Refining Our Understanding of the Hematopoietic Stem Cell Niche

A major therapeutic goal of studying blood-forming hematopoietic stem cells (HSCs) is to understand the mechanisms by which HSCs are maintained in the bone marrow, so that they can be grown outside of the body and used in lieu of or in combination with bone marrow transplantation to treat hematopoietic illnesses. HSCs, as well as other somatic stem cells from different organ systems and organisms, rely on signals from their local microenvironment for their maintenance. However, the identity of the HSC niche is still poorly understood. One new model of the HSC niche is that HSCs, periarteriolar stromal cells, and nerve fibers are closely associated in rare periateriolar niches. Using a novel marker to identify HSCs in three-dimensional confocal images, -catulin-GFP, we measured the distances from thousands of HSCs to various landmarks in the bone marrow. We found that few HSCs are closely associated with either nerve fibers or arterioles. Mice lacking sympathetic nerves exhibit multiple changes in hematopoiesis, especially in response to injury, though all of the studies published so far have systemically ablated sympathetic nerves. This left unresolved the question of whether the changes in hematopoiesis reflect bone marrow denervation itself, or systemic effects of general sympathectomy. To test this, I developed a model for bone marrow-specific neuropathy by conditionally deleting nerve growth factor (Ngf) from bone marrow stromal cells. Using this model, I analyzed the role of bone marrow peripheral nerves in hematopoiesis. I demonstrated that while nerves play no role in bone marrow homeostasis, nerve signaling after bone marrow injury is essential for hematopoietic regeneration. Future studies will build on this work to understand how nerve fibers promote the regeneration of HSCs and bone marrow cells despite not innervating the HSC niche themselves.