Adult Mesenchymal Progenitor (MPC) Regulation of Early Pathogenesis in TSC
Abstract
Focus Area and Significance: This Idea Development Award is directly relevant to the Tuberous Sclerosis Complex Research Program because it addresses stem cell-based initiating events responsible for benign tumor/lesion formation in tuberous sclerosis complex (TSC), a cellular basis of TSC that has not been addressed. This novel investigation has the potential for significant impact in the field of TSC biology. We will develop new research methodology to understand how different cell types interact in TSC and gain a deeper knowledge of TSC signaling pathways and the cellular consequences of TSC deficiency by combining the study of human and mouse model systems. Developing an understanding of the lesion environment and early cell-cell interactions during the initiation of disease will facilitate the identification of novel therapeutics to target the abnormal TSC cells necessary to further manage or cure this debilitating disease. Rationale: TSC affects approximately 40,000 men and women in the United States. TSC2 mutations result in loss of normal TSC2 function and an abnormal activation of cell differentiation and growth. Subsequently, there is an accumulation of abnormal smooth muscle type cells, from an unknown origin, in a variety of tissues. This abnormal accumulation of cells leads to lesion formation in organs including the lung and kidney, compromising organ function. Considerable progress has been made in understanding how decreased TSC function regulates signals inside different cell types. However, our current understanding of which cells become “activated” and how that progresses to organ specific lesions in TSC remains a central unanswered question in disease. I am a Midcareer Investigator dedicated to the study of stem cells in the regulation of adult tissue environments, new to TSC research. We have recently identified a new population of stem cells (mesenchymal stem/progenitor cells) in the adult human and murine lung, skin, and kidney. These stem cells are an important component of the tissue environment, regulating smooth muscle cell function and tissue structure. When these stem cells are abnormal, they negatively affect the blood vessels around them, resulting in loss of tissue structure and function. However, the impact that loss of functional TSC2 in adult stem cells has on smooth muscle cell behavior and TSC lesion formation is unknown. Our preliminary work has demonstrated that this new population of stem cells function as regulatory cells during TSC tumor/lesion formation. While Tsc2-deficient stem cells do not form the lesions themselves, we found that they change the environment of the cells around them and cause abnormal cell growth and loss. Thus, they drive smooth muscle lesion formation in the lung and cysts in the kidney. We therefore hypothesize that loss of TSC2 function in mesenchymal stem cells deregulates the smooth muscle environment and enhances smooth muscle cell de-differentiation to a proliferative and invasive phenotype, resulting in TSC lesions in the lung and cystic kidneys. Aim 1 will test the hypothesis that genetic depletion of MPC tsc2 promotes smooth muscle de-differentiation to a proliferative/invasive cell type in vivo using mice. Aim 2 will test the hypothesis that human TSC2 deficient lung MPC exhibit an invasive phenotype and influence smooth muscle cell proliferation using human cells in mouse models or in cell culture. Expected Results and Long-Term Impact: Successful completion of the proposed studies will demonstrate how dysfunctional TSC2 in stem cells modulates smooth muscle cell environment and function, a novel cellular basis of TSC. Knowledge gained from these studies has the potential to impact not only Veteran family members with TSC, but also patients with lymphangioleiomyomatosis (LAM) and other rare mesenchymal-derived tumor types including perivascular tumors, fibroblastic/myofibroblastic tumors, adipocytic tumors, smooth
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810719
Entities
People
- Susan Majka
Organizations
- United States Army
- Vanderbilt University