A fundamental question of tissue biology concerns how cells adopt different fates, at the right time and location to facilitate lifelong tissue regeneration. My research seeks to understand how a spectrum of inputs, ranging in scale from local cellular interactions to tissue-wide cues, synergistically control the activity of cells in mammalian skin. My long-term goals are to uncover a comprehensive framework of tissue laws that link the needs of a tissue to the behaviors of its cells and understand how these laws adapt during tissue regeneration and aging. Without this fundamental knowledge, we will remain stunted in our efforts to advance regenerative medicine and develop therapeutic strategies for age-associated diseases. A major challenge in addressing this question has been our inability to study changes in cellular behavior in live organisms over time. To overcome this limitation, my research combines intravital multiphoton microscopy with various genetic tools to track tissue-resident stem cell, stromal and immune cell populations over time in the skin of live mice.
As a graduate student in the lab of Valentina Greco, I utilized the cyclic remodeling of the skin hair follicle as a model to study the mechanisms that regulate stem cell pool size and behavior. Live imaging of hair follicles at the growth/regression transition revealed that an expanded stem cell pool undergoes spatiotemporally organized elimination of cells through apoptosis. Unexpectedly, we discovered that during this process hair follicle stem cells act as the major phagocytic population in clearing their apoptotic neighbors. We went on to determine that these stem cell behaviors were dependent on TGF-β signaling from the surrounding mesenchymal niche. Specifically, removal of either TGF-β signaling or the niche itself resulted in the retention and re-expansion of stem cells that would have been lost (Mesa et al. Nature 2015).
This work and others from the Greco lab demonstrate that an extrinsic signal can promote counterbalancing stem cell behaviors. Thus, to understand the heterogeneous stem cell response within a tissue, we tracked the entire behavioral history, or lifetime, of epidermal stem cells over multiple generations. Intriguingly, we found that epidermal stem cells do not exhibit intrinsic bias for one behavior over another, nor do stem cells utilize intrinsic fate mechanisms such as stem cell hierarchy or asymmetric cell divisions (Rompolas*, Mesa* et al. Science 2016). Rather, by tracking all epidermal stem cell activity in large regions of living mice, we show that self-renewal is locally coordinated with epidermal differentiation, with a lag time of 1 to 2 days. In both homeostasis and upon experimental perturbation, we find that differentiation of a single stem cell is followed by division of a direct neighbor, but not vice versa. Finally, we show that exit from the stem cell compartment is sufficient to drive neighboring stem cell self-renewal. Together, these findings establish that epidermal stem cell self-renewal is not the constitutive driver of homeostasis. Instead, it is precisely tuned to tissue demand and responds directly to neighbor cell differentiation. (Mesa*, Kawaguchi*, Cockburn* et al. Cell Stem Cell 2018)
In my postdoctoral studies, I joined the lab of Dan Littman to investigate how immune cells maintain resident fates and support tissue function over the lifetime of the organism. Combining my expertise in live imaging and genetic tools developed in the Littman lab, I found a population of resident macrophages that was lost with age in both mice and humans. Moreover, time-lapse recordings revealed these macrophages cover the blood capillary network and are essential for rapid repair and resolution of microvasculature ischemic events. Strikingly, we found that decline in capillary-associated macrophages (CAMs) with age could be overcome through changes in the aged microenvironment, which could still recruit and maintain new CAMs from blood monocytes to improve capillary resilience to future ischemic events (Mesa, et. al. bioRxiv, 2023).