Hematopoietic stem cells (HSCs) possess the remarkable capacity to self-renew and sustain the entirety of the
blood and immune system throughout the lifetime of an individual. HSC maintenance depends upon signals
and paracrine factors produced by the bone marrow (BM) microenvironment or “niche.” HSC regeneration
following myelotoxicity requires regeneration of vascular ECs within the niche. However, the precise
mechanisms through which BM ECs regulate HSC regeneration remain incompletely understood. Elucidation
of the mechanisms that govern HSC regeneration could have significant medical impact since a substantial
percentage of cancer patients receive HSC-depleting high dose chemotherapy, radiation therapy or
myeloablative hematopoietic cell transplantation in the treatment of their disease. Hematopoietic toxicities from
such regimens commonly cause hospitalizations, infectious complications and delays in curative therapy. We
have identified an autocrine mechanism in which BM ECs secrete a protein, semaphorin 3A (SEMA3A), in
response to myelotoxic irradiation, and this protein binds to an EC receptor, NRP1, causing increased BM EC
death and delayed BM vascular regeneration. We hypothesize that targeted inhibition of SEMA3A or its
receptor, NRP1, on BM ECs will block SEMA3A-NRP1 signaling in BM ECs following injury, thereby facilitating
the regeneration of BM ECs and the BM vascular niche wherein HSCs reside. In so doing, we propose that
early restoration of the BM vasculature will promote HSC regeneration and early hematopoietic reconstitution
after myelosuppression. Indeed, our preliminary results suggest that antibody-mediated inhibition of NRP1
decreases BM apoptosis following irradiation and accelerates BM vascular regeneration in irradiated mice.
Importantly, systemic anti-NRP1 treatment also promotes the early recovery of white blood cells, neutrophils,
myeloid progenitor cells, HSCs with long-term repopulating capacity, and increases survival of irradiated mice.
We propose to utilize pharmacologic and cell-specific genetic models to characterize the functions of SEMA3A
and NRP1 in regulating BM vascular regeneration and hematopoietic regeneration. We will also interrogate the
role of integrin function in mediating SEMA3A effects on BM EC function and will evaluate the effects of
modulation of SEMA3A-NRP1 signaling on human BM EC function and human hematopoietic regeneration.
Our broad, long-term objective is to define the role of the SEMA3A-NRP1 pathway in regulating BM vascular
regeneration as a novel platform for therapeutic human hematopoietic regeneration.