Our long term objectives are to study the development and regeneration of skin ectodermal organs and to apply the principles toward regenerative medicine. Over the last two decades, my laboratory has made a long term commitment to this goal; we have produced several basic scientific discoveries and made conceptual progress toward the advancement of skin regenerative biology. In the next phase, we will consolidate new findings from two recently completed RO1 grants to focus on deciphering the mechanism of phenotypic specification in skin organogenesis, a major challenge in the next phase of cutaneous regenerative medicine. Through progress in stem cell biology and reprogramming technology, scientists are now able to generate epidermal progenitors, in the form of dissociated cells or a keratinocyte monolayer. How to guide these progenitors to form skin with different architecture remains unknown. Understanding these processes is crucial to ensure proper regeneration of a wound graft. A fundamental feature of the skin is the striking regional variation, where distinct skin types (e.g., facial skin and scalp glabrous skin, etc) develop at different body regions to serve different purposes.2,3 We postulate that competent, dissociated, epidermal progenitors interact with dermal cells to form reconstituted skin, a process which is regulated by environmental signals which change over developmental time to generate specific skin appendage phenotypes. We will focus on three fundamental aspects, using the most appropriate animal models for each process. Mouse and human cells are used in Aim 1 whereas chicken skin is used for Aims 2 and 3 because it features remarkable regional differences ideal for experimental analyses.
In Aim 1, we will take a multi-disciplinary approach to study how the reconstituted skin layer is generated from dissociated cells. Time-lapse imaging, transcriptome analyses and molecular perturbation will be used to study how the dissociated cells can self-assemble into a layered configuration via a series of multicellular morphological transitions. We will focus on the roles of MMPs in this morphogenetic transition and will attempt to reactivate the morphogenetic ability in adult mouse and human cells by modifying the Wnt-MMP-ECM module.
In Aim 2, we will study how skin progenitors are specified during regionalization. Our preliminary data suggests that the conversion of scales to feathers proceeds in a stepwise manner via a hierarchy of signaling molecules. Based on preliminary studies, we will focus on the role of Sox genes in establishing this hierarchy.
In Aim 3, we will study the morphogenetic principles of organ shaping. We will focus on the regulation of appendage length using feathers as a model. We will evaluate the hypothesis that complex organ shapes are specified by a core circuit that defines a prototypic phenotype qualitatively and modulator circuits that modify specific dimensional parameters quantitatively in a temporal-spatial manner. We hypothesize that FGF and Zic signaling, respectively, may be examples of such molecular circuits.

Public Health Relevance

We study skin development and regeneration and try to apply the principles we have learned to help patients who suffer from wound injuries. We propose to study environmental conditions that can make dissociated epidermal progenitors form reconstituted skin with functional skin appendages (ie, hairs) and appropriate regional specificity (ie, face, scalp).

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060306-07
Application #
9068772
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2010-09-21
Project End
2020-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90032
Widelitz, Randall B; Lin, Gee-Way; Lai, Yung-Chih et al. (2018) Morpho-regulation in diverse chicken feather formation: Integrating branching modules and sex hormone-dependent morpho-regulatory modules. Dev Growth Differ :
Wu, Ping; Lai, Yung-Chih; Widelitz, Randall et al. (2018) Comprehensive molecular and cellular studies suggest avian scutate scales are secondarily derived from feathers, and more distant from reptilian scales. Sci Rep 8:16766
Wu, Ping; Yan, Jie; Lai, Yung-Chih et al. (2018) Multiple Regulatory Modules Are Required for Scale-to-Feather Conversion. Mol Biol Evol 35:417-430
Lai, Yung-Chih; Liang, Ya-Chen; Jiang, Ting-Xin et al. (2018) Transcriptome analyses of reprogrammed feather / scale chimeric explants revealed co-expressed epithelial gene networks during organ specification. BMC Genomics 19:780
Qiu, Weiming; Chuong, Cheng-Ming; Lei, Mingxing (2018) Regulation of melanocyte stem cells in the pigmentation of skin and its appendages: Biological patterning and therapeutic potentials. Exp Dermatol :
Hughes, Michael W; Jiang, Ting-Xin; Plikus, Maksim V et al. (2018) Msx2 Supports Epidermal Competency during Wound-Induced Hair Follicle Neogenesis. J Invest Dermatol 138:2041-2050
Wang, Shuo; Stiegler, Josef; Wu, Ping et al. (2017) Heterochronic truncation of odontogenesis in theropod dinosaurs provides insight into the macroevolution of avian beaks. Proc Natl Acad Sci U S A 114:10930-10935
Cooke, Thomas F; Fischer, Curt R; Wu, Ping et al. (2017) Genetic Mapping and Biochemical Basis of Yellow Feather Pigmentation in Budgerigars. Cell 171:427-439.e21
Lei, Mingxing; Schumacher, Linus J; Lai, Yung-Chih et al. (2017) Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells. Proc Natl Acad Sci U S A 114:E7101-E7110
Cho, Jung-Hwa; Swanson, Carter J; Chen, Jeannie et al. (2017) The GCaMP-R Family of Genetically Encoded Ratiometric Calcium Indicators. ACS Chem Biol 12:1066-1074

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