Development and maintenance of a properly functioning immune system is dependent upon a properly organized and functioning thymus. Thymic epithelial cells (TECs) make up the structure of the thymus and are responsible for the maintaining its primary functions. Bone marrow transplants can cure many forms of blood-derived cancers as well as non-malignant blood disorders. Unfortunately, particularly in adult patients, bone marrow transplants damage the thymus and in particular TECs resulting in a reduced capacity to fight infection and cancer. Stem cells in a variety of tissues have been identified by their capacity to divide very slowly, the so-called """"""""label retaining cells"""""""" (LRCs). A novel genetically engineered mouse model system, which allows identification and purification of viable Histone 2B-green fluorescence protein tagged stem cells and was successfully used to identify and purify skin stem cells, has been used here to purify thymic epithelial stem cells. Preliminary results show that surgical transfer of these cells under the kidney capsule results in the formation of functional thymic tissue.
The aims of this study will be to: 1) further characterie the recently identified thymic epithelial stem cells with the ability to reform thymic tissue;2) understand the signals and cell to cell interactions that control the maintenance of adult thymic stem cells;3) test the capacity of thymic stem cells and recently developed stem cell lines to enhance the recovery of thymic function in a mouse model of bone marrow transplant. These studies will be instrumental in the design of new clinical strategies to counteract thymic involution as well as the premature thymic degeneration that occurs in response to cancer treatments and BMT. From a developmental standpoint this study will allow the PI to continue to train underserved research students, while enhancing both the scientific productivity of the lab and the impact of the publications produced, enabling a researcher at a minority serving institution to be more competitive for NIH support.
In paradox to the critical importance of the thymus in the development of T cells required for adaptive immunity, the thymus undergoes profound atrophy relatively early in life. Thymic degeneration is evident starting at puberty in humans and contributes to a significant loss of T cell function and the capacity to fight infection. Bone marrw transplants, while potentially curative for many forms of cancer and non-malignant blood disorders, often result in potentially lethal infections and malignant relapse, due to a prolonged loss of T cell function resulting from damage to the thymus induced by pre-transplant therapies. This study addresses a critical unmet clinical need to enhance thymic reconstitution through the identification of adult stem cells capable of reforming functional thymic tissue that may be used in treatment strategies to both minimize damage and hasten recovery of thymic function following BMT or other cytoablative therapies.
|Osada, Masako; Singh, Varan J; Wu, Kenmin et al. (2013) Label retention identifies a multipotent mesenchymal stem cell-like population in the postnatal thymus. PLoS One 8:e83024|
|Osada, Masako; Jardine, Logan; Misir, Ruth et al. (2010) DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration. PLoS One 5:e9062|
|Kovalovsky, Damian; Pezzano, Mark; Ortiz, Benjamin D et al. (2010) A novel TCR transgenic model reveals that negative selection involves an immediate, Bim-dependent pathway and a delayed, Bim-independent pathway. PLoS One 5:e8675|