Abstract
The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.
Matrix Metalloproteinases Instrumental in Wound Healing
Wound healing, the complex process of regenerating dermal and epidermal tissue after skin injury, involves inflammatory, proliferative, and remodeling phases. Members of the MMP gene family are essential to the tissue degradation involved in wound healing; however, the specific function of individual matrix metalloproteinases (MMPs) in wounded tissues requires further study. Using mice deficient in MMP-9, MMP-13, or both, Hattori et al (Am J Pathol 2009, 175:533–546) noted a significant delay in wound closure and histological re-epithelialization compared with wild-type mice. Both MMP-13 and MMP-9 played key roles in keratinocyte migration, and MMP-13 contributed to angiogenesis and contraction in wound healing as well. Topical wound treatment with MMP-9, MMP-13, or basic fibroblast growth factor, which stimulates MMP production, increased the rate of re-epithelialization in these mice, providing a possible therapeutic strategy for treating delayed wound healing.
Endothelial-Mesenchymal Transition in Liver
Idiopathic portal hypertension is a form of high blood pressure in the liver that often results from fibrotic blockage of the peripheral portal veins. Vascular endothelial cells that undergo endothelial-mesenchymal transition to acquire matrix-producing myofibroblastic features may contribute to the fibrosis that causes this blockage. Kitao et al (Am J Pathol 2009, 175:616–626) demonstrate that the cytokine transforming growth factor (TGF)-β1 can induce conversion of human dermal microvascular endothelial cells to collagen-producing cells and that bone morphogenic protein-7, a member of the TGF-β superfamily, can preserve the endothelial phenotype. The serum of patients with idiopathic portal hypertension have elevated levels of TGF-β1, but no difference in levels of bone morphogenic protein-7, as compared with healthy controls. TGF-β1 and bone morphogenic protein-7 may therefore provide a potential target and agent, respectively, for treating idiopathic portal hypertension.
FUT-175 Complements Experimental Autoimmune Encephalomyelitis
Multiple sclerosis is caused in part by autoreactive T cells that attack the myelin sheaths of nerves in the central nervous system. Complement produced during early antigen-presenting cell/T-cell interactions may enhance effector T cell responses. Li et al (Am J Pathol 2009, 175:661–667) therefore examined the effects of FUT-175, a clinical pharmaceutical that prevents complement C3/C5 activation, on the development of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. They found that FUT-175 prevented production of C3a/C5a (activation products) by antigen-presenting cell/T-cell complexes and inhibited specific T cell responses with little nonspecific cytotoxicity. FUT-175 treatment delayed experimental autoimmune encephalomyelitis disease onset, lowered clinical scores, decreased central nervous system inflammation, and reduced demyelination by affecting specific cellular responses rather than autoantibodies. Thus, FUT-175 may be a novel candidate to treat T-cell-mediated diseases such as multiple sclerosis.
Omega-3 Fatty Acids Slow Retinal Degeneration
Age-related macular degeneration (AMD), a leading cause of blindness among the elderly, involves the destruction and deterioration of photoreceptors and the retinal pigment epithelium. Omega-3 polyunsaturated fatty acids have preventative functions in a number of diseases and have been suggested as a risk management option for AMD. Tuo et al (Am J Pathol 2009, 175:799–807) examined the role of omega-3 fatty acids in a mouse model of AMD. A diet high in omega-3 fatty acids slowed the progression of retinal lesions and decreased production of pro-inflammatory derivatives in these mice. Omega-3 fatty acids may therefore provide a viable risk reduction strategy for AMD.
Phox2B+ Neural Progenitors Drive Neuroblastoma Initiation and Progression
Approximately 22% of neuroblastomas, which commonly contain undifferentiated or poorly differentiated neuroblasts, express amplified levels of the oncogene MYCN. To identify the cell types that drive neuroblastoma development and clarify the cellular functions and targets of MYCN in this process, Alam et al (Am J Pathol 2009, 175:856–866) examined TH-MYCN transgenic mice, an animal model of human neuroblastoma. MYCN enhanced proliferation and arrested differentiation of Phox2B+ neuronal progenitors, and both hyperplastic lesions and primary tumors were composed predominantly of these cells. Nestin+ cells, which may serve as precursors of Phox2B+ neuronal progenitors, were also increased in both hyperplastic lesions and primary neuroblastomas. These data indicate that the expansion of Phox2B+ neuronal progenitors may be pathogenic in the development of neuroblastoma and that MYCN may contribute to this process by driving the proliferation of the Phox2B+ neuronal progenitor cell population.
Platelet Endothelial Cell Adhesion Molecule-1 in Angiogenesis
Platelet endothelial cell adhesion molecule-1 (PECAM-1), an adhesion molecule expressed on endothelial cells, leukocytes, and platelets, promotes endothelial cell motility, and anti-PECAM-1 antibodies impair blood vessel formation. Cao et al (Am J Pathol 2009, 175:903–915) further examined the role of PECAM-1 in blood vessel formation in PECAM-1-deficient mice. Vascularization of Matrigel implants and tumor angiogenesis were both inhibited due to loss of endothelial, but not leukocyte, PECAM-1 expression. Filopodia formation was also inhibited in PECAM-1-deficient endothelial cells, which suggests that PECAM-1 may stimulate filopodia formation resulting in endothelial cell motility. As PECAM-1 is not required for embryonic vascular development, PECAM-1 may therefore provide a tumor-specific, low-toxicity target to inhibit angiogenesis in cancer patients.