SOX9 Expression Identifies A Novel Alveolar Stem Cell Population

SOX9 表达鉴定出新型肺泡干细胞群

基本信息

批准号：
9610795
负责人：
Arvind Konkimalla
金额：
$ 4.95万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9610795
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 Cells Epithelium 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 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 regenerative repaired respiratory disease/disorder therapy self-renewal stem cell population stem cells stemness therapeutic target transcription factor transcriptome sequencing

项目摘要

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. !

抽象的虽然长期以来已知肺在成年期间经历了广泛的再生，但特定的茎现在才发现参与此过程的单元。最近的研究表明肺泡II型细胞（肺泡的已知干细胞群）优选激活以增殖遵循不同形式的伤害。我们的初步数据表明我们已经确定了一个新型的干细胞种群位于成年小鼠肺周围。这些细胞构成了II型细胞的子集， Express Sox9，肺发育中存在的转录因子，但其表达以前是一个转录因子被成年时被认为消退了。我们的初步数据表明，Sox9-linege标记的单元膨胀，生成部分左叶肺切除术后，新的肺泡结构优先在肺叶的外围在老鼠中。此外，Sox9+和Sox9负细胞都在3维中上调并重新表达SOX9 器官培养物，进一步表明SOX9在肺泡细胞中促进“干性”。鉴于这些调查结果，我们假设Sox9+细胞是主要的牙槽干细胞，它们优先增殖为了重新填充体内稳态和肺切除术后肺实质，它们是必需的过程，SOX9增强了肺泡细胞的再生和分化潜力。我们将解决这些问题结合了谱系追踪，细胞类型的特异性消融，离体分析和RNA- 测序方法。 AIM 1将解决Sox9+细胞对体内平衡和肺切除术后补偿性肺部生长。 AIM 2将确定Sox9+细胞是否必不可少维持肺泡稳态和伤害修复。 AIM 3将解决Sox9表达是否可以实质上影响肺泡II型细胞的干性。共同回答这些问题将有所帮助确定Sox9+细胞和/或Sox9蛋白是否是可行的治疗靶标，有助于加速肺急性损伤后修复。呢