Adipogenic and myogenic stem cells in brown fat: A study of progenitors and regenerative capacity
Brown adipose tissue (BAT) utilizes stored lipids to generate heat, therefore reducing body fat content and favoring a leaner body composition. Recent identification of metabolically active BAT in adult humans has sparked broad interests in understanding the developmental origin and postnatal homeostasis of BAT. However, the stem cell population that gives rise to BAT during development and maintains BAT mass at postnatal stage has not been characterized. In addition, whether adult BAT has the capacity to regenerate after injury or to proliferate in response to cold is flargely unknown. Furthermore, although BAT and skeletal muscle are known to share a common Myf5 lineage origin, it is unknown if postnatal BAT contains bipotent adipomyogenic stem cells, or subpopulations of unipotent adipogenic and myogenic progenitors. The overall aim of this thesis is to fill in these gaps in knowledge. Using Pdgfra GFP/+ reporter mice to mark the platelet-derived growth factor receptor alpha (Pdgfra) expressing progenitors that give rise to BAT, I show that Pdgfra lineage progenitors contribute to only 3% of cells in the classical intrascapular BAT (isBAT). In contrast, adipogenic progenitors isolated from isBAT and grown in culture are predominantly Pdgfra+. Likewise, GFP+/Sca1+ cells isolated from white adipose tissue (WAT) and intramuscular fat (IMAT) are highly adipogenic in culture. Although genetic ablation of brown adipocytes results in compensatory regrowth of BAT, the Pdgfra+ cells rarely proliferate and contribute to the adipogenesis. Cold stimulation also fails to induce proliferation of the Pdgfra + cells in vivo. Interestingly, BAT contains a population of unipotent Pdgfra– myogenic progenitors. The myogenic progenitors are located in a small flat muscle that penetrates the BAT. Surgical excision or genetic ablation of the skeletal muscle from BAT eliminates its myogenic gene expression signature, which has been thought to be a feature of brown adipocytes. In conclusion, results from this study demonstrate that embryonic and postnatal BAT progenitors are distinct in Pdgfra lineage origin. Adult BAT contains populations of unipotent adipogenic and myogenic stem cells. The results further suggest that skeletal muscle contamination significantly contributes to the previously reported myogenic gene expression in the BAT. This study is the first to systemically characterize stem cells in classical isBAT, and provides critical understanding of the cellular basis of postnatal BAT homeostasis.^
Shihuan Kuang, Purdue University.
Agriculture, Animal Culture and Nutrition