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Identification of novel epidermal progenitors

新表皮祖细胞的鉴定

基本信息

批准号：
10162409
负责人：
REBECCA Jane MORRIS
金额：
$ 16.93万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10162409
关键词：
Acute Address Adult Behavioral Biology Blood Body Surface Bone Marrow Case Study Cells Characteristics Chronic Cutaneous Cytokeratin Data Detection Diagnosis Diagnostic Epidermis Epidermolysis Bullosa Epithelial Epithelial Cells Fluorescent in Situ Hybridization Funding Funding Agency Gastrointestinal tract structure Goals Hair follicle structure Health Hematology Human In Vitro Inflammation Injury Knowledge Laboratories Literature Malignant Neoplasms Mesenchymal Methods Mus Natural regeneration Phagocytes Phenotype Population Proliferating Property Psoriasis Regenerative Medicine Reporting Research Respiratory System Reverse Transcriptase Polymerase Chain Reaction Sampling Source Squamous Cell Papillomas Squamous Epithelium TACSTD1 gene Testing Validation anticancer research design epidermal stem cell epithelial stem cell epithelial to mesenchymal transition high risk human subject in vivo keratinization liquid biopsy macrophage novel prevent progenitor reconstitution recruit skin disorder skin lesion stem cells tissue stem cells tool tumor

项目摘要

The research proposed here addresses the identity of novel epithelial cells in blood and bone marrow. Epithelial cells identified by cytokeratin expression usually cover body surfaces (like epidermis) or line spaces (like the linings of the gastrointestinal and respiratory tracts). However, research has identified cytokeratin+/EpCAM+ bone marrow derived epithelial cells (BMDECs) in “normal, healthy” murine and human subjects. To our knowledge, no one has performed functional analyses and characterization of these cells. This is a significant gap in our knowledge of epithelial biology with ramifications towards human health, particularly with regard to conditions where hair follicle or epidermal stem cells have been damaged or destroyed; in instances of chronic inflammation; or in squamous cancers where we know they can function as tumor initiating cells Moreover, these blood borne epithelial cells currently interfere with liquid biopsies as “contaminating” cells. We therefore hypothesize that BMDECs include a novel population of progenitors that can be recruited to chronically compromised epithelium and regenerate it. Our specific aims are to analyze these cells in vitro and in vivo using strategies that my laboratory and others have developed for identifying epithelial stem cells in hair follicles and epidermis. The significance of functional analysis of BMDECs will contribute to understanding epithelial biology and hematology in general, to the validation of liquid biopsy as a diagnostic tool in cancer research, and help us to achieve our ultimate goal of preventing, diagnosing, and curing chronic cutaneous diseases including cancer and epidermolysis bullosa. The scientific premise supporting this hypothesis is predicated upon: 1) RT-PCR detection of traces of cytokeratin expression in blood and bone marrow of “normal”, healthy human subjects; 2) similar literature reporting rare BMDECs recruited temporarily to the cutaneous epithelium upon acute injury in mice; 3) several high quality case reports; and 4) our own Preliminary Data demonstrating recruitment of BMDECs to a subset of squamous papillomas in mice; and our documenting the presence of BMDECs in “normal” adult mice by four different methods. Therefore, to test our central hypothesis and thereby achieve major milestones towards our ultimate goal, we will answer the following questions. Do BMDECs have phenotypic characteristics of epithelial stem cells? And Do BMDECs behave as epithelial stem cells? Converging evidence suggests that BMDECs are multipotential epithelial progenitors, and because they are likely multipotential epithelial progenitors they could be used in regenerative medicine and in circumstances where the tissue stem cells are chronically compromised. Therefore, this research has the potential to move forward the fields of cutaneous biology, hematology and epithelial biology in general. This is a completely new direction of research that will lead to new sources of funding to determine the mechanism of BMDEC recruitment as well as how to modulate their recruitment.

这里提出的研究解决了血液和骨髓中新型上皮细胞的身份。通过细胞角蛋白表达识别的上皮细胞通常覆盖身体表面（如表皮）或线间隙（如胃肠道和呼吸道的内壁）。然而，研究发现 “正常、健康”小鼠和人类的细胞角蛋白+/EpCAM+ 骨髓来源的上皮细胞 (BMDEC) 科目。据我们所知，没有人对这些细胞进行功能分析和表征。这是我们对上皮生物学知识的一个重大差距，对人类健康产生影响，特别是毛囊或表皮干细胞受损或被摧毁；在慢性炎症的情况下；或者在鳞状癌中，我们知道它们可以发挥作用此外，这些血源性上皮细胞目前干扰液体活检，如 “污染”细胞。因此，我们假设 BMDEC 包含一个新的祖细胞群，可以招募到长期受损的上皮并使其再生。我们的具体目标是分析这些细胞在体外和体内使用我的实验室和其他人开发的用于识别的策略毛囊和表皮中的上皮干细胞。 BMDEC 功能分析的意义有助于理解上皮生物学和血液学，验证液体活检作为一种方法癌症研究中的诊断工具，帮助我们实现预防、诊断和治疗的最终目标治疗慢性皮肤病，包括癌症和大疱性表皮松解症。科学前提支持这一假设的依据是：1) RT-PCR 检测血液中细胞角蛋白表达的痕迹以及“正常”、健康人类受试者的骨髓； 2) 类似文献报道了招募稀有 BMDEC 小鼠急性损伤后暂时作用于皮肤上皮； 3）多篇高质量病例报告；和 4) 我们自己的初步数据表明 BMDEC 募集到小鼠鳞状乳头状瘤的一个子集中；我们通过四种不同的方法记录了“正常”成年小鼠中 BMDEC 的存在。因此，要检验我们的中心假设，从而实现我们最终目标的重大里程碑，我们将回答以下问题。 BMDECs是否具有上皮干细胞的表型特征？并执行 BMDEC 表现得像上皮干细胞？综合证据表明 BMDEC 是多能上皮细胞祖细胞，并且由于它们可能是多潜能上皮祖细胞，因此可用于再生医学以及组织干细胞长期受损的情况下。因此，这研究有可能推动皮肤生物学、血液学和上皮生物学领域的发展一般的。这是一个全新的研究方向，将带来新的资金来源，以确定 BMDEC 招募机制以及如何调节其招募。