formation. Using live imaging of fascia fibroblasts and fate tracing of the fascia extracellular matrix we show that Cx43 inhibition disrupts calcium oscillations in cultured fibroblasts and that this inhibits collective migration of fascia EPFs necessary to mobilize fascia matrix into open wounds. Cell-cell communication through Cx43 thus mediates matrix movement and scar formation, and is necessary for patch repair of voluminous wounds. These mechanistic findings have broad clinical implications toward treating fibrosis, aggravated scarring and impaired wound healing.
AU  - Wan, L.
AU  - Jiang, D.
AU  - Correa-Gallegos, D.
AU  - Ramesh, P.
AU  - Zhao, J.
AU  - Ye, H.
AU  - Zhu, S.
AU  - Wannemacher, J.
AU  - Volz, T.*
AU  - Rinkevich, Y.
C1  - 61202
C2  - 50086
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
SP  - 58-71
TI  - Connexin43 gap junction drives fascia mobilization and repair of deep skin wounds.
JO  - Matrix biol.
VL  - 97
PB  - Elsevier
PY  - 2021
SN  - 0945-053X
ER  -