The role of Src homology 2 domain containing 5' Ionsitol phosphatase-1 in mesenchymal stem cells.
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AbstractBased on earlier findings, some of our initial questions were, as follows: Does SHIP1 have role in the bone marrow niche in maintaining HSC homeostasis and function? Is SHIP1 expressed in mesenchymal stem cells? Does SHIP1 play a functional role in MSC biology? Is SHIP1 deletion in myeloid lineage or mesenchymal lineage sufficient to cause osteoporosis? During the course my graduate thesis work, we have answered these questions and unraveled that SHIP1 is at the nexus of several molecular pathways controlling mesenchymal stem cell biology. In the first aim, we show that under conditions that drive osteolineage differentiation by MSC, SHIP1 limits MSC proliferation and facilitates osteoblast development by repressing the USP1/Id2 axis. The UPS1/Id2 axis was recently shown to promote ‘stemness’ in MSC. Our findings identify a novel SHIP1/USP1/Id2 circuit that controls MSC proliferation and lineage commitment and thus link inositol phospholipid signaling to control of MSC self-renewal and multi-lineage potential by USP1/Id2. Our findings are the first to show that SHIP1 can promote lineage commitment in a population of mesenchymal stem/progenitor cells rather than simply acting as an inhibitor of cell survival and function in differentiated cells. Our findings also provide cellular and molecular explanations for how SHIP1 influences MSC biology, osteolineage development, adipogenesis and osteoporosis. We also provide some very compelling data that represent the first demonstration of in vivo modulation of MSC development and function by small molecule targeting of a cell-signaling pathway that has important metabolic implications. Our analysis of OSXCreSHIPflox/flox mice indicated that as these mice age they lose both bone mass and body fat, we hypothesized then that treatment of aged adult mice with a selective small molecule inhibitor of SHIP1 might achieve the same outcome – reduction of bone mass and body fat. Thus, chapter 2 and 4 includes a series of studies that rather convincingly demonstrate pharmacologic inhibition of SHIP1 significantly reduces both body fat and bone mass in older mice. In addition, in chapter 4, we explore the therapeutic potential of SHIP1/2 inhibition in diabetes and obesity. As previous work by others has shown that SHIP2-/- mice are resistant to diet-induced obesity and diabetes. This led us to hypothesize that pan-SHIP1/2 inhibition (SHIPi), if tolerated, might reduce obesity and improve blood glucose control during aging and/or with consumption of a high fat diet. When paired with our genetic studies in OSXCreSHIP1flox/flox mice these pharmacological studies demonstrate unequivocally that SHIP proteins are molecular targets in both obesity and osteopetrotic diseases. Moreover, we demonstrate for the first time that targeting of cell signaling in the adult MSC compartment can achieve significant metabolic changes that could have translational application in both obesity and osteopetrotic diseases. At this juncture this work represents a potent blend of novel basic and applied findings that have profound implications for regulation of mesenchymal stem cell fate, bone biology as well as for treatment of obesity and bone diseases. In chapter 3 we demonstrate that intracellular signaling by SHIP1 in MSC is demonstrated to have a critical role in the control of HSC output during aging and this increases our understanding of how myeloid bias occurs in aging, and thus could have implications for the development of myeloproliferative disease in aging.
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