Altered tissue repair in hevin‐null mice: Inhibition of fibroblast migration by a matricellular SPARC homolog

Abstract

Matricellular proteins such as hevin, secreted protein acidic and rich in cysteine, and thrombospondin-2 play an important role during tissue repair through their influence on fundamental cellular activities such as adhesion, migration, proliferation, and extracellular matrix synthesis/reorganization. We have investigated the role played by hevin during excisional and incisional cutaneous wound repair in hevin-null mice. Hevin-null animals both close and heal their skin wounds faster than wild-type animals, as evidenced by enhanced macrophage infiltration of wound beds at early time points, the earlier appearance of mature extracellular matrix, and the overall higher maturity score. In addition, fibrovascular invasion of polyvinyl alcohol sponges was more robust in hevin-null mice, a result indicating that differences in cell migration might underlie the observed alterations in wound repair. Experiments in vitro showed that hevin induced the deadhesion and inhibited the migration of primary dermal fibroblasts in a Rac-1-dependent manner. These findings indicate that the differences in wound repair between hevin-null and wild-type animals can be attributed in part to the deadhesive function of hevin and reduced cell migration within dermal wound beds in which this protein is expressed.As the largest organ in the body, the skin has diverse and critical functions that include protection of an organism from its environment, thermoregulation, and immune surveillance.

SPARCL1, a Novel Prognostic Predictive Factor for GI Malignancies: a Meta-Analysis

“…Hurley et al and his colleagues demonstrate that SPARCL1 in the ECM limited cellular ability to form focal adhesions on the collagen matrix and thereby attenuated corresponding biophysical dynamics of the cytoskeletal framework, which have been shown to potentiate migration [29]. SPARCL1 mitigates mediators of focal adhesion activation such as RHO family members also has been proved [30, 31]. Naschberger et al reported that the heterogeneity of tumor microenvironments is regulated by SPARCL1, which promotes cell quiescence and vessel homeostasis and contributes to a favorable prognosis in colorectal carcinoma [32].…”

Unique Transcriptome, Pathways, and Networks in the Human Endometrial Fibroblast Response to Progesterone in Endometriosis

“…It is expressed in many tissues and is associated with collagen fibrils [34]. SPARCL1 expression is downregulated in several tumors and negatively regulates cell cycle progression, cell proliferation, and migration [35,36]. In the present study, SPARCL1 expression was highly upregulated in response to P 4 in hESF nonendo at 6 and 48 h and 14 days, suggesting a major role for the protein product in the P 4 response of hESF, perhaps participating in or directly inhibiting cell cycle progression and enabling differentiation in response to P 4 .…”

Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome

“…Because prostasphere culture requires attachment to an extracellular matrix, and previous studies have shown that Sparcl1 is antiadhesive (10,20), we tested the hypothesis that SPARCL1 may prevent prostate cellular adhesion to various extracellular matrices. SPARCL1 delayed or abrogated adhesion of multiple prostate cancer cell lines and primary benign prostate cells to type I collagen, a key element within the extracellular matrix, and one to which SPARCL1 has been shown to bind (Fig.…”

“…Sparcl1 markedly inhibited prostate epithelial bud elongation; however, comparable expression of proliferation markers in Sparcl1-treated prostate organ cultures suggests that Sparcl1 does not regulate proliferation in the prostate. Because Sparcl1's role in proliferation is varied, we further defined SPARCL1-mediated regulation of prostatic epithelial cell growth (10,18,19). We examined cellular proliferation and death in SPARCL1-treated prostate cells and demonstrated that SPARCL1 did not restrict the growth of multiple prostate cancer cell lines (Fig.…”

“…Among these genes, SPARCL1 (SPARC-like 1/Hevin/SC1), a member of the secreted protein, acidic and rich in cysteine (SPARC) family of matricellular proteins, was down-regulated specifically during embryonic periods of androgen-induced epithelial invasion (6) and in aggressive prostate cancers (6,9). Sparcl1 has been shown to mitigate adhesion and to inhibit both fibroblast migration and wound healing (10). The mechanisms through which Sparcl1 regulates cellular adhesion and migration are not well understood; however, Sparcl1 has been shown to bind type I collagen, a component of the extracellular matrix that potentiates tumor cell migration and invasion (11)(12)(13).…”