Identification of novel epidermal progenitors

新表皮祖细胞的鉴定

• 批准号: 9891616
• 负责人: REBECCA Jane MORRIS
• 金额: $ 20.46万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891616
• 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; Epithelium; 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

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的上皮细胞的身份。 由细胞角蛋白表达确定的上皮细胞通常覆盖在身体表面(如表皮)或线隙。 (如胃肠道和呼吸道的衬里)。然而，研究发现， “正常、健康”小鼠和人骨髓来源上皮细胞的细胞角蛋白+/EpCAM+ 研究对象。据我们所知，还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缺口，对人类健康有影响， 尤其是关于毛囊或表皮干细胞受损或 在慢性炎症的情况下；或者在我们知道它们可以发挥作用的鳞癌中 此外，这些血液传播的上皮细胞目前干扰液体活检，如 “污染”细胞。因此，我们假设BMDEC包括一个新的祖细胞群体， 可以被招募到慢性受损的上皮细胞并再生。我们的具体目标是分析 在体外和体内使用我的实验室和其他人为鉴定这些细胞而开发的策略 毛囊和表皮中的上皮干细胞。BMDECs Will功能分析的意义 有助于了解一般的上皮生物学和血液学，有助于确认液体活检是一种 癌症研究中的诊断工具，并帮助我们实现预防、诊断和治疗癌症的最终目标 治疗慢性皮肤病，包括癌症和大疱性表皮松解症。科学的前提是 支持这一假设的前提是：1)RT-PCR检测到血液中微量的细胞角蛋白表达 和“正常”、健康的受试者的骨髓；2)相似的文献报道罕见的BMDEC被招募 3)几个高质量的病例报告；4) 我们自己的初步数据显示，BMDECs在小鼠的鳞状乳头状瘤亚群中募集； 我们通过四种不同的方法记录了“正常”成年小鼠体内BMDECs的存在。因此，要 测试我们的中心假设，从而实现我们最终目标的主要里程碑，我们将回答 以下是问题。BMDECs是否具有上皮干细胞的表型特征？和做BMDEC 表现为上皮干细胞？越来越多的证据表明BMDECs是多潜能上皮细胞 祖细胞，因为它们可能是多潜能的上皮祖细胞，所以它们可以用于再生 在医学上，以及在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 将军。这是一个全新的研究方向，将导致新的资金来源，以确定 BMDEC的招募机制以及如何调整他们的招募。