Multiscale Models of Wound Cell Plasticity for Regeneration

项目摘要 在再生医学中，理解重写和修复的复杂机制至关重要。 稳定地维持细胞存储器，以便将细胞重新编程为新的、期望的目的地命运。伤口 愈合，涉及在多个空间和时间尺度的关键生物过程，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，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毛囊， 伤口重要的是，大的皮肤伤口可以再生正常的组织成分，特别是新的 毛，而小伤口永远不会。我们假设再生是一种新兴的财产， 许多生物事件在多个时间和空间尺度上的最佳相互作用，包括但不限于 仅限于迁移的表皮、真皮和免疫细胞的转录重编程，以及信号传导 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 整合多个生理系统（例如表皮、真皮、免疫细胞和毛发）的框架 毛囊），以确定关键条件转移损伤修复再生和远离疤痕。的 提出的方法解决了分析单细胞分子数据的前沿多尺度挑战 以及它们与组织中空间动力学的联系。我们将实现三个目标。在目标1中，我们将确定 愈合伤口中表皮、真皮和免疫细胞的再生特异性基因谱变化;在Aim2中， 我们将开发一个综合的多尺度模型来预测多种生物多样性的相对作用和紧急动态， 在目标3中，我们将使用体内鼠模型来测试模型预测， 功能测定和离体人共培养;结合多尺度模拟和统计 因此，我们将能够剖析候选调节因子的再生作用和空间动态。 在这项拟议工作中获得的知识将有助于制定未来的协议， 在临床环境中的再生机制，以在任何损伤（小损伤）后实现稳健的人皮肤再生。 或大）并且具有高效率（即总是实现高密度的再生毛发）。总体见解 了解到的不仅将为皮肤研究带来新的曙光，而且还为其他研究建立了一个基础范式。 上皮系统用于单细胞RNA-seq驱动的细胞谱系追踪的新型计算工具， 多细胞谱系空间动态的鲁棒多尺度模型，以及整体综合多尺度模型。 组织再生的框架将具有广泛的应用，包括用于胚胎发育，固体 肿瘤和许多其它上皮组织甚至非上皮组织。考虑到干/祖细胞的重要性， 细胞再生和肿瘤发生，这些研究也将有重要的意义， 工程和癌症治疗。

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.