Biological tissues appear to “know” their intended final sizes and achieve them precisely and robustly. While,
in principle, a simple negative signaling feedback should be sufficient to explain how a given stem cell lineage
regulates its cellular outputs, in reality it cannot work because most tissues are physically large, with stem cells
and their progeny spread out over centimeter-scale distances. How tissues overcome the microscopic decay
limits of diffusible molecular signals to breach distances orders-of-magnitude in spatial scale remains elusive.
This application is inspired by our serendipitous discovery that FGF and BMP mutant mice are able to grow
super-long and highly imprecise hairs that can exceed the length of normal mouse hairs by 7-fold. Our lineage
analyses suggest that hair stem cells continuously replenish short-lived transit-amplifying (TA) cells spatially
located nearly 1 cm away from the stem cells. Interestingly, our single-cell RNA-sequencing analyses reveal
previously unappreciated heterogeneity of the intermediate epithelial progenitor cells physically located between
the stem and TA cells.
Through an integrated mathematical and experimental approach, this application will focus on testing
our new hypothesis that dynamic equilibrium between two or more intermediate cell states and their associated
cell-cell communications enable feedback information propagation over large spatial scale from TA cells to stem
cells to regulate the new progenitor cell production for hair size control. The first aim of the proposed research
is to profile and quantify the heterogeneity of intermediate epithelial progenitors, and computationally and
experimentally determine the functional link between specific intermediate progenitor states in the hair follicle
and the hair length and its precision. The second aim is to define the cell-cell communication networks within the
epithelial hair follicle lineage, and computationally and experimentally establish how multiple short-range
signaling activities coordinate to form a long-range feedback mechanism that controls progenitor flux between
distant stem and TA cell compartments for proper hair growth. The third aim is to determine the signaling impact
of mesenchymal niche cells, which surround the hair follicle, on the epithelial lineage cells for hair size control.
The study premise is based on novel and extensive preliminary experimental and computational data. The
proposed studies are significant because they will establish new long-range signaling mechanisms and
uncover novel roles of intermediate cell states in tissue size control. The proposed studies are innovative
because they will establish new experimental models for studying tissue size regulation using super-long and
extra-short hair mutant mice and will result in numerous new genetic mouse tools for epithelial stem cell research.
They will also result in several novel mathematical and computational tools for analyzing single-cell RNA-
sequencing data and new spatial models for complex cell lineages, such as in the hair follicle.