Hematopoietic Stem Cell engraftment in the injured niche

摘要： 造血干细胞移植仍然是许多患者的唯一治愈性治疗。 血液病缺乏对造血干细胞和祖细胞如何在体内移植的理解， 再生骨髓阻碍了提高移植效率的新疗法的开发， 特别是当供体干细胞有限时。进展的一个主要限制是缺乏检查工具 原位分化我们已经开发出方法来成像和命运地图几乎所有步骤的血细胞 现场生产。本提案的目的是生成造血细胞植入图谱， 确定当地微环境如何促进移植。 我们已经发现，不同的血窦和巨核细胞亚群识别出不同的生理区域， 高或差供体细胞移植。我们假设高供体细胞植入区域代表了 选择性地促进短期植入的祖细胞小生境。相反，低供体细胞区域 移植代表促进克隆干细胞更新和长期移植干细胞小生境。 我们将从两个方面来检验这一假设。在目标1中，我们将生成一个再生的成像图谱， 造血和测试的假设，祖细胞和干细胞差异定位于不同的骨 骨髓区在目标2中，我们将研究再生过程中独特的小生境的机制。 微环境支持再生造血。

Abstract: Hematopoietic stem cell transplantation remains the only curative treatment for many patients with hematological disease. A lack of understanding of how hematopoietic stem cells and progenitors engraft in the regenerating marrow hampers the development of new therapies to improve transplantation efficiency, especially when donor stem cells are limiting. A major limitation for progress was the lack of tools to examine differentiation in situ. We have developed methods to image and fate map virtually all steps of blood cell production in situ. The objective of this proposal is to generate an atlas of hematopoietic cell engraftment and determine how the local microenvironment promotes engraftment. We have found that different subsets of sinusoids and megakaryocytes identify physically distinct regions of high or poor donor cell engraftment. We hypothesize that regions of high donor cell engraftment represent progenitor niches that selectively promote short-term engraftment. In contrast areas of low donor cell engraftment represent stem cells niches that promote clonal stem cell renewal and long-term engraftment. We will test this hypothesis in two aims. In Aim 1 we will generate an imaging atlas of regenerative hematopoiesis and test the hypothesis that progenitors and stem cells differentially localize to different bone marrow regions. In Aim 2 we will investigate the mechanisms through which unique niches in the regenerating microenvironment support regenerative hematopoiesis.