SOX9 Expression Identifies A Novel Alveolar Stem Cell Population

SOX9 表达鉴定出新型肺泡干细胞群

• 批准号: 10063551
• 负责人: Arvind Konkimalla
• 金额: $ 3.79万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063551
• 关键词: 3-Dimensional; Ablation; Acute; Address; Adult; Affect; Alveolar; Alveolar Cell; Anatomy; Area; Behavior; Biological Assay; Bromodeoxyuridine; Cell Therapy; Cells; Collaborations; Data; Diphtheria Toxin; Disease; Distal; Epithelial; Epithelial Cells; Fibrosis; Fluorescence; Future; Gases; Genetic Transcription; Growth; Heterogeneity; Homeostasis; Inhalation; Injury; Intestines; Label; Lead; Left; Lentivirus; Liver; Lobar; Lobe; Location; Lung; Lung diseases; Maintenance; Mediating; Modeling; Molecular; Multipotent Stem Cells; Mus; Natural regeneration; Organoids; Pancreas; Pathogenesis; Peripheral; Physiology; Pneumonectomy; Population; Process; Proliferating; Pulmonary Emphysema; Pulmonary Surfactant-Associated Protein C; Respiratory physiology; Rodent; Role; SOX9 protein; Skin; Stem Cell Development; Structure; Structure of parenchyma of lung; System; Tamoxifen; Thinness; Type I Epithelial Receptor Cell; Type II Epithelial Receptor Cell; United States; Virus; alveolar epithelium; alveolar homeostasis; alveolar type II cell; cell behavior; cell type; defined contribution; experimental study; injury and repair; lung development; lung lobe; lung regeneration; lung repair; mouse model; novel; progenitor; regeneration following injury; regenerative; repaired; respiratory disease/disorder therapy; self-renewal; stem cell population; stem cell therapy; stem cells; stemness; therapeutic target; transcription factor; transcriptome sequencing

ABSTRACT While the lung has long been known to undergo extensive regeneration during adulthood, the particular stem cells involved in this process are only now being discovered. Recent studies have indicated that a subset of alveolar Type II cells, a known stem cell population of the alveoli, are preferentially activated to proliferate following different forms of injuries. Our preliminary data indicate that we have identified a novel stem cell population located in the periphery of the adult mouse lung. These cells constitute a subset of Type II cells and express SOX9, a transcription factor present in lung development but one whose expression had been previously thought to subside by adulthood. Our preliminary data show that Sox9-lineage labeled cells expand, generating new alveolar structures preferentially in the periphery of the lung lobes following partial left lobe pneumonectomy in mice. Moreover, both Sox9+ and Sox9 negative cells upregulate and re-express SOX9 in 3-dimensional organoid cultures, further suggesting that SOX9 functions to promote “stemness” in alveolar cells. Given these findings, we hypothesize that Sox9+ cells are the primary alveolar stem cell, that they preferentially proliferate to repopulate the homeostatic and post-pneumonectomy lung parenchyma, that they are necessary for these processes, and that SOX9 enhances regenerative and differentiation potential of alveolar cells. We will address these questions using a combination of lineage tracing, cell-type specific ablation, ex vivo assays, and RNA- Sequencing approaches. Aim 1 will address the contribution of Sox9+ cells to both homeostasis and compensatory lung growth following pneumonectomy. Aim 2 will determine whether Sox9+ cells are essential for maintenance of alveolar homeostasis and injury repair. Aim 3 will address whether SOX9 expression can substantially influence the stemness of alveolar Type II cells. Collectively, answering these questions will help determine whether Sox9+ cells and/or SOX9 protein are viable therapeutic targets that will help accelerate lung repair following acute injury. !

摘要 虽然人们很早就知道肺在成年期会经历广泛的再生，但特定的干 参与这一过程的细胞直到现在才被发现。最近的研究表明， 肺泡II型细胞是已知的肺泡干细胞群，优先被激活以增殖 在不同形式的伤害之后。我们的初步数据表明，我们已经鉴定出一种新的干细胞 种群位于成年小鼠肺的外围。这些细胞构成II型细胞的子集，并且 表达SOX9，一种存在于肺发育中的转录因子，但其表达之前 被认为会在成年后消退。我们的初步数据显示，Sox9谱系标记的细胞扩大，生成 左肺部分切除术后新的肺泡结构优先位于肺叶周围 在老鼠身上。此外，Sox9+和Sox9阴性细胞都上调并重新表达三维SOX9 进一步表明SOX9具有促进肺泡细胞“干化”的功能。考虑到这些 发现，我们假设Sox9+细胞是原始的肺泡干细胞，它们优先增殖 为了重新填充内环境平衡和肺切除后的肺实质，它们是这些 SOX9可增强肺泡细胞的再生和分化潜能。我们将解决 这些问题结合了谱系追踪、细胞类型特异性消融、体外分析和RNA- 测序方法。目标1将讨论Sox9+细胞对动态平衡和 全肺切除后代偿性肺生长。目标2将确定Sox9+细胞是否是必不可少的 用于维持肺泡动态平衡和损伤修复。目标3将解决SOX9表达式是否可以 显著影响肺泡II型细胞的干性。总而言之，回答这些问题将有所帮助 确定Sox9+细胞和/或SOX9蛋白是否是有助于加速肺功能的可行治疗靶点 急性损伤后的修复。 好了！