Lipid regulation of the stem cell niche

PROJECT SUMMARY/ABSTRACT
Adult stem cells are progenitor cells capable of tissue regeneration during life through the ability to both self-
renewal and to produce specialized cells upon division. Stem cells reside in microenvironments called “niches”
that integrate systemic cues and provide signals for stem cell maintenance. Over the years, the use of the stem
cell systems present in Drosophila melanogaster has revealed mechanisms that control stem cell niches in
homeostasis and pathology. Recently, a model has emerged pointing to a strong conserved correlation between
lipid accumulation and stem cell loss. Given the power of Drosophila genetics, the readily accessible molecular
tools, the well-characterized stem and niche cell populations, and the high degree of evolutionary conservation
in metabolic genes, the fly testis niche is an ideal model for the intersectional study of metabolism and stem cell
biology in physiological and pathophysiological conditions. Our long-term goal is to understand how changes
in lipid metabolism affect stem cell niche homeostasis. The PI’s published works build a model where the ectopic
accumulation of lipids in the fly testis niche is detrimental to stem cell function. Excess lipid accumulation in stem
cells led to their loss through differentiation. Accordingly, lipid accumulation has been shown to be detrimental
to stem cell maintenance across species. The overall objective of this proposal is to understand mechanistically
how the stem cell niche is affected by conditions that trigger ectopic accumulation of lipids. Preliminary data in
this proposal show that niche (hub) cells are also sensitive to lipid accumulation, and that multiple mechanisms
are likely at play to control lipid levels in the testis stem cell niche. Of note, preliminary data in this proposal show
for the first time that lipid metabolism controls somatic cell fate in the testis by inducing conversion between
niche and somatic stem cells. Hence, our central hypothesis is that lipid accumulation promotes loss of stem
cell niche homeostasis. We will test this hypothesis through three specific aims: 1) determining how
microenvironmental stiffness impacts lipid anabolism and niche homeostasis; 2) characterizing the role of
apolipoproteins in fat-transporting and stem cell maintenance; and 3) investigating the role of lactate transport
(a precursor in lipogenesis) in niche and stem cells. The merit of this study relies on its novelty – showing that
changes in lipid metabolism can promote the conversion between a niche and a stem cell – and on the generation
of a useful paradigm for testing how pathophysiological changes in lipid metabolism yield in loss of stem cell
niches. Given the high incidence of metabolic disorders in the population, understanding how lipid accumulation
affects stem cell niches is pivotal for the development of novel stem cell-based therapies, especially those
targeting metabolic disorders. The proposed studies will also strengthen the research environment at the
University of Louisville, providing opportunities for the training of postdoctoral fellows, graduate and
undergraduate research assistants in the laboratory.