The Biology of Stem Cells in the Human Parasite Schistosoma Mansoni

人类寄生虫曼氏血吸虫干细胞的生物学

• 批准号: 10544522
• 负责人: James J Collins
• 金额: $ 46.93万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544522
• 关键词: Address; Adolescent; Adult; Atlases; Behavior; Biology; Blood; Cells; Chronic; Communities; Data; Development; Disease; Dose; Environment; Failure; Flow Cytometry; Funding; Gene Expression; Genes; Growth; Human; Injury; Malaria; Mechanics; Mediating; Modeling; Modernization; Molecular; Molecular Analysis; Muscle; Natural regeneration; Outcome; Output; Parasites; Parasitic Diseases; Pathology; Pharmaceutical Preparations; Planarians; Platyhelminths; Play; Population; Praziquantel; Process; Proliferating; Public Health; Refractory; Regenerative capacity; Regenerative response; Research; Resources; Role; Schistosoma; Schistosoma mansoni; Schistosomiasis; Site; Skin; Specific qualifier value; Testing; Tissues; combat; egg; fascinate; human pathogen; in vivo; new therapeutic target; novel; novel therapeutics; pathogen; programs; regenerative; repaired; response to injury; single-cell RNA sequencing; stem cell biology; stem cells; tissue regeneration; tissue repair; tool; wound

Schistosomiasis ranks second (behind malaria) as the world’s most devastating parasitic disease. Despite this, treatment relies on a single drug, Praziquantel (PZQ), that has marginal efficacy. This disease is caused by Schistosoma flatworms (schistosomes) that live in the vasculature, producing eggs that spur a variety of chronic pathologies that are exacerbated by the fact that schistosomes can survive in the blood for decades. How these parasites thrive in this hostile environment remains an open question. Our group discovered that adult schistosomes possess a population of somatic stem cells, neoblasts, that are critical for tissue renewal. During our studies of these cells we made a surprising discovery: mechanical injury induces a massive increase in neoblast proliferation at the site of wounding. Because this mirrors what happens in highly regenerative free-living planarian flatworms, we reasoned that schistosomes may possess an uncharacterized regenerative capacity. Whole-body regeneration (i.e., regenerating amputated heads) is not known to occur in schistosomes; yet, classic studies suggest that treatment of adult worms with sub-lethal doses of PZQ results in extensive tissue damage that the worms can repair. Likewise, we find that sublethal concentrations of PZQ induce neoblast proliferation in adult parasites. Furthermore, rapidly growing juvenile schistosomes, which have a massive number of neoblasts, are refractory to PZQ. Thus, PZQ sensitivity and neoblast number are inversely correlated. Given these data, we hypothesize that neoblasts fuel regenerative responses in the worm and we predict these regenerative responses are critical to the parasite’s ability to respond to insults in vivo, including PZQ treatment. To test this hypothesis, we propose two specific aims. In Specific Aim 1, we will use single cell RNA sequencing to describe the cellular lineages that operate during parasite development and determine whether these linages programs are “reactivated” in adult worms following injury. In Specific Aim 2, we will evaluate how well schistosomes are able to restore form and function to their tissues following injury and the extent to which tissue repair relies on neoblasts. We will additionally determine whether neoblast-driven regenerative responses are essential for juvenile and adult parasite survival following PZQ administration in vivo. Together, these studies will be the first to explore schistosome regenerative responses on a molecular level. Because we predict that neoblasts mediate tissue repair following PZQ-induced damage, these studies could also suggest that targeting neoblasts may enhance the efficacy of PZQ, thereby transforming how we treat this disease.

血吸虫病是世界上最具破坏性的寄生虫病，位居第二（仅次于疟疾）。 尽管如此，治疗仍依赖于单一药物吡喹酮 (PZQ)，其疗效有限。 这种疾病是由生活在脉管系统中的血吸虫扁虫（血吸虫）引起的， 产生的鸡蛋会刺激各种慢性疾病，而这些疾病会因以下事实而加剧： 血吸虫可以在血液中存活数十年。这些寄生虫如何在这个充满敌意的环境中茁壮成长 环境仍然是一个悬而未决的问题。我们课题组发现成虫血吸虫具有 一群对组织更新至关重要的成体干细胞（新生细胞）。在我们的 对这些细胞的研究我们有了一个惊人的发现：机械损伤会诱发大量的细胞损伤。 受伤部位新细胞增殖增加。因为这反映了发生的事情 高度再生的自由生活的涡虫扁虫，我们推测血吸虫可能具有 未表征的再生能力。全身再生（即再生 目前尚不清楚血吸虫是否会发生这种情况；然而，经典研究表明 用亚致死剂量的 PZQ 治疗成虫会导致广泛的组织损伤， 蠕虫可以修复。同样，我们发现亚致死浓度的 PZQ 诱导新生细胞 成虫寄生虫的增殖。此外，幼年血吸虫生长迅速，具有 大量的新生细胞对 PZQ 无效。因此，PZQ 敏感性和新生细胞数量 呈反相关关系。鉴于这些数据，我们假设新生细胞为再生提供燃料 蠕虫的反应，我们预测这些再生反应对于寄生虫的 对体内损伤做出反应的能力，包括 PZQ 治疗。为了检验这个假设，我们提出 两个具体目标。在具体目标 1 中，我们将使用单细胞 RNA 测序来描述 在寄生虫发育过程中起作用的细胞谱系，并确定这些谱系是否 成虫受伤后，程序会“重新激活”。在具体目标 2 中，我们将评估 血吸虫在受伤后恢复组织形态和功能的能力如何？ 组织修复对新生细胞的依赖程度。我们将另外确定是否 新生细胞驱动的再生反应对于幼年和成年寄生虫的生存至关重要 PZQ 体内给药后。这些研究将共同​​探索 分子水平上的血吸虫再生反应。因为我们预测新生细胞 介导 PZQ 引起的损伤后的组织修复，这些研究还表明 针对新生细胞可能会增强 PZQ 的功效，从而改变我们治疗该疾病的方式 疾病。