Identifying cellular and molecular mechanisms controlling lineage fate of lymphoid-primed multipotent progenitors and alterations in aging
Hematopoiesis is a dynamic process responsible for producing the cellular components of
the blood system for the life of an organism. With aging, the robustness and function of
the immune system is compromised, in part caused by a general shift in cell production
towards the myeloid cell types at the expense of the lymphoid and erythroid cell types.
This bias can be seen in the ... read moreclinical manifestations of increased risk of myeloid
proliferative disorders and leukemias as well as susceptibility to anemias and infection
in older adults. While hematopoietic stem cells (HSCs) have long been considered to be
the foundation of hematopoietic cell production, recent in vivo lineage tracing studies
have shown that the contribution of multipotent progenitors (MPPs) to long-term,
steady-state hematopoiesis is greater than previously thought. However, how changes in
the composition and function of the MPP compartment contribute to age-related phenotypes
such as myeloid skewing were unknown. To interrogate functional changes of MPP cells in
a high-throughput assay, I developed a novel in vitro culture system that was also
adapted for single cell fate mapping. Using this assay and other techniques, I have
discovered the frequency and function of a particular subset of MPP cells,
lymphoid-primed multipotent progenitors (LMPP/MPP4), decreases with aging. These changes
contribute to increased myeloid production and decreased B-lymphoid production with
aging. In an independent study, I have utilized the high-throughput assay I developed to
screen for epigenetic regulators controlling myeloid versus lymphoid cell production
from LMPP/MPP4 cells. I have discovered that altered expression of the histone lysine
methyltransferase Kmt5a in LMPP/MPP4 cells causes expansion of myeloid cell production
from these progenitors. This study suggests that specific epigenetic mechanisms regulate
lineage production from MPP cells. Together, this work has direct implications for
better understanding the molecular drivers of biased myeloid lineage production from
lymphoid-primed multipotent progenitor cells and how this contributes to age associated
myeloid skewing of hematopoiesis and
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Genetics.
Advisor: Jennifer Trowbridge.
Committee: Gavin Schnitzler, Robert Braun, Steven Munger, and Ewelina Bolcun-Filas.
Keyword: Genetics.read less