The role of PHF6 in the control of hematopoietic stem cell aging.

项目概要/摘要 随着预期寿命的增加，与年龄相关的疾病已成为主要的健康问题。 现在人们认识到干细胞衰老是系统和器官特异性功能的驱动因素 下降。在造血系统中，干细胞衰老的特点是积累 自我更新受损的免疫表型定义的造血干细胞 (HSC) 随着髓系细胞群生成的增加，能力和分化程序发生改变 和淋巴潜能降低。在这里，我们展示了植物同源域的遗传丢失 因子 6 (PHF6) 导致 HSC 连续移植能力增加并消除 与年龄相关的造血衰退的发展，包括功能性造血功能的积累 耗尽的 HSC 表现出骨髓分化偏向和淋巴潜能受损。我们的 中心假设是 Phf6 的缺失会重新配置 HSC 的表观遗传景观 与年龄相关的功能衰退的开始和/或进展。在这里我们将应用 费兰多和拉巴丹实验室在造血和计算方面的综合专业知识 生物学深入探索PHF6失活的造血表型和机制 在 HSC 老化中。为了实现这一目标，我们将分析 Phf6 条件下的干细胞区室 基因敲除小鼠和 CRISPR 指导的 PHF6 失活后的人类造血干细胞 细胞，利用体外和体内干细胞测定结合先进的 应用于单细胞转录组学和表观基因组学的计算分析工具。这些 研究最终将促进新的靶向疗法的开发，旨在改善 老年捐献者造血干细胞的植入能力以及用于治疗 与年龄相关的 HSC 恶化导致的病理。

Project Summary/Abstract As life expectancy increases age-associated pathologies have become a major health problem. It is now recognized that stem cell aging is a driver of systemic and organ-specific functional decline. In the hematopoietic system stem cell aging is characterized by accumulation of immunophenotypically-defined hematopoietic stem cells (HSCs) with impaired self-renewal capacity and altered differentiation programs with increased generation of myeloid populations and decreased lymphoid potential. Here we show that genetic loss of Plant Homeodomain Factor 6 (PHF6) results in increased HSC serial transplantation capacity and abrogates the development of age-associated hematopoietic decay including the accumulation of functionally exhausted HSCs displaying myeloid differentiation bias and impaired lymphoid potential. Our central hypothesis is that loss of Phf6 reconfigures the epigenetic landscape of HSCs blocking the initiation and/or progression of age-associated functional decline. Here we will apply the combined expertise of the Ferrando and Rabadan labs in hematopoiesis and computational biology to explore in depth the hematopoietic phenotypes and mechanisms of PHF6 inactivation in HSC aging. Towards this goal we will analyze the stem cell compartment in Phf6 conditional knockout mice and after CRISPR-directed PHF6 inactivation in human hematopoietic stem cells, leveraging in vitro and in vivo stem cell assays in combination with advanced computational analytical tools applied to single cell transcriptomics and epigenomics. These studies will ultimately facilitate the development of new targeted therapies aimed at improving the engraftment capacity of hematopoietic stem cells from aged donors and for the treatment of pathologies resulting from age-associated HSC deterioration.