Angiogenin Regulates Normal and Malignant Hematopoiesis.
Abstract: Stem and
progenitor cells are critical regulators of tissue homeostasis, regeneration, and
disease. In the hematopoietic system, stem and progenitor cells are required for normal
blood cell production and cell output following stress or in disease. The precise
regulation of primitive cell populations, however, is ill-defined. This thesis
investigates the function of a previously ... read moreunrecognized regulator of normal and malignant
hematopoiesis, angiogenin (ANG). ANG is a secreted, vertebrate-specific ribonuclease
(RNase) known to promote the growth and survival of a number of cell types; however, its
function in the hematopoietic system has remained undefined. In this thesis, ANG is
identified as a cell-type specific regulator of primitive hematopoietic cells.
Specifically, ANG restricts proliferation of hematopoietic stem/progenitor cells (HSPC),
but enhances proliferation of lineage- committed myeloid-restricted progenitor cells
(MyePro). Mechanistically, ANG regulates RNA processing, and this effect is cell
type-specific. In HSPC, ANG promotes generation of tRNA-derived stress-induced small RNA
(tiRNA), which restricts protein synthesis. In MyePro, ANG promotes ribosomal RNA (rRNA)
transcription, which enhances protein synthesis. Work described in this thesis also
demonstrates that bone marrow (BM) niche- derived and hematopoietic cell-derived sources
of ANG regulate proliferation of primitive hematopoietic cells. Importantly, Plexin-B2
(PLXNB2) is identified as the cell surface- receptor of ANG in primitive HSPC and
lineage-committed progenitor cells. Therefore, ANG plays non-cell autonomous and cell
autonomous roles in the regulation of hematopoiesis. This thesis also demonstrates the
clinical relevance of ANG in the hematopoietic system. First, treatment of irradiated
animals with recombinant ANG protein improves survival by preventing or mitigating
radiation-induced bone marrow failure (BMF). Second, ex vivo treatment of mouse and
human HSPC with ANG protein improves hematopoietic regeneration in transplantation.
Third, ANG regulates growth properties of primitive cells derived from patients
diagnosed with chronic myelogenous leukemia, suggesting a therapeutic role in malignant
hematopoiesis. Together, these studies demonstrate that regulation of primitive
hematopoietic cells by ANG is highly relevant in BMF treatment, improved efficacy of
transplantation, and in leukemia.
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisor: Guo-fu Hu.
Committee: Athar Chishti, Ira Herman, Daniel Jay, and David Scadden.
Keyword: Biology.read less