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Generation of human skin organoids from pluripotency (Admin Supplement)

从多能性生成人类皮肤类器官（管理补充）

基本信息

批准号：
10861600
负责人：
Karl Russell Koehler
金额：
$ 45.3万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-17 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10861600
关键词：
3-Dimensional Acute Pain Adipocytes Adipose tissue Adult Afferent Neurons Anatomy Antigen-Presenting Cells Automobile Driving Award Biological Cartilage Cell Communication Cell Therapy Cells Cephalic Chemicals Communication Complex Connective Tissue Cells Data Derivation procedure Dermal Development Disease Disease model Embryo Embryonic Development Engineering Environment Epidermis Fatty acid glycerol esters Fibroblast Growth Factor Fibroblasts Fostering Generations Goals Growing Follicle Hair Hair follicle structure Homeostasis Human Hypersensitivity skin testing Image In Vitro Individual Inflammation Investigation Knowledge Macrophage Malignant Neoplasms Mesenchymal Methodology Modeling Nerve Nerve Endings Neural Crest Cell Neuroglia Neurons Newborn Infant Nociception Nociceptors Organoids Pain Pain Research Parents Pathway interactions Play Population Positioning Attribute Process Production Radial Regulation Research Personnel Research Proposals Resolution Role Schwann Cells Sensory Signal Transduction Site Skin Skin Tissue Skin graft Source Stereotyping Stimulus Study models Surface Ectoderm Sweat Glands System Testing Therapeutic Thick Tissue Microarray Tissues afferent nerve appendage burn therapy cell type chronic pain embryo tissue face skin fetal human pluripotent stem cell human stem cells innovation insight keratinization keratinocyte live cell imaging melanocyte nerve supply neural neuron development novel strategies pain model pain sensation parent project pluripotency progenitor reconstitution skin morphogenesis skin organogenesis stem cells tissue reconstruction wound treatment

项目摘要

ABSTRACT Skin morphogenesis and homeostasis necessitate the assembly of diverse cells originating from different embryonic tissues, which poses a considerable engineering challenge when aiming to construct complex and easily assembled skin in vitro. Such constructs could have significant applications, including cell therapy for burn and wound treatment. The specific issue lies in the commonly used cells for in vitro skin derivation; they lack the capacity to form skin appendages, such as hair follicles and sweat glands, and accessory cells, like melanocytes and adipocytes. Therefore, identifying the pivotal cell signaling mechanisms required to differentiate appendage- bearing skin from progenitor cells, like human pluripotent stem cells (hPSCs), or to stimulate skin appendage induction from adult skin cells, represents a critical barrier to progress. While we can efficiently generate epidermal cells from hPSCs in vitro, the regulation of dermal progenitor cell induction and other components of the skin microenvironment remains uncertain. As such, our long-term objective is to ascertain the chemical and physical signals necessary to recapitulate the development of human skin progenitor cells and reconstitute complex skin. This supplementary project builds upon the progress made in our parent project, "Generation of human skin organoids from pluripotency," by introducing a new aim focused on modeling pain pathways in skin organoids. Firstly, we will test the hypothesis that nociceptive neurons emerge in skin organoids and form specialized nerve endings associated with terminal Schwann cells, akin to human fetal and newborn skin. Additionally, we aim to establish a methodology for generating stereotyped nociceptive innervation of skin organoids grown in a tissue-chip environment for accessible live-cell imaging. Secondly, we will examine the hypothesis that macrophages co-derived in skin organoids can modulate the functional activity of nociceptors, thereby mimicking cell-cell interactions implicated in pain initiation and resolution. Successful completion of these aims will provide preliminary data for innovative new imaging-based investigations into the mechanisms of acute and chronic pain and inflammation in the skin. In alignment with the parent award, we also expect to gain considerable insight into the earliest stages of human skin and pain circuit development for researchers studying skin organogenesis. Furthermore, our efforts may inform strategies for resolving pain associated with conditions that require tissue reconstruction using skin organoid-derived cells.

摘要