Research Interests

Stem cells as agents of physiologic organ adaptation

Animals live in dynamic environments where external conditions vary at cyclic or irregular intervals. When faced with environmental change, an individual’s physiological fitness requires its organ systems to functionally adapt. One type of adult organ adaptation is function-enhancing growth in response to increased physiological demand. In contrast to developmental growth, adaptive growth is reversible, repeatable, and extrinsically induced. However, the mechanistic origins of adaptive flexibility and responsiveness in adult tissues are largely mysterious.

The adult Drosophila midgut is a self-renewing organ analogous to the vertebrate small intestine. Common attributes including cellular physiology, anatomic layout, stem cell lineages, and fate determinants, while simplified in the fly, imply that underlying regulatory principles are likely to be shared. The midgut is a uniquely tractable model to study adaptive growth; not only can gene expression be manipulated and lineages traced at single-cell and whole-tissue levels, but complete population counts of all cell types are possible. I have found that when dietary load increases, midgut stem cells activate a reversible growth program that increases total intestinal cell number and digestive capacity. My goal is to understand how this nutrient-driven mechanism regulates stem cells to achieve lifelong optimization of organ form and function.

Midgut stem cells (green) are dispersed throughout the fly intestinal epithelium. They mediate tissue renewal, injury repair, and adaptive growth.

(left) The midgut is surrounded by layers of circular and longitudinal visceral muscle. (right) A cross section through the gut tube shows the proximity of midgut stem cells (yellow arrows) to visceral muscle fibers expressing insulin-like peptide 3 (green).

How do molecular signals cause stem cells to ‘break’ tissue homeostasis?

I have shown that local production of the nutrient sensor insulin triggers the adaptive stem cell response. Drosophila Insulin-Like Peptide 3 (dILP3) is expressed in gut visceral muscle upon feeding and signals directly to adjacent stem cells, activating proliferation and growth. In continuing work, I will seek to define the features of midgut dILP3 signaling that uniquely suit it to regulate adaptive growth.

How does stem cell heterogeneity play into organ adaptation?

Although adult stem cells have traditionally been viewed as stable and long-lived populations that exhibit invariant asymmetric divisions, emerging evidence from vertebrate and invertebrate systems suggests that stem cell populations are remarkably dynamic. The root causes and significance of adult stem cell dynamics are major questions. In the fly midgut, I have shown that individual stem cells exhibit a diversity of division rates and symmetric:asymmetric division frequencies, with some stem cells regularly switching between symmetric and asymmetric modes. On top of this individuality, the stem cell population as a whole shifts its collective behavior pattern with increased dietary load, accelerating division rates and favoring symmetric division modes to drive organ growth. I will examine the intrinsic and extrinsic sources of midgut stem cell diversity and explore the functional implications of stem cell heterogeneity during adaptive growth.

Symmetric stem cell lineages revealed by twin spot labeling. (left) The two daughters of a stem cell division are differently labeled with RFP and GFP. (right) Subsequent proliferation of the labeled daughters shows that each is a stem cell. While asymmetric divisions predominate during non-growth states, symmetric divisions predominate during adaptive growth.

A ‘population census’ protocol comprehensively counts midgut cells through automated identification and quantitation of cell nuclei in confocal reconstructions of the gut tube. The Cell Profiler-based protocol also provides a visual output of counted objects (above).

How are diverse cellular behaviors coordinated to specify tissue state?

The ultimate goal is to comprehensively understand the network of cell behaviors that drives the dynamics of stem-based epithelia. Interactions between stem cells, their lineages, and the tissue environment integrate to produce a spectrum of physiologic tissue states ranging from homeostatic maintenance, to injury repair, to adaptive resizing. The situation is too complex to be entirely grasped through reductionist experimental approaches. Here, the midgut’s simplicity and tractability make it ideally suited for a quantitative modeling approach. Guided by in vivo cellular data encompassing both normal and perturbed states, in silico modeling will give entry points to fundamental, yet otherwise inscrutable problems—for instance, what mechanism keeps stem cells at a consistent 15-20% of total midgut cells even as total cell number increases four-fold? How does the midgut ‘decide’ what its proper size should be? Why do accelerated stem cell divisions produce growth in some cases and cancer in others? Iterative cycles of modeling and experimentation will reveal the design principles that confer robustness, flexibility, and adaptiveness to stem-based tissues.