Role of myeloid cells in heterotopic ossification (HO) in a burn and incision-induced mouse model

Despite the high frequency of musculoskeletal extremity trauma, little is known about the dynamics of the initial inflammatory response that can result in pathologic healing. Here, we assess the circulatory monocyte/macrophage recruitment to sites of pathologic extremity wound healing as seen with heterotopic ossification (HO). Using single cell transcriptome analyses at key time points, we identify distinct monocyte/macrophage subpopulations that are recruited to the site of HO formation and contribute to ectopic bone development through varied transforming growth factor-1 (Tgfb1) expression. Monocyte/macrophage specific deletion of Tgfb1 leads to altered function of macrophages and reduced HO. We further identify CD47 as a novel target for Tgfb1 regulation on monocytes/macrophages as CD47 activation leads to decreased expression of Tgfb1 in macrophages and systemic treatment with CD47 activating peptide results in attenuation of canonical TGFB1 signaling and HO. These findings elucidate the critical role of monocytes/macrophage subpopulations in aberrant wound healing and provide a novel therapeutic avenue.尽管肌骨四肢创伤的临床发生率极高，但目前对于可引发病理性愈合的初始炎症反应动力学机制仍知之甚少。本研究针对异位骨化（heterotopic ossification, HO）所表现出的四肢创伤病理性愈合过程，探究循环单核细胞/巨噬细胞向损伤部位的募集情况。本研究通过在关键时间节点开展单细胞转录组分析，鉴定出一批特异性募集至异位骨化形成部位的单核细胞/巨噬细胞亚群，这些亚群可通过差异化表达转化生长因子-β1（transforming growth factor-1, Tgfb1）参与异位骨生成过程。特异性敲除单核细胞/巨噬细胞中的Tgfb1，会导致巨噬细胞功能异常，并使异位骨化程度减轻。本研究进一步鉴定出CD47是单核细胞/巨噬细胞上Tgfb1调控的全新靶点：CD47激活可降低巨噬细胞中Tgfb1的表达，而通过CD47激活肽进行全身给药，能够抑制经典TGFB1信号通路并减轻异位骨化。本研究结果阐明了单核细胞/巨噬细胞亚群在异常伤口愈合中的关键作用，并为相关治疗提供了全新方向。

搜集汇总

背景与挑战

背景概述

该数据集是一个关于小鼠异位骨化（HO）机制的研究，通过RNA-Seq单细胞转录组分析，探究了髓系细胞（特别是单核/巨噬细胞亚群）在病理愈合过程中的作用。研究发现Tgfb1表达和CD47调控是关键因素，并提供了19个样本的测序数据，旨在揭示治疗靶点。