Stem cell, tumor and bone marrow microenvironment cross-talk in vivo

越来越多的证据表明，宿主微环境在 调节正常和恶性干细胞的自我更新和分化。具体的地点， 然而，人们对这些干细胞利基的细胞成分和分子细节知之甚少。使用中 活体共聚焦和多光子分子成像技术研究完整小鼠骨骼中的细胞相互作用 骨髓(BM)，我们定义了一种新的血管周围肿瘤和造血干/祖细胞(HSPC) 利基市场。我们已经确定了白血病细胞用来访问这个利基的分子，然而其机制 管理向这些地区过渡的HSC尚未得到界定。此外，这一利基市场在 维持正常的HSC或协调特定的HSC细胞功能尚不清楚。鉴于……的重要性 以造血干细胞为基础的移植治疗以及肿瘤向骨髓转移的临床意义 在理解这些细胞相互作用方面具有巨大的治疗潜力。我们研究的长期目标是 因此，要确定该肿瘤和HSC利基的分子结构和功能意义 使用最先进的活体成像技术，结合细胞和分子生物学方法。 具体地说，我们将1)检查管理这些缝隙中的HSC移植和植入的机制，2) 确定肿瘤生长如何影响生态位，以及肿瘤和良性HSCs是否在生态位内竞争， 3)开发有针对性的纳米颗粒，在血管的精确区域释放包裹的化合物 利基市场。这些纳米粒子将作为一种独特的工具来阐明介导HSC和 肿瘤在壁龛中的增殖，并作为靶向药物递送剂的原型。最终，我们的目标是使用 从这些研究中获得的知识，以设计特定的抗肿瘤治疗，以避免正常的造血 并确定提高干细胞疗法疗效的因素。

A growing body of evidence suggests that the host microenvironment plays an important role in the regulation of both normal and malignant stem cell self-renewal and differentiation. The specific locations, cellular components and molecular details of these stem cell niches are, however, little understood. Using in vivo confocal and multiphoton molecular imaging techniques to study cell interactions in the intact murine bone marrow (BM), we have defined a novel perivascular tumor and hematopoietic stem/progenitor cell (HSPC) niche. We have identified the molecules used by leukemic cells to access this niche, however the mechanisms governing HSC transit to these areas have not yet been defined. Moreover, the role of this niche in maintaining normal HSCs or coordinating specific HSC cell functions is unknown. Given the importance of HSC-based transplantation therapies as well as the clinical significance of tumor metastasis to the BM, there is great therapeutic potential in understanding these cellular interactions. The long-term goals of our research are, therefore, to define the molecular architecture and functional significance of this tumor and HSC niche using state-of-the-art in vivo imaging techniques combined with cell and molecular biology approaches. Specifically, we will 1) examine the mechanisms governing HSC transit and engraftment in these niches, 2) determine how tumor growth impacts the niche and whether tumor and benign HSCs compete within the niche, and 3) develop targeted nanoparticles to release encapsulated compounds in precise regions of the vascular niche. These nanoparticles will serve as a unique tool to elucidate the critical molecules that mediate HSC and tumor proliferation in the niche and as a prototype for a targeted drug delivery agent. Ultimately, we aim to use the knowledge from these studies to design specific anti-tumor treatments that spare normal hematopoiesis and to define factors that improve the efficacy of stem cell-based therapies.