Multiscale Models of Wound Cell Plasticity for Regeneration

伤口细胞再生可塑性的多尺度模型

• 批准号: 10289695
• 负责人: Xing Dai
• 金额: $ 1.01万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289695
• 关键词: Address; Biological; Biological Assay; Biological Process; Cell Lineage; Cells; Cicatrix; Clinical; Coculture Techniques; Complex; Data; Dermal; Destinations; Disease; Embryonic Development; Epidermis; Epithelial; Event; Future; Genes; Hair; Hair follicle structure; Human; Immune; Injury; Knowledge; Light; Memory; Methodology; Molecular; Mus; Natural regeneration; Physiological; Property; Protocols documentation; Regenerative Medicine; Regenerative research; Research; Role; Signal Transduction; Skin; Solid Neoplasm; System; Testing; Tissue Engineering; Tissue Microarray; Tissues; Work; Wound models; cancer therapy; cell type; computerized tools; density; epithelial stem cell; improved; in vivo; injury and repair; insight; multi-scale modeling; novel; predictive modeling; recruit; regenerative; regenerative therapy; restoration; simulation; single cell analysis; single-cell RNA sequencing; skin regeneration; skin wound; stem; stem cells; tissue regeneration; transcriptional reprogramming; tumorigenesis; wound; wound healing

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.

在再生医学中，了解重写和 稳定地维护细胞记忆，以便将细胞重新编程为新的，所需的目的地命运。伤口 康复，涉及多个空间和时间尺度上关键的生物过程，提供了理想的系统 用于研究再生机制。在皮肤中，几个不同的上皮干细胞池，例如 毛囊中的毛囊表皮和不同部位被激活并招募以修复 伤口。重要的是，大型皮肤伤口可以再生组织成分的正常阵列，特别是新的 头发，而小伤口永远无法。我们假设再生是由 许多时间和空间尺度上许多生物事件之间的最佳相互作用，包括但不包括 仅限于迁移表皮，皮肤和免疫细胞的转录重编程以及信号传导 这些细胞及其周围微环境之间的串扰。在这里，我们提出了一个新颖的多尺度 整合多个生理系统的框架（例如表皮，皮肤和免疫细胞和头发 卵泡）确定将伤害修复转向再生并远离疤痕的关键条件。这 提出的方法解决了分析单细胞分子数据的尖端多尺度挑战 以及它们与组织中空间动力学的连接。我们将执行三个目标。在AIM 1中，我们将确定 再生特异性基因谱在愈合伤口中表皮，皮肤和免疫细胞的变化；在AIM 2中， 我们将开发一个综合多尺度模型，以预测多重的相对作用和新兴动态 伤口愈合过程中相互作用的细胞类型；在AIM 3中，我们将使用体内鼠测试模型预测 功能测定和实体人类共同文化；结合多尺度模拟和统计 推断，我们将能够剖析候选调节剂的再生作用和空间动力学。 这项拟议的工作中获得的知识将有助于开发未来的协议来扩大 临床环境中的再生机制，以实现任何受伤后人类皮肤再生的强大（小） 或大效率（即始终达到高密度再生头发）。总体见解 学到的不仅会给皮肤研究带来新的光芒，还将为其他 上皮系统。单细胞RNA-seq驱动的细胞谱系跟踪的新型计算工具， 强大的多尺度模型，用于多个细胞谱系的空间动力学和整体综合多尺度 组织再生框架将具有广泛的应用，包括用于胚胎发育，固体 肿瘤以及许多其他上皮甚至非上皮组织。鉴于STEM/祖先的重要性 细胞在再生和肿瘤发生中，这些研究也将对组织具有重要意义 工程和癌症治疗。