Identification of novel epidermal progenitors

这里提出的研究解决了血液和骨髓中新上皮细胞的身份。 通过细胞角蛋白表达鉴定的上皮细胞通常覆盖体表（如表皮）或线间隙 (like胃肠道和呼吸道的内层）。然而，研究发现， 细胞角蛋白+/EpCAM+骨髓衍生上皮细胞（BMDEC）在“正常，健康”的鼠和人 科目据我们所知，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空白，对人类健康有影响， 特别是对于毛囊或表皮干细胞已经受损的情况， 破坏;在慢性炎症的情况下;或者在鳞状细胞癌中，我们知道它们可以作为 此外，这些血源性上皮细胞目前干扰液体活检， “污染”细胞。因此，我们假设BMDEC包括一个新的祖细胞群体， 可以招募到慢性受损的上皮细胞并使其再生。我们的具体目标是分析 这些细胞在体外和体内使用的策略，我的实验室和其他人已经开发了识别 毛囊和表皮中的上皮干细胞。BMDEC功能分析的意义在于 有助于理解上皮生物学和血液学的一般，以验证液体活检作为一种 癌症研究中的诊断工具，并帮助我们实现预防，诊断和治疗的最终目标。 治疗慢性皮肤病，包括癌症和大疱性表皮病。科学前提 支持这一假设的前提是：1）RT-PCR检测血液中细胞角蛋白表达的痕迹 和“正常”、健康人类受试者的骨髓; 2）报告招募罕见BMDEC的类似文献 小鼠急性损伤后暂时性皮肤上皮; 3）几个高质量的病例报告;和4） 我们自己的初步数据证明了BMDEC在小鼠鳞状乳头状瘤中的募集; 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 测试我们的中心假设，从而实现我们的最终目标的主要里程碑，我们将回答 以下问题。BMDEC是否具有上皮干细胞的表型特征？BMDEC是否 表现为上皮干细胞越来越多的证据表明，BMDEC是多潜能上皮细胞， 祖细胞，并且因为它们可能是多潜能上皮祖细胞，所以它们可以用于再生 药物和在组织干细胞长期受损的情况下。因此本 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，将带来新的资金来源来确定 BMDEC的招聘机制以及如何调节他们的招聘。

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.