The Niche for Extramedullary Hematopoiesis in the Spleen

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The ability to regenerate niches or to create new niches after injury is critical to accelerate tissue repair and may underlie the regenerative capacity of mammalian tissues. Despite its physiological importance, almost nothing is known about how mammalian tissues activate facultative niches after injury. The mouse hematopoietic system provides a dynamic example of new stem cell niche activation. After hematopoietic injury, hematopoietic stem cells (HSCs) mobilize from the bone marrow to the spleen and participate in extramedullary hematopoiesis (EMH), which supplements bone marrow hematopoiesis for as long as the hematopoietic stress persists. The induction of hematopoiesis in the spleen involves the creation or activation of a facultative niche in the spleen, yet no niche in this tissue has been characterized. Understanding the nature of the extramedullary niche in the spleen will clarify how the hematopoietic microenvironment regulates HSC and other progenitor function to reestablish homeostasis after injury. The work in this thesis identifies the cell types in the spleen that are physiologically important sources of the niche factors SCF and CXCL12 during extramedullary hematopoiesis. By using fluorescent reporter alleles for each niche factor, I have discovered that spleen endothelial and perivascular stromal cells secrete SCF, and a subset of spleen perivascular stromal cells secretes CXCL12. Conditional deletion of Scf from spleen endothelial or perivascular stromal cells impairs EMH after injury by depleting HSCs and myeloerythroid progenitors from the spleen. Conditional deletion of Cxcl12 from spleen perivascular stromal cells impairs EMH by depleting myeloerythroid progenitors and mobilizing a minority of HSCs from the spleen. This work conclusively demonstrates that spleen endothelial cells maintain EMH by secreting SCF, and spleen perivascular stromal cells maintain EMH by secreting both SCF and CXCL12. These cell types represent the first stromal populations in the spleen shown to maintain HSCs and EMH after injury. Further analyses of these cells during injury may reveal how hematopoietic niches are created.

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The file named "INRA-DISSERTATION-2017.pdf" is the primary dissertation file. A supplemental movie file ("Video 1.mp4") is also available and may be viewed individually.
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