Cell–matrix interactions governing skin repair: matricellular proteins as diverse modulators of cell function

Figures & data

Figure 1 Schematic representation of the phases and timeline of the skin healing process in mice. Four overlapping phases shown schematically result in wound closure. The cellular processes at each stage are described in detail in “Normal skin healing process in mice”.

Table 1 Influence of genetic deletion of matricellular proteins on skin healing in mice

Matricellular protein	Influence on excisional skin healing	Reference
SPARC	A significant delay in wound closure and granulation tissue formation and extracellular matrix protein production in small (6 mm) wounds in SPARC-null mice compared with wild-type mice	28
	A significant increase in the rate of wound closure in SPARC-null compared with wild- type mice at 4 and 7 days postwounding 5 mm excisional wounds	82
TSPI	Delayed wound closure (by 6 days) and impaired granulation tissue in transgenic mice overexpressing TSPI in the skin compared with wild-type when 6 mm excisional wounds were created	122
	TSPI-null and TSPI/TSP2-null mice demonstrated reduced vascularization and impaired inflammatory phase compared with wild-type mice, while TSP2-null mice were similar to wild-type mice	62
TSP2	At 14 days postwounding, the vascular density in wild-type, TSPI-null, and TSPI/TSP2 double-null mice was the same, but TSP2-null wounds remained highly vascularized	123
	At I4 days postwounding 6 mm excisional wounds, TSP2-null mice showed greater neovascularization and MMP-2 compared with wild-type mice	124
	The levels of MMP-2, MMP-9, TIMP-I, TIMP-2, and soluble vascular endothelial growth factor were increased in 6 mm excisional wounds in TSP2-null mice compared with wild-type mice	125
Tenascin-X	No differences between tenascin-X-null and wild-type mice were noted in the rate of wound closure or in expression of fibrillar collagen during excisional wound healing (8 mm)	80
Tenascin-C	Healing of 6 mm excisional wounds was not significantly altered in tenascin-C-deficient mice compared with wild-type mice	79
Hevin	Closure and maturity of cutaneous excisional 5 mm wounds were accelerated in hevin-null compared with wild-type mice	61
CCN2	Fibroblast-specific deletion of CCN2 does not affect cutaneous wound healing of 4 mm wounds, evident by no difference in collagen content, myofibroblast differentiation, and proliferation in CCN2-null and wild-type mice	43
Periostin	Excisional wound (3 mm) closure was delayed in periostin-null mice coupled with a delay in re-epithelialization and reduced proliferation of keratinocytes	101
	During excisional wound (6 mm) healing, periostin-null mice had a reduced level of myofibroblast differentiation compared with wild-type mice. The attenuated myofibroblast differentiation in periostin-null mice was rescued by addition of recombinant periostin-containing scaffolds	42
	Incisional wounding re-established embryonic pattern of periostin deposition in adult skin	33
Osteopontin	Osteopontin-mutant mice resulted in disorganization of matrix and an alteration of collagen fibrillogenesis, leading to smaller diameter collagen fibrils after incisional wound healing	73
Galectin-7	Galectin-7-deficient mice displayed a reduced re-epithelialization potential compared with wild-type littermates during wound healing of a superficial scratch along the length of the tail, and this effect was attributed to a defect in cell migration	126

Abbreviations: SPARC, secreted protein acidic and rich in cysteine; TSP, thrombospondin; MMP, matrix metalloproteinase; TIMP, tissue inhibitors of metalloproteinase.

Figure 2 α-Smooth muscle actin expression is significantly reduced in periostin knockout mice compared with wild-types at 7 days postwounding. Red arrows mark the wound edge.

Abbreviations: E, epidermis; GT, granulation tissue.

Table 2 Known expression profiles of matricellular proteins in human wounds

Matricellular protein	Expression in normal human skin healing	Reference
SPARC	Unknown	N/A
Thrombospondin-1	Thrombospondin-1 expression is upregulated following injury and peaks during early wound healing from days I to 3 where expression is most prominent in the tissue adjacent to the epidermal layer. A steep decrease in thrombospondin-I expression occurs from days 5 to 9 as the wound heals.	104
	At day 7, thrombospondin-I is localized in the matrix, and at day 9 thrombospondin-I expression decreases and becomes more specific for the larger vascular structures
Thrombospondin-2	Unknown	N/A
Tenascin	Two days postwounding, tenascin is visible around the fibroblastic cells of the wound area. Beginning at 3 to 5 days postwounding, tenascin is observed as a network-like structure. As wounds age, tenascin staining intensity in the granulation tissue decreases but remains present at 1.5 months.	36
	Tenascin expression shows upregulation in the papillary dermis adjacent to hyperproliferative epidermis but is not found underneath the leading edge of the migrating keratinocyte sheet. Following re-epithelialization, tenascin is expressed in the wound bed	106
Tenascin-C	During the early phase of wound healing in situ, mRNA hybridization identified migrating basal keratinocytes as the main source of tenascin-C, with maximal expression observed at 7 days, coinciding with wound closure. Tenascin-C protein is observed beneath the migrating keratinocytes at 2 and 4 days. At 7 days, tenascin-C is observed in the dermis, with peak expression at I4 days	107
	Tenascin-C expression increases in the dermis during wound healing, where it colocalizes with fibrillin-2	127
Hevin	Unknown	N/A
CCN proteins	In the epidermis, CCN3 mRNA levels are downregulated during re-epithelialization (2 weeks postwounding) and return to baseline levels at 4 weeks. Protein expression is downregulated at 2 and 3 weeks and returns to normal levels by 4 weeks. CCN5 mRNA and protein levels are downregulated in the epidermis during healing up to 4 weeks postwounding
	In the dermis, CCNI mRNA levels are upregulated at I week postwounding and return to baseline by week 2. CCN2, CCN3, and CCN5 mRNA levels are downregulated at 24 hours, 24 hours, and 3 days, respectively. CCN2 returns to baseline levels at 3 days, with CCN3 and CCN5 returning to baseline levels at 4 weeks postwounding. CCN2 protein is observed at I week postwounding, associated with extracellular matrix proteins. CCN3 and CCN5 protein expression is strongly downregulated in the wounded dermis	108
Periostin	Unknown	N/A
Osteopontin	Unknown	N/A

Abbreviations: SPARC, secreted protein acidic and rich in cysteine; N/A, not applicable; mRNA, messenger ribonucleic acid.

Figure 3 Periostin expression is reduced in human nonhealing skin wounds and correlates with a reduction in α-SMA expression and collagen content. Tissue was isolated at elective amputation from an 83-year-old female with type 2 diabetes.

Abbreviation: SMA, smooth muscle actin.

Figure 4 Temporal expression profiles of matricellular proteins during skin healing.

Abbreviations: TSP, thrombospondin; TN, tenascin; SPARC, secreted protein acidic and rich in cysteine.