The mammary gland (MG) is composed of epithelial and surrounding stromal cells that are highly dynamic during puberty, pregnancy, lactation, and post-lactational involution. In the stroma, lipid-filled adipocytes exhibit greatest plasticity whe they regress during lactation and repopulate the gland during involution. The timing of repopulation suggests a functional role for adipocytes in the reconstruction of the MG epithelium during involution, but the cellular and molecular mechanisms that drive their regeneration are not well understood. I have identified an adipocyte precursor cell (APC) population in the MG. This adipogenic population is crucial for regenerative processes in other tissues, such as hair follicle growth and muscle regeneration after injury. Whether this APC population plays a role in MG reconstruction is not known. During involution, adipocytes could repopulate the MG stroma through either adipogenesis, in which APCs differentiate to regenerate mature adipocytes; lipogenesis (lipid filling) of mature adipocytes that exist in the MG throughout lactation; and/or transdifferentiation of epithelial cells into adipocytes. In order to determine which of these mechanisms occurs, I will use in situ genetic lineage tracing mediated by Cre recombinase to identify whether mature adipocytes in the repopulated gland after involution are derived from APCs, mature adipocytes, or another cell lineage. Understanding the mechanisms of adipocyte repopulation will enable me to then evaluate whether adipocytes produce signals that control the reconstruction of the MG during involution. The ability of the MG to undergo multiple rounds of tissue development, degeneration, and reconstruction provides a unique model to evaluate mechanisms of tissue plasticity in adults, which is broadly relevant for many disciplines in regenerative medicine. Furthermore, the MG stroma has been implicated in problems with lactation due to maternal obesity, as well as tumor metastasis in pregnancy-associated breast cancer. In this research, I will establish a functional context for adipocytes in the MG that holds therapeutic potential for addressing these public health concerns.
The mammary gland undergoes a massive cellular restructuring to end lactation and prepare for future rounds of breastfeeding, which is critical to providing nutrition for infants and protecting them from disease. In this project we will use genetic mouse models to determine the role of adipocyte (fat) stem cells in facilitating this reconstructive process, which is largely unknown but of interest given the important role of adipocytes in regenerating skin and muscle tissue after injury. Information revealed in this study is broadly relevant for understanding how adult stem cells maintain healthy tissues and respond to injury, and holds specific therapeutic potential for problems with lactation and breast reconstruction after mastectomy.
| Zwick, Rachel K; Rudolph, Michael C; Shook, Brett A et al. (2018) Adipocyte hypertrophy and lipid dynamics underlie mammary gland remodeling after lactation. Nat Commun 9:3592 |
| Zwick, Rachel K; Guerrero-Juarez, Christian F; Horsley, Valerie et al. (2018) Anatomical, Physiological, and Functional Diversity of Adipose Tissue. Cell Metab 27:68-83 |
