Dr Herman leads the Tufts Center for Innovations in Wound Healing Research
Cytoskeletal dynamics and cell migration: Control of wound healing, vascular remodeling and tissue regeneration
Based on prior work and current analyses that are ongoing in the lab, we postulate that the regulation of isoactin-based cell motility is precisely regulated by a repertoire of actin-associating proteins that collectively signal through the actin network to influence cell shape and motility. We currently take advantage of vascular and epithelial cell model systems, as well use molecular genetic approaches that implement adenoviral-mediated gene delivery approaches and transgenic animals to test whether our hypotheses are valid. In turn, fundamental insights derived from these experiments are helping us to develop innovative strategies capable of enhancing or abrogating cell motility, during wound healing or the vascular pathologies that accompany age-related macular degeneration, diabetic retinopathy or tumor progession, respectively.
Figure 1. Localization of β actin is confined to regions of advancing cytoplasm. Note that rhodamine anti-β actin IgG is exclusively localized at the leading edge of crawling cells in response to injury. (Nuclei: Blue; Stress fibers: Green)
Molecular control of microvascular morphogenesis: insights into physiologic and pathologic angiogenesis
Our work in the angiogenesis of wound healing and pathologic angiogenesis is focused around our devotion to understanding the molecular signaling cascades that control microvascular remodeling during aging, diabetes and chronic wound healing. To these ends, we have developed several in vitro and animal model systems to enable our dissection of mechanisms, interrogation of specific hypotheses as well as perform high throughput screenings of relevant libraries: all efforts focused on developing innovative strategies capable of accelerating the angiogenesis of wound healing or inhibiting the unwanted vascular proliferative lesions present in the posterior pole of the human eye, which accompany diabetic retinopathy or age-related macular degeneration. In turn, this work has also permitted our recent development of novel therapeutics that promote cell migration and accelerate wound healing as well as helped to foster the production of innovative 3-D wound healing models and therapeutics.
Figure 2. The figure illustrates steps involved in microvascular morphogenesis.
To gain insight into the molecular and cellular mechanisms regulating the cellular responses to injury and wound healing, microvascular remodeling during developmental and disease-associated processes, and the cytoskeletal mediated responses to pathogenic challenge, we are focusing our attention and efforts using several hypothesis-driven and screening-based approaches, taking advantage of many different approaches, including molecular genetics, cell biology, bioengineering, biochemistry, biophysics and imaging technology. Key diseases that we are targeting include chronic wound healing, diabetic retinopathy, age-related macular degeneration, pathogenic bacterial infections, hypertension, tumor angiogenesis and atherosclerosis. Our in vitro and in vivo approaches incorporate quantitative analyses of (1) tissue activation and remodeling, (2) cytoskeletal and matrix-dependent signaling mechanisms and (3) efforts aimed at revealing therapeutic entry points, whether to interfere with unwanted vascular proliferative disorders, or strategies focused on promotion of new blood vessel growth where ischemia-related injury is problematic.
Figure 3. The figure illustrates our intersecting areas of focus, all of which are influenced by cell migration, microenvironmental signaling, and vascular remodeling or angiogenesis.
Understanding the molecular mechanisms of host-pathogen interactions: signaling through the network of actin effectors
Recent work has revealed that the novel isoactin-specific signaling complex of proteins discovered in the lab plays a pivotal role in regulating the remodeling of the apical actin network, which is critical for the host cell's adaptive response to bacterial challenge and pathogenesis. By creating mutant stable cell lines, we have begun to characterize the common molecular mechanisms mediating such diverse phenomena as attaching and effacing lesion formation during enteropathogenic bacterial infection and the cytoskeletal effector network and reciprocal signaling cascades required to initiate and sustain bacterial pathogenesis.
Figure 4. The points at which some bacterial pathogens interact with actin effectors are illustrated.