2014 — 2018 |
Plikus, Maksim V |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Induction of Fat Regeneration in Skin Wounds by Hair Follicle Signaling @ University of California-Irvine
DESCRIPTION (provided by applicant): The process of wound healing is critical to restoring integrity and homeostasis after significant skin injuries. Although embryonic skin can heal by regenerating itself completely, adult skin is only capable of partial repair, altering the skin's integrity at the site of injury. Cutaneous adipose tissue is thought to poorly regenerate during wound healing, and because scars lack adipose tissue, they often assume debilitating hypertrophic, keloid, or atrophic characteristics. Lack of adipose regeneration is also a major cause of long term morbidity following extensive soft tissue trauma or surgical resection, such as tumor removal. We have identified the previously unknown phenomenon of adipose tissue neogenesis in large cutaneous wounds that occurs under the instructive signaling of de novo hair follicles. This application will focus on identifying permissive epigenetic changes and novel signaling cues generated by neogenic hair follicles in the wound environment that guide de novo regeneration of cutaneous fat. Our recent lineage analyses show that instead of recruiting already committed adipose precursors from the wound's edges and simply stimulating their differentiation to lipid-laden adipocytes, neogenic hair follicles guide de novo adipogenic cell fae acquisition by otherwise non-adipogenic wound myofibroblasts. Our studies demonstrate that acquisition of adipose identity by wound myofibroblasts critically depends on reactivation of Zfp423 signaling, the lead adipogenic commitment pathway in embryogenesis. Our studies also implicate hair follicle-derived BMP signaling inputs as the critical regulators of adipogenic fate commitment in wound scar tissue. The first goal of the proposed research is to establish the epigenetic changes in wound myofibroblasts that permit their adipogenic competence. Specifically, we will focus on epigenetic changes in Zfp423, the developmental master-regulator gene characterized by an exceptionally CpG-dense promoter. The second goal is to establish the mechanism by which BMP signaling events generated in the wound around neogenic hair follicles promote de novo fat formation. Ultimately, we want to be able to replicate these signaling events in hairless wounds for the purposes of inducing cutaneous fat regeneration. We anticipate that the proposed studies will help uncover new mechanisms that allow adult skin to expand lineage plasticity during wound repair. They could also have applicability to the development of new scarless wound healing strategies.
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0.981 |
2018 — 2021 |
Dai, Xing (co-PI) [⬀] Nie, Qing [⬀] Plikus, Maksim V |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Multiscale Models of Wound Cell Plasticity For Regeneration @ University of California-Irvine
PROJECT SUMMARY In regenerative medicine, it is critically important to understand the complex mechanisms that rewrite and stably maintain cellular memory in order to reprogram cells to the new, desired destination fates. Wound healing, involving critical biological processes at multiple spatial and temporal scales, provides an ideal system for studying regenerative mechanisms. In skin, several distinct pools of epithelial stem cells, such as those in the interfollicular epidermis and different parts of the hair follicle, become activated and recruited to repair the wound. Importantly, large skin wounds can regenerate the normal array of tissue constituents, specifically new hairs, while small wounds never can. We hypothesize that regeneration is an emerging property arising from the optimal interplay between many biological events at multiple temporal and spatial scales including, but not limited to, transcriptional reprogramming of migrating epidermal, dermal and immune cells, as well as signaling crosstalk between these cells and their surrounding microenvironment.. Here, we propose a novel multiscale framework integrating multiple physiological systems (e.g. epidermal, dermal, and immune cells and hair follicles) to identify critical conditions for shifting injury repair toward regeneration and away from scarring. The proposed methodology addresses cutting-edge multiscale challenges in analyzing single-cell molecular data and their connections with spatial dynamics in tissues. We will carry out three aims. In Aim 1, we will identify regeneration-specific gene profile changes in epidermal, dermal, and immune cell in healing wounds; in Aim 2, we will develop an integrative multiscale model to predict the relative roles and emergent dynamics of multiple interacting cell types during wound healing; and in Aim 3, we will test model predictions using in-vivo murine functional assays and ex vivo human co-culture; in combination with multiscale simulations and statistical inference, we will thus be able to dissect the regenerative roles and spatial dynamics of candidate regulators. The knowledge gained in this proposed work will help to develop future protocols for augmenting the regeneration mechanisms in clinical settings to achieve robust human skin regeneration after any injury (small or large) and with high efficiency (i.e. always achieve high density of regenerating hairs). The overall insights learned will not only shed new light into skin research, but also establish a founding paradigm for other epithelial systems. The novel computational tools for single-cell RNA-seq-driven cell lineage tracking, the robust multiscale models for spatial dynamics of multiple cell lineages, and the overall integrative multiscale framework of tissue regeneration will have broad applications, including for embryonic development, solid tumors, and many other epithelial and even non-epithelial tissues. Given the importance of stem/progenitor cells in regeneration and tumorigenesis, these studies will also have important implications for tissue engineering and cancer treatment.
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0.981 |