Multiscale Models of Wound Cell Plasticity for Regeneration

项目总结 在再生医学中，理解重写和重写的复杂机制至关重要 稳定地维持细胞记忆，以便将细胞重新编程为新的、所需的目的地命运。伤口 治疗，涉及多个空间和时间尺度上的关键生物过程，提供了一个理想的系统 用于研究再生机制。在皮肤中，几个不同的上皮干细胞池，例如在 毛囊间表皮和毛囊的不同部分被激活并被招募来修复 伤口。重要的是，大型皮肤创伤可以再生正常的组织成分阵列，特别是新的 毛发，而小伤口永远不会。我们假设再生是一种新兴的属性，它产生于 多种时间和空间尺度上的许多生物事件之间的最佳相互作用，包括但不是 仅限于，迁移的表皮、真皮和免疫细胞的转录重新编程以及信号 这些细胞与其周围微环境之间的串扰。在这里，我们提出了一种新的多尺度 整合多种生理系统(如表皮、真皮、免疫细胞和头发)的框架 卵泡)，以确定将损伤修复转移到再生而不是结疤的关键条件。这个 提出的方法解决了单细胞分子数据分析中的前沿多尺度挑战 以及它们与组织中的空间动力学的联系。我们将实现三个目标。在目标1中，我们将确定 愈合伤口的表皮、真皮和免疫细胞中再生特异性基因图谱的变化；在目标2中， 我们将开发一个综合的多尺度模型来预测多个 在伤口愈合过程中相互作用的细胞类型；在目标3中，我们将使用体内小鼠来测试模型预测 功能分析和体外人类共培养；与多尺度模拟和统计相结合 推断，我们因此将能够剖析候选调节者的再生角色和空间动态。 在这项拟议工作中获得的知识将有助于开发未来的议定书，以增强 临床环境中的再生机制，可在任何损伤(小的)后实现强大的人体皮肤再生 或较大)和高效率(即始终实现高密度的再生毛发)。总体洞察力 学习不仅将为皮肤研究带来新的曙光，还将为其他人建立一个创建范例 上皮性系统。用于单细胞RNA序列驱动的细胞谱系跟踪的新型计算工具 多细胞系空间动力学的稳健多尺度模型，以及整体综合多尺度 组织再生框架将有广泛的应用，包括用于胚胎发育、固体 肿瘤，以及许多其他上皮性组织，甚至非上皮性组织。鉴于茎/祖细胞的重要性 细胞在再生和肿瘤发生中的作用，这些研究也将对组织有重要的意义 工程学和癌症治疗。

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.