Graduate Student, Tufts University
Craniofacial birth defects, such as cleft palate, fetal alcohol syndrome, and microcephaly occur in more than one in every six hundred births. Infants with these developmental defects are challenged with severe physical, mental, and social difficulties. Despite the prevalence and seriousness of craniofacial abnormalities, there are limited medical treatments available to the people affected by these birth defects. To promote the advancement of treatment options that correct craniofacial abnormalities in humans, we must first understand how craniofacial morphology is established and maintained in vertebrate model organisms. For the past decade, research has primarily focused on discovering the causes of craniofacial abnormalities in vertebrates. Our alternative approach takes advantage of results obtained from previous studies to investigate the possibility of reversing abnormal craniofacial morphology. We know that craniofacial defects can be resolved because of a study carried out by our collaborators in the Levin lab at Tufts University in 2012; they demonstrated that Xenopus laevis tadpoles can normalize abnormal craniofacial morphology prior to metamorphosis. We have established that pre-metamorphic X. laevis tadpoles can self-correct some, but not all, malformed craniofacial features resulting from a range of mechanical, genetic, or chemical perturbations. Therefore, we now aim to characterize this improvement of abnormal craniofacial morphology at the tissue level and to elucidate the underlying mechanisms that regulate this self-correction in Xenopus tadpoles.
Abstract: The ratio of matrix metalloproteinases (MMPs) to the tissue inhibitors of metalloproteinases (TIMPs) in wounded tissues strictly control the protease activity of MMPs, and therefore regulate the progress of wound closure, tissue regeneration and scar formation. Some amphibians (i.e. axolotl/newt) demonstrate complete regeneration of missing or wounded digits and even limbs; MMPs play a critical role during amphibian regeneration. Conversely, mammalian wound healing re-establishes tissue integrity, but at the expense of scar tissue formation. The differences between amphibian regeneration and mammalian wound healing can be attributed to the greater ratio of MMPs to TIMPs in amphibian tissue. Previous studies have demonstrated the ability of MMP1 to effectively promote skeletal muscle regeneration by favoring extracellular matrix (ECM) remodeling to enhance cell proliferation and migration. In this study, MMP1 was administered to the digits amputated at the mid-second phalanx of adult mice to observe its effect on digit regeneration. Results indicated that the regeneration of soft tissue and the rate of wound closure were significantly improved by MMP1 administration, but the elongation of the skeletal tissue was insignificantly affected. During digit regeneration, more mutipotent progenitor cells, capillary vasculature and neuromuscular-related tissues were observed in MMP1 treated tissues; moreover, there was less fibrotic tissue formed in treated digits. In summary, MMP1 was found to be effective in promoting wound healing in amputated digits of adult mice.
Pub.: 26 Mar '13, Pinned: 08 Jun '17
Abstract: In contrast to the limited regenerative ability found in human wound healing, which often results in unsatisfying and deficient scar formation, urodele amphibians, with the Mexican axolotl as a prime example, expose an extraordinary regenerative capacity. This regeneration leads to a perfect restoration of tissue architecture, function, and aesthetics with the axolotl being actually able to reclaim complete limbs. Evolutionary considerations suggest that regeneration might be a biologic principle which also underlies human wound healing. Experimental findings, such as comparative studies on transforming growth factor-β and fibroblast growth factor accentuate this assumption. Regeneration, as recent data indicate, might be a question of adaptive immunity. The loss of regenerative potency correlates with the decrease of regeneration in most species, whereas the Mexican axolotl lacks adaptive immunity throughout its life. The characterization of molecular pathways as a prerequisite for any control of regenerative processes sets an increasing indication toward the transfer into human beings. Some regenerative techniques, eg, recombinant transforming growth factor-β have already emerged. Molecular findings suggest that there is an intrinsic regenerative capacity in humans which might be initiated under appropriate circumstances. The Mexican axolotl is liable to diverse surgical and molecular approaches. Though well-known among developmental biologists, its exploitation for experimental Plastic Surgery still has to be established. We therefore intend to give an introduction to amphibian regeneration and the common evolutionary roots of regeneration and human wound healing, as we believe that Plastic Surgery takes a unique advantage of performing basic research on amphibian regeneration.
Pub.: 16 Oct '10, Pinned: 08 Jun '17
Abstract: Regeneration and tumorigenesis share common molecular pathways, nevertheless the outcome of regeneration is life, whereas tumorigenesis leads to death. Although the process of regeneration is strictly controlled, malignant transformation is unrestrained. In this review, we discuss the involvement of TP53, the major tumor-suppressor gene, in the regeneration process. We point to the role of p53 as coordinator assuring that regeneration will not shift to carcinogenesis. The fluctuation in p53 activity during the regeneration process permits a tight control. On one hand, its inhibition at the initial stages allows massive proliferation, on the other its induction at advanced steps of regeneration is essential for preservation of robustness and fidelity of the regeneration process. A better understanding of the role of p53 in regulation of regeneration may open new opportunities for implementation of TP53-based therapies, currently available for cancer patients, in regenerative medicine.Cell Death and Differentiation advance online publication, 21 October 2016; doi:10.1038/cdd.2016.117.
Pub.: 22 Oct '16, Pinned: 08 Jun '17