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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.

摘要皮肤形态发生和稳态需要来自不同组织的不同细胞的组装。胚胎组织，这在旨在构建复杂且在体外容易组装的皮肤。这样的构建体可能具有重要的应用，包括烧伤的细胞治疗和伤口处理。具体问题在于用于体外皮肤衍生的常用细胞;它们缺乏形成皮肤附属物的能力，如毛囊和汗腺，以及辅助细胞，如黑色素细胞和脂肪细胞。因此，确定附件分化所需的关键细胞信号传导机制，从祖细胞（如人多能干细胞（hPSC））中产生皮肤，或刺激皮肤附件从成人皮肤细胞诱导，代表了进展的关键障碍。虽然我们可以有效地产生表皮细胞从hPSC在体外，调节真皮祖细胞诱导和其他成分，皮肤微环境仍然不确定。因此，我们的长期目标是确定化学品和物理信号必须重演人类皮肤祖细胞的发展和重建复杂的皮肤。这一补充项目建立在我们的母项目“生成来自多能性的人类皮肤类器官”，引入了一个专注于皮肤疼痛通路建模的新目标类有机体首先，我们将测试伤害性神经元出现在皮肤类器官中并形成的假设。与末端雪旺细胞相关的特殊神经末梢，类似于人类胎儿和新生儿的皮肤。此外，我们的目标是建立一种方法，产生刻板的伤害性神经支配的皮肤在组织芯片环境中生长的类器官，用于可访问的活细胞成像。第二，我们会研究假设皮肤类器官中共同衍生的巨噬细胞可以调节伤害感受器的功能活性，从而模拟涉及疼痛起始和消退的细胞-细胞相互作用。成功完成这些 aims将提供初步数据，用于创新性的新成像研究，以了解急性慢性疼痛和皮肤炎症。与母公司奖项一致，我们还希望获得对人类皮肤和疼痛回路发育的最早阶段有相当深入的了解，皮肤器官发生此外，我们的努力可能会为解决与疾病相关的疼痛提供策略。需要使用皮肤类器官来源的细胞进行组织重建。