Browsing by Subject "Adipose Tissue"
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Item Adipose-Derived Stromal Cells Contribute To Spinal Cord Repair But Are Not Neural-Crest Derived Stem Cells(2007-08-08) Wrage, Philip Charles; Tansey, Malu G.Neurodegeneration and injury to the nervous system are characterized by a loss of neurons - and often supporting glia - at the afflicted site. Neurons of the adult CNS are terminally differentiated, non-mitotic cells that are connected within specific circuits. These characteristics present a challenge to the development of treatments for degeneration or injury of the nervous system. The limited spatial distribution, as well as limited migration and differentiation potentials of adult NSCs, severely restrict the ability of adult NSCs to contribute to repair or regeneration in the wake of injury or degenerative disease progression. Adipose-derived adult stromal (ADAS) cells have been reported to give rise to cells of both mesodermal and ectodermal origin (e.g. osteocytes, chondrocytes, cardiac myocytes, neurons, and glia) and are easily harvested and cultured in vitro. Neural crest derived tissues have the extraordinary capacity to give rise to a wide range of tissue types: neurons and glia of the peripheral nervous system, adrenal glands, chondrocytes and osteocytes of the head and neck, smooth muscle cells of the cardiac outflow tract, and melanocytes among others. Given the reported ability of neural crest-derived cells and ADAS cells to give rise to bone, cartilage, muscle, and nerve tissues, I hypothesized that ADAS cells might be neural crest-derived cells that had migrated to the periphery, had remained resident within the adipose tissue of adult mammals, and had maintained early developmental plasticity. This hypothesis was not supported by lineage tracing experiments. Additionally, I found that ADAS cells were not capable of differentiating into functional neurons in vitro or in an in vivo model of spinal cord injury. However, ADAS cells altered the growth inhibitory environment of the lesioned cord and contributed to axon migration despite their inability to undergo neural differentiation. Based on these results, further research is warranted into the mechanisms by which ADAS cells create a growth permissive environment in the lesioned spinal cord.Item Genetic Analysis of Adipose Lineage and Development(2008-05-13) Tang, Wei; Graff, Jonathan M.Adipose tissues protect t against traumatic and thermal insults, and regulate lifespan, reproduction and metabolism. The importance of forming the appropriate number of adipocytes is highlighted by the significant metabolic disturbances that accompany too few (lipodystrophy) or too many (obesity) adipocytes. Most of our current understanding about adipocyte formation come from in vitro culture studies. Little is known about adipose development in vivo because of the lack of genetic tools. To this end, I generated a few knock-in mice that offer both spatial and temporal controls to manipulate gene expression in adipose tissues. Here I demonstrate the application of one of the tools, PPARgamma tTA, in exploring some important aspects of adipose development, such as the adipose depot specification, the identity of adipocyte progenitor cells and their anatomical niche. Adipose tissues form throughout the body in various places in a stereotypical pattern, with each adipose depot displaying distinctive properties. As the first step to understand depot specificity, I used the PPARgamma tTA mice for lineage tracing on adipose tissues, and found that each adipose depot is specified at very distinctive developmental stages, suggesting that different adipose depots are derived from distinct origins. With new genetic tools, I also marked and isolated adipogenic progenitors. I found that the majority of adipocytes descend from a pool of PPARgamma -expressing proliferateing progenitors already commited early in post-natal life, prior to the development of most adipocytes. These progenitors are morphologically and moleculary distinct from adipocytes, have high potential to undergo adipogenesis both in vitro and in vivo after transplantation. Interestingly, some progenitors reside in the mural cell compartment of blood vessels that supply adipose depots and not in vessels of other tissues. The identification of the adipocyte progenitor and localization to the blood vessel wall indicate the presence of a vascular niche in adipose development and provide a basis to examine the interplay between adipogenesis and angiogenesis that could be exploited as a new avenue for obesity and diabetes therapies.Item Hedgehog Signaling Plays a Conserved Role in Inhibiting Fat Formation(2006-08-11) Gao, Xiaohuan; Graff, JonathanThe involvement of hedgehog (Hh) signaling in cell determination and differentiation in a wide variety of tissues in both invertebrates and vertebrate has been well established. However, relative little is known about its function in formation of adipose tissues. To address this question, Drosophila and mammalian models were used to analyze its potential role. Components of the Hh pathway were expressed in the Drosophila fat body. Activating Hh signaling specifically in fat body inhibited fly fat formation. Conversely, blocking Hh signaling specifically in fat body stimulated fly fat formation. Analysis in mammalian models suggested the presence of functional Hh signaling in murine developing fat, adult fat and in mammalian adipogenic models. Down-regulation of Hh signaling marked the stage of terminal differentiation. In 3T3-L1 preadipocyte cell line, addition of recombinant murine sonic Hh (Shh) potently inhibited adipogenic differentiation dose-dependently, resulting in decreased intracellular triglyceride accumulation and reduced mRNA levels of established adipogenic genes. Treatment of KAAD-cyclopamine, an antagonist of Hh signaling, promoted adipogenesis. Activating or blocking Hh signaling genetically produced similar effects as pharmacological treatment. Additional study in multipotent cell lines, NIH3T3 and C3H10T1/2, reinforced the inhibitory role of Hh signaling in adipogenesis. However, the inhibition was effective only when Hh signaling was activated during early stage of adipogenesis. Epistasis tests suggested Hh signaling functioned upstream of PPARgamma . Mechanistic studies showed that Hh signaling might act as a molecular switch, likely mediated by anti-adipogenic transcrition factors such as GATA2, to divert preadipocytes as well as multipotent mesenchymal prescursors away from adipogenesis to osteogenesis. My study on the function of Hh signaling in fat formation of both invertebrates and vertebrates suggested that Hh signaling played a conserved role in inhibiting fat formation and highlighted the potential of the Hh pathway as a therapeutic target for osteoporosis, lipodystrophy, diabetes and obesity.