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

越来越多的证据表明，宿主微环境在宿主免疫中起着重要作用。 调节正常和恶性干细胞的自我更新和分化。具体地点， 然而，这些干细胞小生境的细胞组分和分子细节知之甚少。使用in 活体共聚焦和多光子分子成像技术研究小鼠完整骨中细胞相互作用 骨髓（BM），我们已经定义了一种新的血管周围肿瘤和造血干/祖细胞（HSPC） 利基我们已经确定了白血病细胞进入这个小生境所使用的分子，然而， 对这些地区的高铁过境管理尚未确定。此外，这一利基在 维持正常HSC或协调特定HSC细胞功能是未知的。鉴于必须 基于HSC的移植疗法以及肿瘤转移到BM的临床意义， 在理解这些细胞相互作用方面有很大的治疗潜力。我们研究的长期目标 因此，确定这种肿瘤和HSC小生境的分子结构和功能意义 使用最先进的体内成像技术结合细胞和分子生物学方法。 具体而言，我们将1）研究HSC在这些小生境中的转运和植入机制，2） 确定肿瘤生长如何影响小生境以及肿瘤和良性HSC是否在小生境内竞争， 以及3）开发靶向纳米颗粒以在血管的精确区域释放包封的化合物 利基这些纳米颗粒将作为一种独特的工具来阐明介导HSC的关键分子， 肿瘤在小生境中的增殖，并作为靶向药物递送剂的原型。最终，我们的目标是利用 从这些研究中获得的知识可以设计出特定的抗肿瘤治疗方法， 并确定提高干细胞治疗效果的因素。

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.