Hematopoietic Stem Cell engraftment in the injured niche

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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.