Mammalian digit regeneration progresses through consistent stages: histolysis, inflammation, epidermal closure, blastema formation, and finally redifferentiation. What we do not yet know is how each stage can affect others. Questions of stage timing, tissue interactions, and microenvironmental states are becoming increasingly important as we look toward solutions for whole limb regeneration. This study focuses on the timing of epidermal closure which, in mammals, is delayed compared to more regenerative animals like the axolotl. We use a standard wound closure device, Dermabond (2‐octyl cyanoacrylate), to induce earlier epidermal closure, and we evaluate the effect of fast epidermal closure on histolysis, blastema formation, and redifferentiation. We find that fast epidermal closure is reliant upon a hypoxic microenvironment. Additionally, early epidermal closure eliminates the histolysis stage and results in a regenerate that more closely replicates the amputated structure. We show that tools like Dermabond and oxygen are able to independently influence the various stages of regeneration enabling us to uncouple histolysis, wound closure, and other regenerative events. With this study, we start to understand how each stage of mammalian digit regeneration is controlled.
In mammals, macrophages are known to play a major role in tissue regeneration. They contribute to inflammation, histolysis, re-epithelialization, revascularization and cell proliferation. Macrophages have been shown to be essential for regeneration in salamanders and fish, but their role has not been elucidated in mammalian epimorphic regeneration. Here, using the regenerating mouse digit tip as a mammalian model, we demonstrate that macrophages are essential for the regeneration process. Using cell-depletion strategies, we show that regeneration is completely inhibited; bone histolysis does not occur, wound re-epithelialization is inhibited and the blastema does not form. Although rescue of epidermal wound closure in the absence of macrophages promotes blastema accumulation, it does not rescue cell differentiation, indicating that macrophages play a key role in the redifferentiation of the blastema. We provide additional evidence that although bone degradation is a component, it is not essential to the overall regenerative process. These findings show that macrophages play an essential role in coordinating the epimorphic regenerative response in mammals.
In mammals, macrophages are known to play a major role in tissue regeneration. These cells contribute to inflammation, histolysis, re-epithelialization, re-vascularization and cell proliferation. While macrophages have been shown to be essential for epimorphic regeneration in salamanders and fish, their role has not been elucidated in mammalian epimorphic regeneration. Here, using the mouse digit tip model as a mammalian model of epimorphic regeneration, we demonstrate that macrophages are essential for the regeneration process. Using cell depletion strategies, we show that regeneration is completely inhibited; bone histolysis does not occur, wound re-epithelization is inhibited and the blastema does not form. Rescue of epidermal wound closure, in the absence of macrophages, promotes blastema accumulation but not differentiation indicating that macrophage play a role in re-differentiation. Additionally, inhibition of osteoclasts and the degradation process is not sufficient to inhibit regeneration. These findings show that macrophages play an essential role in coordinating the epimorphic regenerative response in mammals.
Various methods have been explored to enhance antibodybased cancer therapy.
Molecular mechanisms responsible for lymphoma resistance to apoptosis often involve the bcl-2 pathway. In this study, we investigated the cell signaling pathways activated in bcl-2-overexpressing human mantle cell lymphoma cell lines (JVM-2 and Z-138) that have been treated with oblimersen, a molecular gene silencing strategy that effectively suppresses bcl-2 in vitro and in vivo. Z-138 cells expressed higher levels of bcl-2 and were more sensitive to the effects of bcl-2 silencing, mediated by oblimersen or bcl-2 small interfering RNA, in vitro. Tumors derived following injection of Z-138 cells were sensitive to oblimersen as judged by decreases in tumor growth rate and decreases in cell proliferation (as measured by Ki-67). Immunohistochemistry and Western blot analysis of oblimersen-treated Z-138 tumors revealed a dose-dependent decrease in bcl-2 levels and an associated increase in the proapoptotic proteins caspase-3 and caspase-9. Silencing bcl-2 in Z-138 xenografts revealed an associated dose-dependent suppression of bax, a decrease in nuclear factor-KB and phospho-nuclear factor-KB, and transient loss of p53 levels. Coimmunoprecipitation studies suggest that the latter observation is mediated by an association between bcl-2 and phosphomdm2. Bcl-2 silencing also led to p27 down-regulation and coimmunoprecipitation studies point to a role for bcl-2 in regulation of p27 localization/degradation. Bcl-2 silencing was also correlated with loss of cyclin D1a protein levels but not cyclin D1b levels. Coimmunoprecipitation studies indicate that bcl-2 may mediate its effects on cyclin D1a via interaction with p38 mitogen-activated protein kinase as well as a previously unreported interaction between bcl-2 and cyclin D1a. [Mol Cancer Ther 2008;7(4):749 -58]
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