Kai Mesa, PhD

HHMI Fellow of The Jane Coffin Childs Memorial Fund for Medical Research

PhD Genetics, Yale University, 2017

In my PhD lab, I focused on understanding the cellular mechanisms that maintain and regulate tissue resident stem cell populations. A major challenge in addressing this question has been the inability to study stem cells in their native tissue environment. To overcome this limitation, I helped to develop a two-photon microscopy based imaging approach to track the skin-resident stem cell populations in live mice. 

At the beginning of my PhD 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 I discovered that during this process hair follicle stem cells act as the major phagocytic population in clearing their apoptotic neighbors. I 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 my PhD lab demonstrate that an extrinsic signal can promote counterbalancing stem cell behaviors, such as death/eating or differentiation/proliferation. Thus, to understand the heterogeneous stem cell response within a tissue, I tracked the entire behavioral history, or lifetime, of epidermal stem cells over multiple generations. Intriguingly, I found in collaboration with another lab member 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). 

In the Littman lab, I am interested in investigating the astonishing ability of limb regeneration following amputation. In mammalian species including mice and humans, this regenerative capability has been restricted to the digit tip. Both digit tip and complete limb regeneration follow a stereotypic process termed epimorphic regeneration where a heterogeneous population of progenitor cells, termed the blastema, form at the injury site to replace the multiple tissues lost. The initial events during the inflammatory response that permit blastema rather than scar or tumor formation in mammals are largely unknown.  Work from our lab and others has established diverse roles for macrophages in orchestrating the inflammatory response for both scarring, regenerative as well as cancer outcomes. Additionally, recent work has implicated an essential role for macrophages in models of epimorphic regeneration. However, it remains unclear how macrophages and the inflammatory response, in general, facilitate epimorphic regeneration while suppressing tumorigenesis. To address this fundamental question, I will use the adult mouse digit tip which displays stereotypic regenerative or scarring outcomes dependent on amputation site. This in combination with diverse genetics tools developed in our lab to study inflammatory cell dynamics in vivo, will provide insights into how injury-induced inflammation yields a permissive tissue environment for epimorphic regeneration, rather than scar tissue or aberrant neoplasms (such as cancer) from forming.

 
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Publications:

Rompolas, P*, Mesa, KR*, et al. Spatiotemporal coordination of stem cell commitment during epidermal homeostasis. Science (2016). (*equal contribution)

Mesa, KR, Rompolas, P & Greco, V. The dynamic duo: niche/stem cell interdependency. Stem Cell Reports (2015).

Mesa, KR et al. Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool. Nature (2015).

Pineda, C*, Park, S*, Mesa, KR, et al. Intravital imaging of hair follicle regeneration in the mouse. Nature Protocols (2015).

Mesa, KR & Greco, V. Linking morphogen and chromatin in the hair follicle. Dev. Cell (2013).

Rompolas, P, Mesa, KR & Greco, V. Spatial organization within a niche as a determinant of stem-cell fate. Nature (2013).

Prakash, A, Mesa, KR et al. Alveolar macrophages and Toll-like receptor 4 mediate ventilated lung ischemia reperfusion injury in mice. Anesthesiology(2012).

Wilhelmsen, K, Mesa, KR, et al. ERK5 protein promotes, whereas MEK1 protein differentially regulates, the Toll-like receptor 2 protein-dependent activation of human endothelial cells and monocytes. J. Biol. Chem. (2012).

Wilhelmsen, K, Mesa, KR, et al. Activation of endothelial TLR2 by bacterial lipoprotein upregulates proteins specific for the neutrophil response. Innate Immun. (2012).