Stem Cells: a Matter of Life and Death
Stem
cells ( play a pivotal role in fueling homeostasis and regeneration While
much focus has been given to self renewal and differentiation pathways regulating
SC fate, little is known regarding the specific mechanisms utilized for their
elimination During my Ph D I determined that the pro apoptotic protein ARTS
(a Septin 4 isoform) is highly expressed in cells comprising the intestinal SC (
niche and that its deletion protects cells from undergoing apoptosis As a result,
the Sept 4 /ARTS crypt displays heightened proliferation and, in culture, generates
massive cystic organoids due to enhanced Wnt/β catenin signaling Importantly, mice
deleted for Sept 4 /ARTS exhibit resistance against intestinal damage in a manner
dependent upon ISCs Finally, I was able to show that ARTS interacts with XIAP in
intestinal crypt cells and that deletion of XIAP can abrogate Sept 4 /ARTS
dependent phenotypes in an epistatic manner (Koren et al Nature Communications,
2018 These results indicate that ISCs utilize specific apoptotic proteins for their
elimination representing a unique therapeutic target
Currently
I am testing distinct compounds that have been identified via high
throughput in vitro and in silico screening platforms, for their potential to
therapeutically block the ARTS/ XIAP interface It is my greatest hope that my findings
may one day serve as a staple for human disease treatments
In
the skin, the presence of a distinct SC population that maintains the interfollicular
epidermis ( is highly debated We found that basal keratinocytes marked by Thy 1
do not express T cell markers, express a unique transcriptional profile, cycle
significantly slower than basal epidermal progenitors and display significant
expansion potential in vitro Multicolor lineage tracing analyses and mathematical
modeling reveals that Thy 1 basal keratinocytes do not compete neutrally alike IFE
progenitors and contribute long term to both epidermal replenishment and wound
repair Importantly, ablation of Thy 1 cells in T cell deficient mice strongly impairs
these processes, thus indicating the non redundant function of Thy 1 SCs in the
epidermis Taken together, these findings indicate the existence of a distinct slow
cycling SC population that plays a critical role in epidermal homeostasis and
