Research

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The goal of the laboratory is to understand how adult stem cells and their microenvironment adapt to diverse diets in the context of tissue regeneration and cancer initiation. Towards this end, we are studying the effects of dietary interventions such as calorie restriction (CR) and high fat diet-induced obesity on intestinal stem cell (ISC) function in the mammalian small intestine. Since ISCs, like all adult stem cells, posses the ability to self-renew (i.e. generate daughter stem cells) and the capacity for multipotent differentiation (i.e. generate lineage-committed progenitors and ultimately all mature tissue-specific cell types), they likely play an important role in remodeling the intestine in response to diet-induced physiologies. A majority of ISCs express the leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) and reside at the bottom intestinal crypts nestled between Paneth cells, which constitute a component of the stem cell cellular neighborhood or “niche”. The Paneth cell niche elaborates myriad growth factors and cues necessary for the maintenance of Lgr5+ ISCs. This intercalated positioning of Lgr5+ ISCs and their Paneth cell niche make the intestine an elegant system for deciphering the autonomous versus non-autonomous (or niche-mediated) effects of diet on stem cell self-renewal and differentiation.

Currently, we are elucidating the molecular mechanisms underpinning this interaction between ISCs and Paneth cells in CR and will complement this by studying the response of this interaction in obesity. By comparing how ISCs adapt to diverse diets, we will gain a deeper understanding of how the intestine integrates physiology with its growth and why some diets reduce or augment the risk of colon cancer.

 

Figure 1. Dietary Regulation of Stem Cells in Tissue Homeostasis:
(adapted from Yilmaz et al Cell Stem Cell 2014)

Figure 1A
(A) Intrinsic (dark green) and extrinsic (orange) diet-sensing mechanisms integrate diet-induced physiology with tissue homeostasis. Stem cells (blue) and their niche (green) sense physiologic cues such as hormones, growth factors, and nutrients to dynamically alter the production of differentiated cells (pink).

Figure 1B
(B) Calorie restriction boosts regeneration in diverse tissues by increasing stem cell numbers and function. Niche-derived signals mediate some of the response of calorie restriction on stem cells.

Figure 1C
(C) Diet-induced obesity is associated with an abundance of nutrients, growth factors, and hormones that eventually leads to physiologic disequilibrium, including insulin resistance, diabetes, and metabolic syndrome. This state reduces tissue repair, in part due to dysfunction of stem cells, their niches, or both.

 

Figure 2. Diet and Cancer Initiation:
(adapted from Yilmaz et al Cell Stem Cell 2014)

Figure 2A
(A) In tissues that follow a stem cell paradigm, stem cells (red) acquire early oncogenic events (red arrow) that lead to transformation and tumor formation.

Figure 2B
(B) Calorie restriction augments stem cell numbers and function in diverse tissues and is proposed to have antitumor initiation and growth effects. If stem cell numbers increase with calorie restriction and they undergo some of the early changes that give rise to tumors, calorie restriction may potentially increase tumor incidence. It is possible that autonomous and nonautonomous protective mechanisms are activated in stem cells with calorie restriction, which neutralize the effects of a larger, more robust stem cell pool. Another possibility may be that the antigrowth effects of calorie restriction on tumor growth mask its effects on initiation. Tumors arising in calorie restriction may remain below detection threshold because they are small in size.

Figure 2C
(C) Diet-induced obesity has untoward effects on tissue repair and cancer incidence. Although stem cell numbers can decrease with chronic obesity, the susceptibility of differentiated cells to undergo transformation can also increase as has been noted to occur with inflammation. In this case, early oncogenic events can occur in stem cells and differentiated cells, effectively increasing the pool of cells that can undergo early transformation. Surplus growth factors, nutrients, and hormones then drive tumor progression and growth.

 

Figure 3: Calorie Restriction

Figure 3