Scar formation is a problem of great clinical importance. Adult skin wounds heal with scar while fetal skin has the capacity to heal without scar. In fetal rat skin, the transition from scarless fetal-type repair to adult-type repair with scar occurs between days 16.5 (E16) and 18.5 (E18) of gestation. The underlying mechanism causing this transition is not known. However, TGF-beta1 has been implicated as a potential regulator of this transition to adult-type repair. We have identified fibromodulin (FM), a member of the small leucine-rich proteoglycan (SLRP) family and modulator of TGF-beta1 activity, as a potentially anti-fibrotic ligand. Unlike other SLRPs, FM expression inversely correlates with scarring in both fetal and adult rat models of wound repair. Using a fetal rat model, we are the first group to demonstrate that fibromodulin is a biologically significant mediator of scarless repair and that administration of exogenous fibromodulin inhibits scar formation in normally scarring fetal wounds and ameliorates scar in adult wounds. Immunohistochemistry and RT-PCR analysis suggest that fibromodulin may exert its anti-fibrotic effect by decreasing TGF-beta1 bioavailability. These preliminary results demonstrate the feasibility of manipulating adult wounds to achieve scarless, fetal-like repair by altering levels of fibromodulin. Therefore, fibromodulin may have great therapeutic potential to improve wound healing. We hypothesize that FM is essential to fetal scarless wound repair and that fetal FM-null mice will lose their capacity for scarless repair. Furthermore, the loss of FM modulation may increase scarring in late gestation fetal wounds, while the exogenous administration of FM may reverse this process. If proven true, we further hypothesize that TGF-beta and collagen binding properties of FM protein are essential for scarless repair. In this proposal, our first aim is to investigate the role of FM in wound healing using a FM-null mouse model. The first part of aim 1 will examine the histologic phenotypes and functional characteristics (e. g., tensile strength) of the FM-null wounds relative to wildtype controls. The second part of aim 1 will examine gene expression patterns of fetal and adult wound repair in FM-null mice with specific emphasis on possible redundant functions and compensation mechanisms among the SLRPs.
Our second aim i s to determine the functional properties of FM in scar reduction. Various recombinant FM proteins, which differ in their TGF-beta and collagen binding properties, will be constructed and tested for in vitro TGF-beta1 and/ or collagen binding properties. The various recombinant FM proteins will then be applied topically to wildtype fetal and adult mice to determine their respective efficacies in scar reduction as well as to FM-null fetal and adult mice to determine their respective potentials in ameliorating the cutaneous effects of FM deficiency. This will not only confirm that FM is critical for scarless repair, but also establish that the wound healing impairment in FM-null fetal mice is not the result of any systemic or developmental alterations induced by FM deficiency.
This aim i s labor-intensive and will extend into a future RO1 grant proposal. If no differences are discerned between FM-null and wildtype mice, then double deficient mice, such as lumican and FM knock-outs may be substituted for the remainder of the study. Our long-term goal is to effectively reduce dermal scarring and induce dermal regeneration in adult tissues by understanding the anti-fibrotic mechanism of fibromodulin and other TGF-beta modulators.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-GMA-1 (01))
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Lumelsky, Nadya L
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University of Southern California
Schools of Medicine
Los Angeles
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Zheng, Zhong; Nguyen, Calvin; Zhang, Xinli et al. (2011) Delayed wound closure in fibromodulin-deficient mice is associated with increased TGF-?3 signaling. J Invest Dermatol 131:769-78
Khorasani, Hooman; Zheng, Zhong; Nguyen, Calvin et al. (2011) A quantitative approach to scar analysis. Am J Pathol 178:621-8