Development and regulation of stem cell lineages in skin

皮肤干细胞谱系的发育和调节

• 批准号: 10486832
• 负责人: Isaac Brownell
• 金额: $ 78.39万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486832
• 关键词: ATAC-seq; Afferent Neurons; Cell Differentiation process; Cell Lineage; Development; Embryo; Environment; Genetic Transcription; Hair follicle structure; In Vitro; Maintenance; Merkel Cells; Merkel cell carcinoma; Modeling; Mus; Neurosecretory Systems; Process; Regulation; Sensory; Signal Transduction; Skin; Touch sensation; Work; cell behavior; experimental study; interest; intraepithelial; mouse genetics; novel; perineural; single-cell RNA sequencing; stem cell population; stem cells

Following up on prior work that identified the perineural microenvironment as a regulator of hair follicle stem cells, we have completed a project describing a perivascular niche for hair follicle stem cells. Moreover, we have identified that sensory touch domes in the skin, and the Merkel cells housed there are also regulated by associated Shh signaling from sensory neurons. We have continued experiments demonstrating that touch domes are a novel and distinct cell lineage within the skin maintained by their own stem cell population. We have also investigated the developmental requirements for Merkel cell formation in skin. We have found that establishing the Merkel cell touch dome lineage in embryonic skin requires a cascade of Wnt, Eda, and intraepithelial Shh signaling. We have identified multiple transcriptional networks that are responsible for formation or maintenance of Merkel cells in mouse skin. Ongoing work using single cell RNA-seq and ATAC-seq investigates the transcriptional requirements for Merkel cell differentiation. We are applying our understanding of Merkel cell development to generate an in vitro differentiation model of Merkel cell formation. These studies have identified neuroendocrine lineage factors that are important for both normal Merkel cell formation and are critical in Merkel cell carcinoma.

跟进先前的工作，将周围的微环境确定为毛囊干细胞的调节剂，我们已经完成了一个描述毛囊干细胞血管周期壁裂的项目。此外，我们已经确定了皮肤中的感觉接触圆顶，并且所包含的默克尔细胞也受到感觉神经元的相关SHH信号的调节。我们继续进行实验，表明触摸圆顶是皮肤中由其自身的干细胞种群维持的新型细胞谱系。我们还研究了皮肤中默克尔细胞形成的发育要求。我们发现，在胚胎皮肤中建立默克尔细胞触摸圆顶谱系需要一系列Wnt，EDA和上皮内SHH信号传导。我们已经确定了多个转录网络，这些网络负责形成或维持小鼠皮肤中的默克尔细胞。使用单细胞RNA-SEQ和ATAC-SEQ进行的正在进行的工作研究了默克尔细胞分化的转录要求。我们正在应用对默克尔细胞发育的理解来产生默克尔细胞形成的体外分化模型。这些研究已经确定了对正常默克尔细胞形成至关重要的神经内分泌谱系因子，对于默克尔细胞癌至关重要。

项目成果

Merkel cells and touch domes: more than mechanosensory functions?

默克尔细胞和触摸穹顶：不仅仅是机械感觉功能？

• DOI: 10.1111/exd.12456
• 发表时间: 2014
• 期刊: Experimental dermatology
• 影响因子: 3.6
• 作者: Xiao,Ying;Williams,JonathanS;Brownell,Isaac
• 通讯作者: Brownell,Isaac

PD-L1 inhibition with avelumab for metastatic Merkel cell carcinoma.

• DOI: 10.1080/17512433.2018.1445966
• 发表时间: 2018-04
• 期刊: Expert review of clinical pharmacology
• 影响因子: 4.4
• 作者: Gaiser MR;Bongiorno M;Brownell I
• 通讯作者: Brownell I

Low pH reprograms somatic murine cells into pluripotent stem cells: a novel technique with therapeutic implications.

低 pH 值将小鼠体细胞重新编程为多能干细胞：一种具有治疗意义的新技术。

• DOI: 10.4161/cbt.28414
• 发表时间: 2014
• 期刊: Cancer biology & therapy
• 影响因子: 3.6
• 作者: Williams,JonathanS;Xiao,Ying;Brownell,Isaac
• 通讯作者: Brownell,Isaac