SPARC-thrombospondin-2-double-null Mice Exhibit Enhanced Cutaneous Wound Healing and Increased Fibrovascular Invasion of Subcutaneous Polyvinyl Alcohol Sponges

Abstract

S U M M A R YSecreted protein acidic and rich in cysteine (SPARC) and thrombospondin-2 (TSP-2) are structurally unrelated matricellular proteins that have important roles in cellextracellular matrix (ECM) interactions and tissue repair. SPARC-null mice exhibit accelerated wound closure, and TSP-2-null mice show an overall enhancement in wound healing. To assess potential compensation of one protein for the other, we examined cutaneous wound healing and fibrovascular invasion of subcutaneous sponges in SPARC-TSP-2 (ST) double-null and wild-type (WT) mice. Epidermal closure of cutaneous wounds was found to occur significantly faster in ST-double-null mice, compared with WT animals: histological analysis of dermal wound repair revealed significantly more mature phases of healing at 1, 4, 7, 10, and 14 days after wounding, and electron microscopy showed disrupted ECM at 14 days in these mice. ST-double-null dermal fibroblasts displayed accelerated migration, relative to WT fibroblasts, in a wounding assay in vitro, as well as enhanced contraction of native collagen gels. Zymography indicated that fibroblasts from ST-double-null mice also produced higher levels of matrix metalloproteinase (MMP)-2. These data are consistent with the increased fibrovascular invasion of subcutaneous sponge implants seen in the double-null mice. The generally accelerated wound healing of ST-double-null mice reflects that described for the single-null animals. Importantly, the absence of both proteins results in elevated MMP-2 levels. SPARC and TSP-2 therefore perform similar functions in the regulation of cutaneous wound healing, but fine-tuning with respect to ECM production and remodeling could account for the enhanced response seen in ST-double-null mice.

Deficiency of SPARC suppresses intestinal tumorigenesis in APCMin/+ mice

“…[21][22][23] This is also consistent with recent studies showing that Sparc (and Sparc thrombospondin-2 double mutants) showed increased wound healing as a consequence of increased dermal fibroblast migration. 24 Taken together our data highlight a novel role for Sparc, and possibly other Sparc family members, in adenoma formation. We have shown that Sparc is upregulated at the early stages of intestinal tumorigenesis and is required for efficient tumorigenesis.…”

SPARC is expressed by macroglia and microglia in the developing and mature nervous system

“…Although tenascin-C deficiency does not cause a reduction in neural stem cells or their progeny in vivo (Kazanis et al, 2007), this may be another example of functional redundancy between matricellular proteins (Sage, 2001;Barker et al, 2005b;Puolakkainen et al, 2005).…”

Matricellular proteins and biomaterials

“…(Table 2) (Barker et al, 2005; Bornstein et al, 2004; Kyriakides and Bornstein, 2003; Kyriakides and Maclauchlan, 2009; Kyriakides et al, 1999; Puolakkainen et al, 2003, 2005). Specifically, mice that lack matricellular proteins display decreased capsule thickness or increased vascularity, both interesting phenotypes from the perspective of designing materials to minimize the FBR (Barker et al, 2005; Bornstein et al, 2004; Kyriakides and Bornstein, 2003; Kyriakides and Maclauchlan, 2009; Kyriakides et al, 1999; Puolakkainen et al, 2003, 2005). Moreover, reduction of TSP-1 or TSP-2 led to altered structural properties of the collagenous capsule as well as increased vascularity within the capsule (Kyriakides and Bornstein, 2003; Kyriakides and Maclauchlan, 2009; Kyriakides et al, 2001; Kyriakides et al, 1999; Reinecke et al, 2013).…”

“…Even though these effects were not due to released SPARC peptides, the approach highlights the utility of incorporating features of proteins like SPARC to tune the degradability of engineered scaffolds. An additional consideration for future investigation is that SPARC-TSP-2-double-null mice exhibit reduced FBR and improved wound healing (when compared to either single KO or WT mice) (Puolakkainen et al, 2005). Therefore, it could be beneficial to manipulate the levels of both proteins in wound healing and the FBR.…”